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Rey, Imelda, Agung Putra, Dharma Lindarto, and Fauzi Yusuf. "Relationship between CD 163 Tumor-Associated Macrophages and Colorectal-Cancer Stem Cell Markers." Open Access Macedonian Journal of Medical Sciences 9, B (October 19, 2021): 1381–86. http://dx.doi.org/10.3889/oamjms.2021.7188.
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BACKGROUND: Colorectal-cancer stem cells (CR-CSCs) represent a specific subpopulation of colorectal cancer (CRC) cells, which are characterized by the expression of CD133 and CD166. Tumor-associated macrophages (TAMs), found near CSCs may represent polarized macrophages, which are characterized by CD163 expression. In most tumors, TAMs may promote aggressive tumor development, leading to poor prognoses. AIM: The aim of this study was to determine whether any association exists between CD163 expression in TAMs and CD133 and CD166 expression in CR-CSCs. METHODS: This study used a cross-sectional design that was conducted at the General Hospital and affiliates in Medan, from September 2018 to July 2019. CRC tissues were collected from colonoscopy biopsies and surgical resections performed on CRC patients, who fulfilled all necessary inclusion and exclusion criteria and provided informed consent. Subjects were divided into high- and low-CD163-level groups. We analyzed the expression levels of CD163, CD133, and CD166 using immunohistochemical (IHC) assays. RESULTS: A total of 118 CRC patients were enrolled in this study, of whom 58.5% were male. No significant differences in hemoglobin, leukocyte, or platelet levels were observed between high- and low-level CD163 expression. We didn’t find any significant association of CD163 TAM with CRC histological grade and TNM stagings. Significant associations were found between the CD 163 expression level and the CD133 expression level (p < 0.001) and between the CD 163 expression level and the CD166 expression level (p< 0.001). Increased TAM levels of CD163 was associated with 2.770-fold and 2.616-fold increased risks of elevated CD133 and CD166 levels, respectively. CONCLUSION: An association was found between the expression levels of CD163 in TAMs and the expression levels of CD133 and CD166 in CR-CSCs.
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S. Kirshenbaum, Arnold, Yuzhi Yin, J. Bruce Sundstrom, Geethani Bandara, and Dean D. Metcalfe. "Description and Characterization of a Novel Human Mast Cell Line for Scientific Study." International Journal of Molecular Sciences 20, no. 22 (November 6, 2019): 5520. http://dx.doi.org/10.3390/ijms20225520.
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Background: Laboratory of allergic diseases 2 (LAD2) human mast cells were developed over 15 years ago and have been distributed worldwide for studying mast cell proliferation, receptor expression, mediator release/inhibition, and signaling. LAD2 cells were derived from CD34+ cells following marrow aspiration of a patient with aggressive mastocytosis with no identified mutations in KIT. Another aspiration gave rise to a second cell line which has recently been re-established (LADR). We queried whether LADR had unique properties for the preclinical study of human mast cell biology. Methods: LADR and LAD2 cells were cultured under identical conditions. Experiments examined proliferation, beta-hexosaminidase (β-hex) release, surface receptor and granular protease expression, infectivity with HIV, and gene expression. Results: LADR cells were larger and more granulated as seen with Wright–Giemsa staining and flow cytometry, with cell numbers doubling in 4 weeks, in contrast to LAD2 cells, which doubled every 2 weeks. Both LADR and LAD2 cells released granular contents following aggregation of FcεRI. LADR cells showed log-fold increases in FcεRI/CD117 and expressed CD13, CD33, CD34, CD63, CD117, CD123, CD133, CD184, CD193, and CD195, while LAD2 cells expressed CD33, CD34, CD63, CD117, CD133, CD193 but not CD13, CD123, CD184, or CD195. LADR tryptase expression was one-log-fold increased. LADR cell and LAD2 cell chymase expression were similar. Both cell lines could be infected with T-tropic, M-tropic, and dual tropic HIV. Following monomeric human IgE stimulation, LADR cells showed greater surface receptor and mRNA expression for CD184 and CD195. Expression arrays revealed differences in gene upregulation, especially for the suppressor of cytokine signaling (SOCS) family of genes with their role in JAK2/STAT3 signaling and cellular myelocytomatosis oncogene (c-MYC) in cell growth and regulation. Conclusions: LADR cells are thus unique in that they exhibit a slower proliferation rate, are more advanced in development, have increased FcεRI/CD117 and tryptase expression, have a different profile of gene expression, and show earlier infectivity with HIV-BAL, LAV, and TYBE when compared to LAD2 cells. This new cell line is thus a valuable addition to the few FcεRI+ human mast cell lines previously described and available for scientific inquiry.
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Florian, Stefan, Karoline Sonneck, Alexander W. Hauswirth, Maria-Theresa Krauth, Wolfgang R. Sperr, and Peter Valent. "Phenotyping of Neoplastic (CD34+/CD38−/CD123+) Stem Cells in Myeloid Malignancies Reveals Expression of Multiple Molecular Targets." Blood 106, no. 11 (November 16, 2005): 1381. http://dx.doi.org/10.1182/blood.v106.11.1381.1381.
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Abstract Recent data suggest that myeloid neoplasms are organized hierarchically in terms of self renewal and maturation of early progenitor cells, similar to normal myelopoiesis. In acute myeloid leukemia (AML), the NOD/SCID mouse-repopulating leukemic stem cells usually co-express CD123 with CD34, but lack CD38. So far, however, little is known about expression of other markers and targets on these progenitors. In the present study, expression of target antigens on CD34+/CD38− cells was analyzed by multicolor flow cytometry in patients with AML (n=18), myelodysplastic syndromes (MDS, n=6), chronic myeloid leukemia (CML, n=8), systemic mastocytosis (SM, n=9), and normal bone marrow (n=5). The IL-3Ra chain (CD123) was found to be expressed on CD34+/CD38− cells in a majority of all patients in all disease-categories. Independent of the type of disease, the vast majority of these stem cells also co-expressed aminopeptidase-N (CD13) and the target receptor CD44 in all patients. CD34+/CD38− progenitor cells expressed variable amounts of the Mylotarg® receptor CD33, KIT (CD117), HLA-DR, and AC133 (CD133). With regard to AC133, two distinct subpopulations of progenitor cells were detected in many cases, namely a CD133+ and a clearly CD133- cell-fraction. In patients with AML, the levels of CD33 varied from patient to patient with a broad range of reactivity, whereas in most patients with MDS, CML, and SM, CD33 was found to be consistently expressed on most progenitors. In most patients, neoplastic stem cells did not express substantial amounts of the GM-CSF receptor alpha chain (CD116), Thy-1 (CD90), E-NPP3 (CD203c), MDR-1 (CD243), or PAR-2. In the normal bone marrow, CD34+/CD38− cells co-expressed CD13, CD44 and CD45, but did not express CD33, CD116, or CD123. In conclusion, neoplastic stem cells in various myeloid neoplasms appear to express a similar phenotype including target receptors such as CD13, CD33, and CD44. These antigens may thus be attractive targets of therapy in AML. However, since many of these targets are not expressed on all stem cells in all patients, the elimination of the entire clone may require combinations of targeted antibodies or use of additional drugs. In other cases (CD13, CD44, CD45), the target antigen is also expressed on normal stem cells, so that targeted therapy is likely to be an ablative maneuver and thus would require a combined stem cell transplantation approach.
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Kanazawa, Tokunori, Kentaro Ohara, Kazunari Yoshida, and Hikaru Sasaki. "PATH-59. HISTOPATHOLOGICAL INVESTIGATION OF THE 1p/19q-CODELETED GLIOMAS RESECTED FOLLOWING ALKYLATING AGENTS CHEMOTHERAPY." Neuro-Oncology 21, Supplement_6 (November 2019): vi156. http://dx.doi.org/10.1093/neuonc/noz175.654.
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Abstract BACKGROUND Little is known about histopathological changes after chemotherapy in lower-grade gliomas (LrGGs). METHODS We investigated 15 1p/19q-codeleted gliomas resected following tumor volume decrease after alkylating agents chemotherapy in comparison with their pre-chemotherapy specimens. Histopathological changes by chemotherapy were evaluated by hematoxilyn-eosin staining and immunohistochemistry for Ki-67/MIB-1, CD68 as pan macrophage/monocyte marker, CD163 as presumed marker of M2 polarity, and nestin and CD133 as markers of glioma stem cells (GSCs). RESULTS Histologically, there were several presumed chemotherapy-related changes in the post-chemotherapy specimens, with the most frequent findings being sparse glial background and abundant foamy cell infiltration. The Ki-67/MIB-1 indices significantly decreased, and CD68+ cells significantly increased after chemotherapy. The increasing rate of CD68+ cells in the post-/pre-chemotherapy specimens was prone to be associated with patients’ progression-free survival (PFS) and overall survival (OS), but not tumor response. The number of CD163+ cells and the ratio of nestin+ cells and CD133+ cells significantly increased after chemotherapy. The number of CD163+ cells, the ratio of nestin+ cells and CD133+ cells, and M2 (CD163+)/M1+M2 (CD68+) ratio in the post-chemotherapy specimens were negatively correlated with patients’ PFS and OS. There was no difference between chemotherapy regimens (temozolomide versus nitrosourea-based) in the number of CD163+ cells and the ratio of nestin+ and CD133+ cells. CONCLUSIONS GSCs in conjunction with M2 macrophages constitute the mechanism of resistance to and recurrence after alkylating agents chemotherapy in LrGGs.
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Sebert, Marie, Elodie Lainey, Sylvain Thepot, Maximilien Tailler, Lionel Ades, Claude Gardin, Pierre Fenaux, Guido Kroemer, and Simone Boehrer. "Erlotinib Inhibits ABC Transporters of AML Progenitors with Stem Cell Features and Increases Chemosensitivity to Current AML Drugs." Blood 116, no. 21 (November 19, 2010): 2163. http://dx.doi.org/10.1182/blood.v116.21.2163.2163.
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Abstract Abstract 2163 Background: Treatment failure in AML is attributed to the persistence of AML progenitors able, among others, to efflux chemotherapeutic drugs via ABC-transporters. Increased efflux capacity is considered a stem cell feature, and therapeutic inhibition may increase chemosensitivity and help eradicate this progenitor population. Nevertheless, clinical studies assessing a potential benefit of ABC-inhibitors in AML treatment showed no significant survival advantage, possibly because AML cells express different ABC-transporters and classical inhibitors target only a restricted type of efflux channels. We assessed the efficacy of the TKI erlotinib (Erlo) to antagonize drug efflux via most important AML-associated efflux channels, ie P-gp, MRP and BCRP. Methods: Overall drug efflux via ABC-transporters (substrate: mitoxantrone-MTZ), and specific efflux via P-gp (substrates: DioC23 and rhodamine-123), MRP (substrates: calcein and CDCFDA) and BCRP (substrate: Hoechst 33342) were quantified by FACS at 1h and 6h following incubation with 10mM Erlo. Biochemical inhibitors of the respective ABC-transporters (CSA, verapamil, MK-571, KO143) served as controls. Surface expression of P-gp, MRP and BCRP was quantified by FACS. To assess chemosensitivity, 10mM Erlo was combined to AraC (100nM), doxorubicine (Dox, 100nM), or VP-16 (1mM) and apoptosis over-time (24, 48, 72h) quantified by DioC3(6)/PI staining. Assays were carried out in myeloid cell lines (KG-1, MOLM-13, HL-60) and ex vivo AML cells (n=3). Immaturity of AML cells was determined in 2 samples by comparing CD34+ versus CD34- cells, and in one pt by co-staining for CD34, CD38, CD123 and CD133. Results: We found that I) Erlo inhibited efflux via P-gp and MRP as demonstrated by increased intracellular retention of DioC23/Rho-123, and calcein/CDCFDA, respectively; II) this degree of inhibition was higher in KG-1 cells than in MOLM-13 or HL-60 cells; III) inhibition of drug efflux was observed already at 1h of incubation, increased over time (6h); IV) Erlo increased intracellular retention of MTZ faster (at 1h with a further increase at 6h) and at least to the same extent than a combination of all three biochemical efflux inhibitors, showing that Erlo's capacity to hinder drug efflux is not restricted to a single ABC-transporter: V) surface expression of P-gp, MRP and BCRP was strongest on KG-1 cells and not altered upon 1h and 6h of Erlo incubation VI) Erlo increased Dox- and VP16-induced apoptosis (48h KG-1: Erlo alone 20%, Dox alone 10%, VP-16 alone 20%, Erlo+Dox: 40%, VP-16+Erlo: 70%), while having no impact on AraC-induced apoptosis; VI) this pattern of chemosensitization was observed in all myeloid cell lines, but once more most pronounced in KG-1 cells. To test the hypothesis that Erlo has comparable effects in pt-derived AML cells ex vivo, we showed by concomitant cell surface staining that I) immature AML subpopulations had a higher efflux capacity (notably via P-gp) than their more mature counterparts (i.e. in one pt with chemoresistant AML: DioC23/Rho-123 fluorescence twice as high in the CD34-/CD38+, CD123+, CD133- than in the CD34+/CD38dim, CD123-, CD133+ subpopulation); II) cell surface expression of P-gp is twice as high in this more immature population (CD34+/CD38dim, CD123-, CD133+) than in CD34-/CD38+, CD123+, CD133+ cells; III) Erlo antagonizes drug efflux via P-gp and MRP at 1h (increasing further at 6h) of incubation; IV) this effect is most pronounced in the immature progenitor cells (1h: decrease of DioC23/Rho-123 efflux in CD34-/CD38+, CD123+, CD133- cells by about 50% and in the more immature CD34-/CD38+, CD123-, CD133+ cells by about 70%); V) Erlo diminishes cell surface expression of P-gp (48h), most effectively in the progenitor populations (by 30% in the CD34-/CD38+, CD123+, CD133- cells versus 50% in CD34-/CD38+, CD123+, CD133- cells); VI) Erlo is able to retain MTZ in both CD34- and CD34+ AML-subpopulations; VII) these effects are accompanied by an increased sensitivity towards Dox and VP-16; VIII) Erlo-induced chemosensitization is higher in the CD34+ than in CD34- AML cells. Conclusions: We here provide novel evidence that erlotinib is able to overcome the stem cell features of increased expression and functionality of ABC-transporters thereby antagonizing the intrinsic chemoresistance of (immature) AML cells. Those results suggest a potential clinical interest of combining erlotinib to chemotherapy in AML Disclosures: Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Consultancy.
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Chen, Ling, Stephanie Jean-Noel, Kevin Hall, Ying Shi, and Griffin P. Rodgers. "In Vitro Hematopoietic Lineage Interconversion from Human Bone Marrow Stem and Progenitor Cells." Blood 104, no. 11 (November 16, 2004): 4160. http://dx.doi.org/10.1182/blood.v104.11.4160.4160.
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Abstract The cell surface antigen, CD133, marks a fraction of hematopoietic stem and progenitor cells and has been successfully used to study their differential biology. To evaluate the differentiating capacity of stem/progenitor cells, we cultivated purified normal human bone marrow CD133 selected cells for 2 weeks with erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF) to induce erythroid or myeloid differentiation, respectively. After the second week of cultivation, we reversed the seeding environment of the two populations by placing EPO treated cells into a G-CSF environment and G-CSF treated cells into an EPO environment for an additional 2-week culture. The cells produced in the culture were phenotypically defined by morphology and flow cytometry, and genotypically by RNA and proteomic analyses. Three-color flow cytometry was used for identifying CD133+ progenitors, CD36+ erythroid and CD13+ myeloid cells, as shown in Table 1. The morphology of the cultured cells, assessed by Wright-Giemsa staining, is consistent with the conversion of cellular specific markers. Rapid analysis of gene expression demonstrated co-expression of 76% of 266 genes analyzed among the erythroid and myeloid lineages. Furthermore, proteomic analysis exhibited the sharing of 33% of 9518 expressed protein spots assayed in the two populations after the first 2-week culture, and 32% after 2 weeks of the switch culture. Our data clearly demonstrate that the committed erythroid and myeloid precursors are able to change their fate and can switch into the opposite cell type by a conversion pathway under a specifically defined condition. We termed this switch as interconversion, considering conversion of hematopoietic cells to non-hematopoietic cells. Furthermore, the observations presented in this study show that cytokines used can improve the conversion. We are developing a mathematical model describing the kinetics of hematopoietic stem/progenitor cell transitions into specific lineages, along with the conversion of committed cells based on multiple potential energy wells corresponding to different cell states and cytokines. Table 1. Expression of cell surface markers after 4-week culture D0 1 week 2 weeks 4 weeks CD expression (%) E G E G E2w →G2w → G2w E2w Data are presented as a mean of at least 2 experiments. E: EPO; G: G-CSF; E2w or G2w: EPO or G-CSF treatment for two weeks. CD133+ 96.19 15.74 13.6 0.24 0.36 0.01 0.63 CD36+ 0 60.37 27.39 96.37 25.87 45.41 68.54 CD13+ 0.43 35.41 57.29 24.41 92.1 85.87 37.76 CD133+ / CD36+ 0.44 22.24 15.97 0.12 0.18 1.55 7.65 CD133+ / CD13+ 1.24 19.43 13.36 0.36 1.09 13.31 14.92 CD36+ / CD13+ 0.09 41.25 17.80 23.69 54.1 46.60 79.41
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Chen, Haiming, Mingjie Li, Eric Sanchez, Cathy S. Wang, Ariana M. Berenson, Jennifer Li, Jeffrey A. Steinberg, et al. "Characterization of Cancer Stem Cells in Multiple Myeloma." Blood 112, no. 11 (November 16, 2008): 495. http://dx.doi.org/10.1182/blood.v112.11.495.495.
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Abstract Cancer stem cells persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Development of specific therapies targeted at cancer stem cells gives hope for improvement in the survival and quality life of cancer patients. Multiple myeloma (MM) is a cancer characterized by clonal expansion of terminally differentiated B cells. In order to characterize whether cancer stem cells can be identified in these patients, fresh bone marrow biopsies with 90% MM cells from MM patients were implanted into the superficial gluteal muscle of C.B-17 severe combined immunodeficient (SCID) mice. The tumors were excised from donor mice two months following implantation, and digested with proteinase-E to produce a single cell suspension. These cells were analyzed using flow cytometry to identify specific cellular phenotypes within the tumor population. Approximately 13% of the tumor cells were CD138+ cells, 1–2% CD20+ cells and 2–3% CD133+ cells. To examine gene expression within these populations, we isolated the tumor cells using immunomagnetic bead selection. Cells (1X108) were incubated with 200ml of anti-CD138 microbeads and either anti-CD133 or CD20 microbeads. The cell suspension was applied to the magnetic column and unbound cells were passed through the column by washing followed by centrifugation, and finally resuspended. Total RNA was purified from the cells and gene expression of each population was examined using RT-PCR analysis of specific previously identified stem cell-related transcription factors. β-catenin plays a critical role in stem cell development; and, furthermore, the Wnt-β-catenin signaling pathway is important for maintaining the balance of proliferation versus differentiation in the stem cell population. The gene expression of KLT-4, Oct-4, SOX2, and C-myc has recently been shown to convert nonterminally differentiated B cells into a pluripotent stem cell state. In our studies, we found that the CD20+/CD138− and CD133+/CD138− subpopulations both expressed high levels of β-catenin, KLT-4, Oct-4, SOX2, and C-myc. These small populations of tumor cells are likely to represent MM cancer stem cells as they express genes consistently identified in cancer stem cells identified in other types of cancers. We unexpectedly found that CD138+ cells also expressed β-catenin, KLT-4, Oct-4, SOX2, and C-myc. This population of cells might be a “premature” tumor cell in MM at a middle stage of tumor cell differentiation which ultimately differentiates into a mature MM cell. Only CD20−/CD138− cells showed no expression of β-catenin, KLT-4 and SOX2 and markedly reduced Oct-4 gene expression whereas the amount of C-myc gene expression was similar to the levels in the other tumor cell subtypes. Only CD133−/CD138− cells lost β-catenin and showed a reduction in Oct-4 gene expression but still expressed the KLT-4, SOX2, and C-myc genes. To further examine these cancer stem cell and mature tumor cell populations in terms of growth in vivo, we have injected subcutaneously CD20+/CD138−, CD133+/CD138−, CD20−/CD138−, and CD133−/CD138− tumor cell subpopulations back into SCID mice. We will assess growth of cells from these subtypes in vivo as determined by changes in tumor volume and Ig protein levels. We also will determine the sensitivity of these subtypes in vivo to treatment with a variety of agents with anti-MM activity including bortezomib, lenalidomide, melphalan, and Doxil. These studies have uncovered specific subpopulations within the tumor clone of MM and identified differences in expression of genes known to be involved in stem cell function. Further work should lead to specific treatments that can effectively treat these different subpopulations within the tumor clone in MM.
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Greco, N. J., V. J. Pompili, H. M. Lazarus, D. Adler, T. Lasser, R. Fox, L. Solchaga, et al. "Correlative Cellular Analyses in a Phase I Trial (Safety and Efficacy of Autologous Intracoronary Stem Cell Injections in Total Coronary Artery Occlusions (SEACOAST)) of Autologous Bone Marrow-Derived CD133 Cells." Blood 108, no. 11 (November 16, 2006): 1689. http://dx.doi.org/10.1182/blood.v108.11.1689.1689.
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Abstract Correlative laboratory studies were developed in a phase I trial to evaluate the safety of intracoronary injection of escalating doses of bone marrow (BM) CD133+ cells in patients with chronic coronary ischemia. Concurrent with patient cellular therapy, CD133+ cells were phenotyped and tested functionally with endothelial cell colony formation and in vitro and in vivo transmigration. BM (194 ± 11 ml) was isolated from patients meeting study inclusion criteria. CD133+ cells (20 ± 13 x 106, 84 ± 7% purity and 76 ± 7% viability (7AAD)) were isolated using the CliniMACS device (Miltenyi). Contaminating cells following the CliniMACS selection were: < 5% of CD3, CD3neg/CD56, CD19 (immature/mature), CD14, and CD71 cells with 5% CD61, 8% CD13+ SSChigh. BM, PB (peripheral blood), cord blood (CB)-derived endothelial progenitor cells (EPC) were assessed by a culture assay (StemCell Technologies) scoring early outgrowth CFU-EC. SEACOAST patients yielded significantly less colonies compared to controls of matched PB and BM (donors 28–48 yrs) and CB: normal donor (ND) PB, 65; ND BM, 40; CB, 43; SEACOAST patient PB, 2, SEACOAST patient BM, 1. Transmigration assays were used to evaluate the functionality of selected CD133+ cells to chemotactic agents stromal derived factor-1 (SDF-1) and vascular endothelial growth factor (VEGF). Selected CD133+ cells were recovered, resuspended in DMEM/1% HSA media and after a 37°C incubation for 16–20 hrs, 5 x 104 CD133+ cells were added to transwells (5 mm) for 3 hours. Transmigrated cells were quantitated by flow cytometry using anti-CD45, anti-CD133 antibodies, and Fluorosphere beads. Surface expression on ND BM CD133+ cells of CXCR4 and VEGF-R2 was 0–16.4% and 1.2–4.3%, respectively. Transmigration was effected by 200 ng/ml (range of 16–62%) but not to 10 ng/ml VEGF. For CD133+ cells devoid of the expression of CXCR4, SDF-1-induced transmigration was absent. Expression of CXCR4 and VEGF-R2 on clinical trial patient-selected CD133+ cells was 0–5% and 0–2%, respectively, and transmigration was 5–19% to 200 ng/ml SDF-1 but not to 10 ng/ml VEGF. Patient selected CD133+ cells or PB mononuclear cells (PBMC), ND CD133+ cells, or a vehicle control were injected via a left intraventricular route into NOD/SCID mice with a femoral artery ligation immediately after injury. Doppler flow measurements were obtained weekly for 6 weeks comparing the perfusion ratio of ischemic/healthy limbs. At 28 days, perfusion ratios were statistically higher in study groups receiving ND CD133+ cells (0.51 ± 0.06) compared to controls (0.37 ± 0.03, p=0.025). Mice receiving patient CD133+ cells (0.46 ± 0.04) or PBMC (0.37 ± 0.08) did not show statistically significant improvement over control animals (p= 0.07, p= 0.94, respectively). BM was harvested to assess human engraftment by cytometric analysis. Mice injected with 0.5 x 106 patient BM CD133+ cells showed <0.2% huCD45+ cells compared to 1.6 ± 0.4% ND BM huCD45+. Beyond the demonstrated safety of the delivery of CD133+ cells (>70% purity and >70% viability) to chronic ischemic patients via an intracoronary route, important correlative in vitro and in vivo assays has demonstrated the diminished potency of BM-derived CD133+ cells as compared to CB and ND PB and BM-derived cells.
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Anbarlou, Azadeh, Amir Atashi, Masoud Soleimani, Mahshid AkhavanRahnama, Mahbobeh Bohloli, and Majid Mossahebi-Mohammadi. "Differential characteristics of CD133+ and CD133− Jurkat cells." In Vitro Cellular & Developmental Biology - Animal 51, no. 6 (January 29, 2015): 556–61. http://dx.doi.org/10.1007/s11626-015-9869-z.
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FERRANDINA, G., G. BONANNO, L. PIERELLI, A. PERILLO, A. PROCOLI, A. MARIOTTI, M. CORALLO, et al. "Expression of CD133-1 and CD133-2 in ovarian cancer." International Journal of Gynecologic Cancer 18, no. 3 (May 2008): 506–14. http://dx.doi.org/10.1111/j.1525-1438.2007.01056.x.
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Cancer stem cells have been isolated from several solid tumors including prostate, colon, liver, breast, and ovarian cancer. Stem cells isolated from nervous system and prostate express CD133 antigen, which is widely used to isolate hematopoietic stem and progenitor cells. The aims of this study were to investigate the expression of the CD133-1 and CD133-2 epitopes in primary ovarian tumors and to biologically characterize CD133+ovarian cancer cells, also according to clinicopathologic parameters. Tissue specimens were obtained at primary surgery from 41 ovarian carcinomas; eight normal ovaries and five benign ovarian tumors were also collected. Flow cytometry with monoclonal antibodies against CD133-1 and CD133-2 epitopes was employed. FACS (fluorescence activated cell sorting) analysis enabled the selection of CD133+cells, whose epithelial origin was confirmed by immunofluorescence analysis with monoclonal anti-cytokeratin 7. CD133+cells gave rise to a 4.7 ± 0.9-fold larger number of colonies than that documented in CD133−population (P< 0.001). Moreover, CD133+cells showed an enhanced proliferative potential compared to CD133−cells. The percentages of CD133-1- and CD133-2-expressing cells were significantly lower in normal ovaries/benign tumors with respect to those in ovarian carcinoma. Both the percentages of CD133-1- and CD133-2-expressing cells were significantly lower in omental metastases than in primary ovarian cancer (P= 0.009 and 0.007 for CD133-1- and CD133-2-expressing cells, respectively). There seems not to be any difference in the distribution of the percentage of CD133-1- and CD133-2-expressing cells according to clinicopathologic parameters and response to primary chemotherapy. CD133-1 and CD133-2 may be useful in order to select and enrich the population of CD133+ovarian tumor cells, which are characterized by a higher clonogenic efficiency and proliferative potential.
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Wang, Haiwei, Xinrui Wang, Liangpu Xu, Ji Zhang, and Hua Cao. "A pan-cancer perspective analysis reveals the opposite prognostic significance of CD133 in lower grade glioma and papillary renal cell carcinoma." Science Progress 104, no. 2 (April 2021): 003685042110109. http://dx.doi.org/10.1177/00368504211010938.
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CD133 is a valuable prognostic marker in multiple types of cancer. However, the expression, methylation levels, and prognostic relevance of CD133 have not been evaluated in a pan-cancer perspective. The expression and methylation levels of CD133 across different types of cancer were determined using The Cancer Genome Atlas (TCGA) dataset. Univariate cox regression and Kaplan-Meier survival were used to determine the prognostic significance of CD133 expression and methylation. CD133 was highly expressed in papillary renal cell carcinoma (PRCC) or pancreatic adenocarcinoma (PAAD). Correspondingly, PAAD and PRCC had low CD133 methylation levels. Through pan-cancer perspective analysis, we found that CD133 high expression was a poor prognostic factor in lower grade glioma (LGG), while, CD133 high expression was a good prognostic factor in PRCC. Moreover, genes positively correlated with CD133 expression were associated with the poor clinical outcomes of LGG. In PRCC, genes negatively correlated with CD133 expression were correlated with the poor overall survival. Furthermore, CD133 expression levels were highly correlated with the CD133 methylation levels in LGG or PRCC. Correspondingly, CD133 hypermethylation was a good prognostic factor in LGG. On the contrary, CD133 hypomethylation was a good prognostic factor in PRCC. We also found that CD133 was highly expressed and hypomethylated in wild type IDH subgroup of LGG. CD133 was highly expressed and hypomethylated in low stages and type1 of PRCC. CD133 high expression and hypomethylation were bad prognostic factors in LGG, while, CD133 high expression and hypomethylation were good prognostic factors in PRCC.
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Kloskowski, Tomasz, Joanna Jarząbkowska, Arkadiusz Jundziłł, Daria Balcerczyk, Monika Buhl, Kamil Szeliski, Magdalena Bodnar, et al. "CD133 Antigen as a Potential Marker of Melanoma Stem Cells: In Vitro and In Vivo Studies." Stem Cells International 2020 (December 23, 2020): 1–10. http://dx.doi.org/10.1155/2020/8810476.
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Melanoma is the most dangerous type of skin cancer. Cancer stem cells (CSCs) are suspected to be responsible for the cancer recurrence and in the consequence for cancer therapy failure. CD133 is a potential marker for detection of melanoma CSCs. Experiments were performed on the B16-F10 mouse melanoma cell line. CD133+ cells were isolated using an immunomagnetic cell sorting technique. After isolation proliferative and clonogenic potential of CD133+, CD133- and CD133+/- were evaluated. The potential of CD133+ and CD133- cells for tumor induction was conducted on C57BL/6J mouse model. Three different cell quantities (100, 1000, 10000) were tested. Tumor morphology, number of mitoses, and tumor necrosis area were analyzed. Average 0.12% CD133+ cells were isolated. Compared to CD133- and unsorted CD133+/- cells, CD133+ cells were characterized by the higher proliferative and clonogenic potential. These properties were not confirmed in vivo, as both CD133+ and CD133- cells induced tumor growth in mouse model. No statistical differences in mitosis number and tumor necrosis area were observed. Simultaneous detection of CD133 antigen with other markers is necessary for accurate identification of these melanoma cancer stem cells.
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Wu, Ju-gang, Ji-wei Yu, Rui-qi Lu, Shou-lian Wang, Xiao-chun Ni, Lin-hai Zheng, and Bo-jian Jiang. "Preliminary Study on the Expression and the Clinical Significance of CD133 in Peripheral Blood of Patients with Gastric Adenocarcinoma." ISRN Gastroenterology 2014 (February 6, 2014): 1–11. http://dx.doi.org/10.1155/2014/245329.
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Background. Significances of CD133 mRNA in peripheral blood mononuclear cells (PBMCs) of gastric adenocarcinoma (GC) patients were investigated. Methods. Correlations of CD133 mRNA expression in PBMCs on clinicopathological parameters or CD133 protein expression were analyzed. Receiver operating characteristic curve according to bright scale value (BSV) of CD133 mRNA was used to group patients for prognosis analysis. Results. BSV of preoperative CD133 mRNA in PBMCs in GC was significantly higher than that in volunteers or in GU. Invasive depth or metastatic lymph node number for higher BSV of preoperative CD133 mRNA and invasive depth or lymphatic vessel invasion for higher BSV of postoperative CD133 mRNA in the PBMCs were identified. Patients with CD133+ expression in primary lesion had a significantly higher expression of preoperative CD133 mRNA in the PBMCs. The expression of preoperative or postoperative CD133 mRNA in PBMCs related positively to CD133 mRNA expression in primary lesion. Patients with higher expression of preoperative or postoperative CD133 mRNA shared significantly shorter survival compared with that in lower expression group. Conclusion. Higher levels of preoperative or postoperative CD133 mRNA in PBMCs of GC correlated positively to the lymphatic metastasis and the BSV of CD133 mRNA in primary lesion, indicating the poorer survival.
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LI, JI, XIAO-YAN ZHONG, ZONG-YU LI, JIN-FANG CAI, LIN ZOU, JIAN-MIN LI, TAO YANG, and WEI LIU. "CD133 expression in osteosarcoma and derivation of CD133+ cells." Molecular Medicine Reports 7, no. 2 (December 13, 2012): 577–84. http://dx.doi.org/10.3892/mmr.2012.1231.
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Abbasian, Javaneh, and Damiano Rondelli. "Early Cross-Talk between Cord Blood CD34+ or CD133+ Cells and Allogeneic T Cells Regulates the Differentiation of Dendritic Cell Precursors." Blood 104, no. 11 (November 16, 2004): 2141. http://dx.doi.org/10.1182/blood.v104.11.2141.2141.
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Abstract It has been previously described that CD34+ blood or marrow progenitors expressing costimulatory ligands are committed to the dendritic cell (DC) lineage. In this study we addressed the question of whether initial contact with allogeneic lymphocytes may differently affect hemopoietic stem cells (HSC) with alloantigen presenting capacity. Human CD34+ and CD133+ cord blood (CB) cells were obtained after immunomagnetic purification. Initially, both HSC fractions were irradiated and tested with allogeneic blood mononuclear cells (MNC) (ratio 1:2) in primary mixed leukocyte culture (MLC) for 6 d. CD34+ and CD133+ CB cells induced similar activation of allo-responders, with increased numbers of CD3+CD69+, CD3+CD25+ and CD8+CD134+ (OX-40+) cells, as well as allogeneic T cell proliferative response (mean Stimulation Index: 19±5 and 16±5, respectively) (n=6). Then, to evaluate the effect of allogeneic effectors on HSC, we tested non-irradiated CD34+ or CD133+ cells in co-culture with irradiated allogeneic MNC or purified T-cells for 6 d, or with medium alone as control, and observed a brisk proliferation of both HSC fractions only upon stimulation with allogeneic cells (mean Stimulation Index: 17±2; n=3). Interestingly, costimulatory blockade with CTLA4-Ig resulted in 70% inhibition of HSC proliferation, suggesting that B7:CD28 signaling is necessary to the T cell-mediated HSC growth. Finally, CD34+ or CD133+ cells that had been cocultured with irradiated allogeneic T cells for 6 d, were harvested, irradiated and rechallenged as stimulators in MLC (S:R ratio=1:2). Progenitors derived from both CD34+ and CD133+ cells induced a significantly greater T cell alloresponse as compared to the same freshly isolated HSC (overall mean Stimulation Index: 134±54 vs 24±8, p=0.03; n=4 exp). The phenotypic kinetics of CD34+ and CD133+ CB cells upon contact with irradiated T cells, showed a rapid upregulation of CD86 within 24 h (on average from 2±1% to 7±2%, and from <1% to 4±1%, respectively, n=3), and at 3 and 6 d of culture both CD34+ and CD133+ CB cells progressively became larger and included a population of HLA-DR+CD14+CD86+CD11c+ progenitors, on average 16% of cultured progenitors (n=3), consistent with the phenotype of DC precursors. In addition, irradiated allogeneic lymphocytes induced the generation of CD1a+ DC after 8 d of culture with CD34+ cells or CD133+ cells (7% and 9% CD1a+ cells, respectively), in the absence of exogenous cytokines. Therefore, we show here that CB CD34+ and CD133+ are similarly enriched in progenitors capable of stimulating allogeneic T cell responses in-vitro. Moreover, we demonstrate that an early crosstalk of cord blood HSC (CD34+ and CD133+ cells) and allogeneic T cells leads to the reciprocal activation and to the rapid proliferation and differentiation of DC precursors, that elicit potent alloimmune responses. Future studies aimed at either selectively abrogating this subset of progenitors, or blocking HSC-induced T cell activation, will be developed in the attempt of facilitating the induction of tolerance in allogeneic HSC transplantation.
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Jung, Kyung-Ho, Jin Hee Lee, Mina Kim, Eun Ji Lee, Young Seok Cho, and Kyung-Han Lee. "Celecoxib-Induced Modulation of Colon Cancer CD133 Expression Occurs through AKT Inhibition and Is Monitored by 89Zr Immuno-PET." Molecular Imaging 2022 (January 7, 2022): 1–12. http://dx.doi.org/10.1155/2022/4906934.
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We developed an immuno-PET technique that monitors modulation of tumor CD133 expression, which is required for the success of CD133-targeted therapies. Methods. Anti-CD133 antibodies were subjected to sulfhydryl moiety-specific 89Zr conjugation. 89Zr-CD133 IgG was evaluated for specific activity and radiolabel stability. Colon cancer cells underwent binding assays and Western blotting. Biodistribution and PET studies were performed in mice. Results. 89Zr-CD133 IgG showed excellent target specificity with 97.2 ± 0.7 % blocking of HT29 cell binding by an excess antibody. Intravenous 89Zr-CD133 IgG followed biexponential blood clearance and showed CD133-specific uptake in HT29 tumors. 89Zr-CD133 IgG PET/CT and biodistribution studies confirmed high HT29 tumor uptake with lower activities in the blood and normal organs. In HT29 cells, celecoxib dose-dependently decreased CD133 expression and 89Zr-CD133 IgG binding that reached 19.9 ± 2.1 % ( P < 0.005 ) and 50.3 ± 10.9 % ( P < 0.001 ) of baseline levels by 50 μM, respectively. Celecoxib treatment of mice significantly suppressed tumor CD133 expression to 67.5 ± 7.8 % of controls ( P < 0.005 ) and reduced tumor 89Zr-CD133 IgG uptake from 15.5 ± 1.4 % at baseline to 12.3 ± 2.0 % ID / g ( P < 0.01 ). Celecoxib-induced CD133 reduction in HT29 cells and tumors was associated with substantial suppression of AKT activation. There were also reduced HIF-1α accumulation and IκBα/NFκB phosphorylation. Conclusion. 89Zr-CD133 IgG PET provides high-contrast tumor imaging and monitors celecoxib treatment-induced modulation of tumor CD133 expression, which was found to occur through AKT inhibition. This technique may thus be useful for screening drugs that can effectively suppress colon cancer stem cells.
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Simbulan-Rosenthal, Dougherty, Vakili, Ferraro, Kuo, Alobaidi, Aljehane, et al. "CRISPR-Cas9 Knockdown and Induced Expression of CD133 Reveal Essential Roles in Melanoma Invasion and Metastasis." Cancers 11, no. 10 (October 3, 2019): 1490. http://dx.doi.org/10.3390/cancers11101490.
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CD133, known as prominin1, is a penta-span transmembrane glycoprotein presumably acancer stem cell marker for carcinomas, glioblastomas, and melanomas. We showed that CD133(+)‘melanoma-initiating cells’ are associated with chemoresistance, contributing to poor patientoutcome. The current study investigates the role(s) of CD133 in invasion and metastasis. Magneticactivatedcell sorting of a melanoma cell line (BAKP) followed by transwell invasion assays revealedthat CD133(+) cells are significantly more invasive than CD133(−) cells. Conditional reprogrammingof BAKP CD133(+) cells maintained stable CD133 overexpression (BAK-R), and induced cancer stemcell markers, melanosphere formation, and chemoresistance to kinase inhibitors. BAK-R cellsshowed upregulated CD133 expression, and consequently were more invasive and metastatic thanBAK-P cells in transwell and zebrafish assays. CD133 knockdown by siRNA or CRISPR-Cas9 (BAKR-T3) in BAK-R cells reduced invasion and levels of matrix metalloproteinases MMP2/MMP9. BAKR-SC cells, but not BAK-R-T3, were metastatic in zebrafish. While CD133 knockdown by siRNA orCRISPR-Cas9 in BAK-P cells attenuated invasion and diminished MMP2/MMP9 levels,doxycycline-induced CD133 expression in BAK-P cells enhanced invasion and MMP2/MMP9concentrations. CD133 may therefore play an essential role in invasion and metastasis viaupregulation of MMP2/MMP9, leading to tumor progression, and represents an attractive target forintervention in melanoma.
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Zhong, Zhi-Yong, Bao-Jun Shi, Hui Zhou, and Wen-Bo Wang. "CD133 expression and MYCN amplification induce chemoresistance and reduce average survival time in pediatric neuroblastoma." Journal of International Medical Research 46, no. 3 (January 11, 2018): 1209–20. http://dx.doi.org/10.1177/0300060517732256.
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Objectives Neuroblastoma (NB) is the most common pediatric solid tumor derived from the sympathetic nervous system. MYCN is amplified in nearly half of patients with NB, and its association with rapid disease progression and poor outcome is controversial. Characterization of cancer stem cells (CSCs) in NBs has been rarely studied. This study was performed to determine whether MYCN and CD133+ CSCs are associated with chemotherapy resistance and the survival time of patients with NB. Methods Fifty patients with an unequivocal pathological diagnosis of NB were recruited. MYCN expression levels were measured before therapy. CSCs were derived and their multipotency tested by directed differentiation. The patients’ responses to chemotherapy and average survival time were compared among the groups as follows: CD133+, CD133−, MYCN amplification ≥5 times (i.e. MYCN≥5), MYCN<5, CD133+ plus MYCN≥5, and CD133− plus MYCN<5. Results CD133+ CSCs differentiated into neuron-like cells. CD133+ patients had a significantly poorer response to chemotherapy than did CD133− patients. CD133+ plus MYCN≥5 patients had a significantly shorter average survival time than did CD133− plus MYCN<5 patients. Conclusions CD133+ CSCs are chemoresistance. CD133 expression and MYCN amplification can be used together as a prognostic indicator of disease outcome.
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Wong, A., S. Mitra, and P. Gupta. "Targeting brain tumor stem cells using a bispecific antibody directed against CD133+ and EGFRvIII+." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2022. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2022.
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2022 Background: Using the marker CD133, cancer stem cells (CSCs) have been demonstrated for glioblastomas (GBMs) and medulloblastomas. However, CD133 is also present on normal neural stem cells. EGFRvIII is a tumor specific EGF receptor. We hypothesized that a recombinant bispecific antibody directed against CD133 and EGFRvIII would be a highly specific reagent. Methods: Single chain antibodies (scFv) were cloned for anti-EGFRvIII and anti-CD133 using existing hybridomas and published sequences. scFv were cloned into a bicistronic vector containing a human CH3 constant domain. The bispecific antibody (BsAb) contains the anti-CD133 (AC133) and anti-EGFRvIII single chain Fv; monospecific but bivalent reagents for anti-CD133 and anti-EGFRvIII were also constructed. Results: U87 cells were co-transfected with increasing amounts of CD133 and decreasing amounts of EGFRvIII cDNAs. The BsAb showed the highest binding for cells expressing both epitopes, whereas Di-EGFRvIII and Di-AC133 had the highest affinity for cells expressing high levels of individual antigens. When cells expressing both antigens were mixed with cells expressing high levels of either antigen alone, the BsAb only recognized CD133+/EGFRvIII+ cells. We then explored the efficiency of tumor cell killing. Using human CD16-expressing NK cells as the effectors at an effector:target ratio of 10:1 and an 83 nM antibody concentration, the BsAb induced 86% lysis of U87-EGFRvIII/CD133 cells, 42.5% in U87-vIII but only 27.3% in U87-CD133 cells. Di-EGFRvIII efficiently induced cytotoxicity in U87-EGFRvIII/CD133 and U87vIII cells but not in U87-CD133 cells. Di-CD133 was the least effective at inducing ADCC. Finally, we studied the ability of the BsAb to induce ADCC on tumor spheres and normal neurospheres. The BsAb showed at least 4X greater lysis on tumor spheres that were CD133+/EGFRvIII+ over normal neurospheres expressing CD133 alone at an E:T of 10:1. This was seen at concentrations as low as 0.83 nM. Conclusions: A recombinant bispecific antibody directed against CD133 and EGFRvIII is highly specific for cells that are positive for both antigens, but poorly targets cells expressing CD133 alone. It can potentially be used as a therapeutic agent for specifically targeting CD133+/EGFRvIII+ cancer stem cells. No significant financial relationships to disclose.
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Gisina, Alisa, Svetlana Novikova, Yan Kim, Dmitry Sidorov, Stanislav Bykasov, Nadezhda Volchenko, Andrey Kaprin, Victor Zgoda, Konstantin Yarygin, and Alexey Lupatov. "CEACAM5 overexpression is a reliable characteristic of CD133-positive colorectal cancer stem cells." Cancer Biomarkers 32, no. 1 (August 24, 2021): 85–98. http://dx.doi.org/10.3233/cbm-203187.
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BACKGROUND: CD133 (prominin-1) is the most commonly used molecular marker of the cancer stem cells (CSCs) that maintain tumor progression and recurrence in colorectal cancer. However, the proteome of CSCs directly isolated from colorectal tumors based on CD133 expression has never been investigated. OBJECTIVE: To reveal biomarkers of CD133-positive colorectal CSCs. METHODS: Thirty colorectal tumor samples were collected from patients undergoing bowel resection. CD133-positive and CD133-negative cells were isolated by FACS. Comparative proteomic profiling was performed by LC-MS/MS analysis combined with label-free quantification. Verification of differentially expressed proteins was performed by flow cytometry or ELISA. CD133-knockout Caco-2 and HT-29 cell lines were generated using CRISPR-Cas9 gene editing. RESULTS: LC-MS/MS analysis identified 29 proteins with at least 2.5-fold higher expression in CD133-positive cells versus CD133-negative cells. Flow cytometry confirmed CEACAM5 overexpression in CD133-positive cells in all clinical samples analyzed. S100A8, S100A9, and DEFA1 were differentially expressed in only a proportion of the samples. CD133 knockout in the colon cancer cell lines Caco-2 and HT-29 did not affect the median level of CEACAM5 expression, but led to higher variance of the percentage of CEACAM5-positive cells. CONCLUSIONS: High CEACAM5 expression in colorectal cancer cells is firmly associated with the CD133-positive colorectal CSC phenotype, but it is unlikely that CD133 directly regulates CEACAM5 expression.
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Song, Yeonhwa, Sanghwa Kim, Hyeryon Lee, Joo Hwan No, Hyung Chul Ryu, Jason Kim, Jee Woong Lim, Moonhee Kim, Inhee Choi, and Haeng Ran Seo. "Chromenopyrimidinone Controls Stemness and Malignancy by suppressing CD133 Expression in Hepatocellular Carcinoma." Cancers 12, no. 5 (May 8, 2020): 1193. http://dx.doi.org/10.3390/cancers12051193.
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Hepatocellular carcinoma (HCC) is a highly malignant human cancer that has increasing mortality rates worldwide. Because CD133+ cells control tumor maintenance and progression, compounds that target CD133+ cancer cells could be effective in combating HCC. We found that the administration of chromenopyrimidinone (CPO) significantly decreased spheroid formation and the number of CD133+ cells in mixed HCC cell populations. CPO not only significantly inhibited cell proliferation in HCC cells exhibiting different CD133 expression levels, but also effectively induced apoptosis and increased the expression of LC3-II in HCC cells. CPO also exhibits in vivo therapeutic efficiency in HCC. Specifically, CPO suppressed the expression of CD133 by altering the subcellular localization of CD133 from the membrane to lysosomes in CD133+ HCC cells. Moreover, CPO treatment induced point mutations in the ADRB1, APOB, EGR2, and UBE2C genes and inhibited the expression of these proteins in HCC and the expression of UBE2C is particularly controlled by CD133 expression among those four proteins in HCC. Our results suggested that CPO may suppress stemness and malignancies in vivo and in vitro by decreasing CD133 and UBE2C expression in CD133+ HCC. Our study provides evidence that CPO could act as a novel therapeutic agent for the effective treatment of CD133+ HCC.
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Simbulan-Rosenthal, Cynthia M., Anirudh Gaur, Hengbo Zhou, Maryam AbdusSamad, Qing Qin, Ryan Dougherty, Leala Aljehane, et al. "CD133 Is Associated with Increased Melanoma Cell Survival after Multikinase Inhibition." Journal of Oncology 2019 (July 16, 2019): 1–19. http://dx.doi.org/10.1155/2019/6486173.
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FDA-approved kinase inhibitors are now used for melanoma, including combinations of the MEK inhibitor trametinib, and BRAF inhibitor dabrafenib for BRAFV600 mutations. NRAS-mutated cell lines are also sensitive to MEK inhibitionin vitro, and NRAS-mutated tumors have also shown partial response to MEK inhibitors. However, melanoma still has high recurrence rates due to subpopulations, sometimes described as “melanoma initiating cells,” resistant to treatment. Since CD133 is a putative cancer stem cell marker for different cancers, associated with decreased survival, we examined resistance of patient-derived CD133(+) and CD133(-) melanoma cells to MAPK inhibitors. Human melanoma cells were exposed to increasing concentrations of trametinib and/or dabrafenib, either before or after separation into CD133(+) and CD133(-) subpopulations. In parental CD133-mixed lines, the percentages of CD133(+) cells increased significantly (p<0.05) after high-dose drug treatment. Presorted CD133(+) cells also exhibited significantly greater (p<0.05) IC50s for single and combination MAPKI treatment. siRNA knockdown revealed a causal relationship between CD133 and drug resistance. Microarray and qRT-PCR analyses revealed that ten of 18 ABC transporter genes were significantly (P<0.05) upregulated in the CD133(+) subpopulation, while inhibition of ABC activity increased sensitivity, suggesting a mechanism for increased drug resistance of CD133(+) cells.
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Foris, Vasile, Gabor Kovacs, Leigh M. Marsh, Zoltán Bálint, Martin Tötsch, Alexander Avian, Philipp Douschan, et al. "CD133+ cells in pulmonary arterial hypertension." European Respiratory Journal 48, no. 2 (April 21, 2016): 459–69. http://dx.doi.org/10.1183/13993003.01523-2015.
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Circulating mononuclear cells may play an important role for the vascular remodelling in pulmonary arterial hypertension (PAH), but studies addressing multiple progenitor populations are rare and inconsistent.We used a comprehensive fluorescence-activated cell sorting analysis of circulating mononuclear cells in 20 PAH patients and 20 age- and sex-matched controls, and additionally analysed CD133+ cells in the lung tissue of five PAH transplant recipients and five healthy controls (donor lungs).PAH patients were characterised by increased numbers of circulating CD133+ cells and lymphopenia as compared with control. In PAH, CD133+ subpopulations positive for CD117 or CD45 were significantly increased, whereas CD133+CD309+, CD133+CXCR2+ and CD133+CD31+ cells were decreased. In CD133+ cells, SOX2, Nanog, Ki67 and CXCR4 were not detected, but Oct3/4 mRNA was present in both PAH and controls. In the lung tissue, CD133+ cells included three main populations: type 2 pneumocytes, monocytes and undifferentiated cells without significant differences between PAH and controls.In conclusion, circulating CD133+ progenitor cells are elevated in PAH and consist of phenotypically different subpopulations that may be up- or downregulated. This may explain the inconsistent results in the literature. CD133+ type 2 pneumocytes in the lung tissue are not associated with circulating CD133+ mononuclear cells.
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Hayashi, T., H. Tao, M. Jida, T. Kubo, H. Yamamoto, H. Otani, Y. Sano, and S. Toyooka. "Expression of CD133, a possible marker for cancer stem cells (CSCs), in small cell lung cancer (SCLC) cell lines and non- small cell lung cancer (NSCLC) cell lines." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22100-e22100. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22100.
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e22100 Background: Cancer stem cell (CSCs) are believed to play important roles in tumor development, recurrence or metastasis. Identification of CSCs may have a therapeutic significance. CD133 expression has been shown on a minority of various human cancer cells with high capability of self-renewal and proliferation. Therefore, CD133 is thought to be one of possible markers for CSCs. Regarding human lung cancers, the existence, prevalence or roles of CD133 positive cells has not been fully understood. Methods: We examined CD133 mRNA by quantitative real-time PCR and sorted CD133-positive cells by fluorescence-activated cell sorting (FACS) using human small cell lung cancer(SCLC) and non-small cell lung cancer (NSCLC) cell lines. We evaluated differences of cell proliferation between CD133-positive and -negative cells by MTS assay in vitro and by subcutaneous injection for non- obese diabetic/severe combined immunodeficiency (NOD/SCID) mice in vivo. Results: CD133 expression was almost restricted in SCLC cell lines. CD133 mRNA expression or CD133-positive cell population was scarcely observed in NSCLC cell lines. In two SCLC cell lines examined (NCI-H82 and NCI-H69), CD133 positive cells had higher tumorgenicity both in vivo and in vitro than NSCLC cell lines. Conclusions: The expression status of CD133 is totally different between NSCLCs and SCLCs, probably reflecting the difference of these progenitor cells. Our results indicate that CD133-positive cells in SCLC cell are responsible for tumor growth. However, in view of their wide prevalence, CD133-positive cells do not seem to be a candidate for CSCs, at least in cell lines. To investigate the molecular and functional characteristics of CD133-positive cells may lead to a new therapeutic strategy for human lung cancers, especially for SCLCs. No significant financial relationships to disclose.
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Lu, Ruiqi, Gang Zhao, Yulong Yang, Zhaoyan Jiang, Jingli Cai, and Hai Hu. "Inhibition of CD133 Overcomes Cisplatin Resistance Through Inhibiting PI3K/AKT/mTOR Signaling Pathway and Autophagy in CD133-Positive Gastric Cancer Cells." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381986431. http://dx.doi.org/10.1177/1533033819864311.
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Cisplatin is widely used as the standard gastric cancer treatment, but the relapse and metastasis are common as intrinsic or acquired drug resistance. CD133 has been widely known to be associated with chemoresistance in various cancer cells. In this study, we focused on investigating the function and mechanism of CD133 underlying cisplatin resistance in gastric cancer cell line KATO-III. We detected CD133 expression by using quantitative real-time polymerase chain reaction and Western blot and found that expression of CD133 was upregulated in cisplatin resistance of KATO-III cells (Cis-KATO-III) compared with KATO-III cells, indicating the role of CD133 in regulating cisplatin resistance of KATO-III cells. Then we sorted the Cis-KATO-III cells into CD133-positive (CD133+) pools and measured the proliferation and apoptosis after the cell is transfected with pc-CD133 and sh-CD133 by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay and flow cytometry. The results showed that the inhibition of CD133 inhibited the cell viability and promoted the cell apoptosis after cisplatin treatment. Furthermore, we found that inhibition of CD133 downregulated the expression of PI3K/AKT and promoted the expression of mammalian target of rapamycin, thus inhibited the autophagic activity in the Cis-KATO-III cells after cisplatin treatment. Besides, we also verified the effects of CD133 in vivo. The results indicated that inhibition of CD133 enhanced the Cis-KATO-III cell sensitivity to cisplatin by regulating PI3K/AKT/mTOR signaling pathway. In summary, our data provide new insight that CD133 activates the PI3K/AKT/mTOR signaling transduction pathway, resulting in activation of autophagy and cisplatin resistance of Cis-KATO-III cells. These results may offer a novel therapeutic target in cisplatin-resistant gastric cancer.
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Madjd, Zahra, Elham Erfani, Elmira Gheytanchi, Maziar Moradi-Lakeh, Ahmad Shariftabrizi, and Mohsen Asadi-Lari. "Expression of CD133 Cancer Stem Cell Marker in Melanoma: A Systematic Review and Meta-Analysis." International Journal of Biological Markers 31, no. 2 (April 2016): 118–25. http://dx.doi.org/10.5301/jbm.5000209.
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Background CD133-positive melanoma cells are thought to be melanoma-initiating cells with cancer stem cell (CSC) characteristics. Some researchers have reported that CD133-negative subsets can also initiate tumors, so the clinical significance of a CD133-positive subpopulation of cells in melanoma remains controversial. This systematic review was designed to assess the value of CD133 as a CSC marker in melanomas. A meta-analysis was also performed to cumulatively analyze the data on CD133 expression levels in the selected studies. Materials and Method Eligible studies were identified via an electronic search through various databases including PubMed, MEDLINE, Ovid MEDLINE, and Web of Science (from May 2005 through September 2014) using the following keywords: “CD133 or prominin-1”, “cancer stem cells”, and “melanoma”. Only articles in which CD133 antigen was detected by immunohistochemistry (IHC) were included. A meta-analysis was performed to identify any association between CD133 expression and clinical outcomes. Results Two hundred and ninety-nine melanoma cases from 5 studies were evaluated for expression levels of CD133 using IHC. Large heterogeneity was observed among the results (p<0.001, I2 = 94%). Approximately 47.9% (95% CI 23.7%-72.1%) of the studied melanoma cases had high CD133 expression. The I2 value and Q-test p value for heterogeneity were 89.0% and <0.001, respectively, and the pooled estimate of CD133 expression was 61.7% (95% CI 25.1%-98.4%). Conclusions Our findings suggest that CD133 is not yet proven to be an appropriate biomarker in identifying CSCs of melanoma. Thus, detection of CD133 in combination with other putative CSC markers may be more valuable for clinical application.
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Eisenwort, Gregor, Barbara Peter, Katharina Blatt, Sabine Cerny-Reiterer, Gregor Hoermann, Irina Sadovnik, Martin Bilban, et al. "Identification of a Neoplastic Stem Cell in Human Mast Cell Leukemia." Blood 124, no. 21 (December 6, 2014): 817. http://dx.doi.org/10.1182/blood.v124.21.817.817.
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Abstract Leukemic stem cells (LSCs) have recently been identified as an important target of therapy in various human leukemias and related blood cell disorders. Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by abnormal growth and accumulation of mast cells (MCs) in various organ systems, including the bone marrow (BM). Whereas patients with indolent SM (ISM) have a normal life-expectancy, patients with more advanced forms of SM have a poor prognosis. In these patients, neoplastic MCs are usually resistant against conventional drugs and various targeted drugs. MC leukemia (MCL) is the rare leukemic variant of advanced SM, defined by a rapidly devastating expansion of immature MCs in various hematopoietic organs and a poor prognosis with short survival times. Although MCL is considered a stem cell disease, little is known about the origin and phenotype of MCL-initiating LSCs. We examined the phenotypic and functional characteristics of putative LSCs in patients with aggressive SM (ASM, n=12) and MCL (n=6). Putative LSCs were identified and characterized phenotypically by flow cytometry. Highly enriched, sorted LSCs were injected into NOD-SCID-IL-2Rγ-/- mice exhibiting a 220 amino acid isoform of human membrane-bound hSCF (NSGSCF). We found that disease-initiating and propagating LSCs reside within a CD34+ fraction of the MCL clone. Whereas cell fractions containing CD34+ cells as well as highly enriched CD34+ cells produced engraftment in NSGSCF mice with a MCL-like disease (43-77% human MCL cells in mouse BM after 10-22 weeks), no substantial engraftment was produced by MC-rich but stem cell-depleted, KIT+/CD34─ cell fractions obtained from the same patients (<1% engraftment in mouse BM). In dilution experiments, engraftment of CD34+ cells was documented down to a minimum of 50 cells per mouse. The identity of engrafting MCL cells was confirmed by morphology, phenotyping and molecular studies demonstrating the presence of KIT mutations that were initially detected in the primary MCL samples used. Moreover, we were able to confirm long-term engraftment by successful serial transplantations into secondary recipient mice. In consecutive experiments, we were able to show that CD45+/CD34+/CD38─ cells also produce leukemic engraftment in NSGSCF mice. As assessed by flow cytometry, these CD34+/CD38─ MCL LSCs were found to express several stem cells markers, including aminopeptidase-N (CD13), leukosialin (CD43), Pgp-1 (CD44), the IL-3R alpha-chain (CD123), AC133 (CD133) and CXCR4 (CD184). In addition, in most patients examined, MCL LSCs were found to display IL-1RAP, a surface antigen that is otherwise expressed in CML LSCs but is not expressed in normal stem cells. In addition, MCL LSCs were found to express various cell surface targets, including CD33 and CD52. By contrast, MCL LSCs did not express CD2, CD25, CD26 and CLL-1. The more mature progenitor cell fractions (CD34+/CD38+) were found to stain positive for CD13, CD33, CD43, CD44, CD90, CD117, CD123, CD133 and CD184. Mature clonal MCs expressed a similar phenotype, including molecular markers and targets, such as CD13, CD30 CD33, CD52 and CD184. In patients with ISM and aggressive SM (ASM), the CD34+/CD38─ stem cells exhibited a similar surface marker profile compared to MCL, but expressed lower levels of CD133 and did not express IL-1RAP. In the validation phase of our study, we examined the effects of target-specific antibodies. As assessed by flow cytometry, the CD52-targeting antibody alemtuzumab was found to induce complement-dependent lysis of CD34+ and CD34+/CD38─ cells in all MCL samples analysed. Furthermore, pre-incubation of MCL cells with alemtuzumab prior to injection into NSGSCF mice resulted in a significantly reduced engraftment (2.7±4.1%) after 22 weeks. In conclusion, our data show that the MCL clone originates from a primitive hematopoietic stem cell that co-expresses CD34, CD123, CD133 and IL-1RAP but lacks CD25 and CD26. In addition, our data show that MCL LSC express a number of clinically relevant surface targets, including CD33, CD52 and CD117 (KIT). These observations may facilitate LSC detection and isolation in MCL and may lead to the development of novel LSC-eradicating treatment concepts in this highly aggressive and drug-resistant form of leukemia. Disclosures Valent: Novartis: Consultancy, Honoraria, Research Funding.
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Fanning, L. R., M. R. Finney, D. G. Winter, S. Kadereit, J. Banks, N. Greco, M. Kozik, V. Pompili, and M. J. Laughlin. "Umbilical Cord Blood Derived CD133+ Cells: Homing Capability in Vasculogenesis and Immunogenicity." Blood 106, no. 11 (November 16, 2005): 3041. http://dx.doi.org/10.1182/blood.v106.11.3041.3041.
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Abstract Human CD133+ cells constitute a phenotypically and functionally distinct population of endothelial stem and precursor cells that may play a role in postnatal angiogenesis. CD133+ homing to stimuli, IL-8 production and immunogenic properties are anticipated important characteristics to consider in potential use of allogeneic UCB CD133+ as a therapeutic in arterial ischemia. CD133+ cells were isolated from UCB mononuclear cells (MNC) by magnetic bead selection (AutoMACS, Miltenyi Biotech) according to manufacturer’s protocol and analyzed by flow cytometry. Yields per cord blood unit averaged 1.05 x 106 cells (+/− 0.7 SEM n=30). Surface phenotyping of UCB CD133+ showed co-expression of VEGFR2 (3.5%), CD105 (22.7%) and CXCR4 (8.7%) ligand for SDF-1. Both HLA-DR (57.6%) and HLA-ABC (66.5%) were expressed on CD133+ cells suggesting that CD133+ cells may be capable of presenting immunostimulatory antigens and eliciting an allogeneic reaction. To test this, we performed 96 hour mixed lymphocyte reactions (MLR) using healthy adult peripheral blood MNC as responders stimulated by irradiated (30Gy) CD133+ from UCB (ratio 3:1). Proliferation was measured by 3H-thymidine incorporation. CD133+ and MNC from UCB induced proliferation from allogeneic healthy adult MNC in vitro (46939 +/− 2764 and 49548 +/− 2018 cpm respectively, n=2). MLR studies with CSFE-stained responder cells revealed equivalent rates of lymphocyte cell division comparing selected UCB CD133+ and MNC cells used as stimulators. Comparison studies of responding lymphocyte cytokine production including pro-inflammatory protein assays are ongoing. Initial angiogenic protein assays of CD133+ cells demonstrated elevated levels of IL-8 production as compared to MNC (103+/−380 pg/mL greater in CD133+ than MNC from the same UCB unit) when cultured for 24h in basal media. Transwell migration assays of CD133+ cells to SDF-1 (100ng/mL) demonstrated a 1.8 ± 0.7 fold increase in homing compared to a negative control, coinciding with the CXCR4 expression observed on these cells. In summary, UCB derived CD133+ cells demonstrate homing capability as well as potential for cellular recruitment (IL-8 production) for angiogenesis and cellular therapeutics. CD133+ cells selected from UCB maintain immunostimulatory capacity and initiate proliferation of adult MNC. Further studies of UCB derived CD133+ pro-inflammatory potential; cell recruitment and homing to ischemic signals are warranted.
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Sartelet, H., E. Haddad, T. Imbriglio, M. Arsenault, S. Ohta, S. Barrette, D. Sinnett, C. Laverdiere, L. Oligny, and G. Vassal. "Expression of CD133 and poor outcome in neuroblastoma associated with chemoresistance mediated by AKT pathway." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 10007. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.10007.
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10007 Background: Neuroblastoma is a frequent childhood cancer with very heterogeneous prognosis. Recent studies showed that CD133 expression is an independent prognostic marker for low survival in several cancers like medulloblastoma. The aim of our study is to determine the prognostic value of CD133 expression in a large population of neuroblastoma and to determine the chemoresistance of neuroblasts expressing CD133. Methods: 280 tumor samples of neuroblastoma were screened for CD133 expression. Patients had a median follow-up of 7.15 years. One hundred eighteen patients were under one year of age with a median age of 27 months. There were 67 stage 1, 46 stage 2, 43 stage 3, 99 stage 4, and 25 stage 4S. The association of CD133 expression with relapse and survival were determined through univariate and multivariate analysis. Sensitivity of purified CD133+ neuroblasts isolated from 2 human neuroblastoma cell lines (SKNSH and NB10) to doxorubicin, vincristine and cisplatin was evaluated in vitro, as single agents or in combination with LY294002, a AKT inhibitor. Results: CD133 was expressed in 95 of 280 tumors (33%). There was a significant association between CD133 expression and the following poor prognosis co-variates: age (p<0.0001), INSS stage (p<0.0001), MYCN amplification (p<0.0001). Patients with a CD133+ tumor had a three year event-free and overall survival of 43±5% and 51±5%, respectively, as compared to patients with a CD133- tumor with 88±2% (P<0.001) and 95±2% (p<0.001). In a multivariate model, CD133 expression was independently associated with a decreased overall survival (p = 0.003) in the entire cohort. In vitro purified CD133+ neuroblasts were significantly resistant to chemotherapy as compared to their CD133- cells counterpart, but not in presence of the AKT inhibitor. In vitro treatment of unsorted neuroblasts with the three anticancer drugs significantly enriched the CD133+ subpopulation but not in presence of the AKT inhibitor. CD133plus; significantly expressed higher levels of activated proteins in the AKT pathway than CD133−. Conclusions: CD133 is independently associated with a worse outcome in patents with neuroblastoma. This prognosis factor is associated with in vitro resistance to chemotherapy involving activation of the AKT pathway. No significant financial relationships to disclose.
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Solly, Francoise, Lauren Rigollet, Pascale Flandrin-Gresta, Karine Augeul-Meunier, Emmanuelle Tavernier-Tardy, Nathalie Nadal, Denis Guyotat, and Lydia Campos. "CD133+ Acute Myeloid Leukemia (AML) Cells Exhibit Higher Clonogenic Capacity and Higher Levels of pAKT and Bcl-2 Proteins Than Their Negative Counterpart." Blood 116, no. 21 (November 19, 2010): 1721. http://dx.doi.org/10.1182/blood.v116.21.1721.1721.
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Abstract Abstract 1721 Introduction: CD133 is a transmembrane protein expressed by hematopoietic stem cells and other cell types, whose physiological functions remain unknown. To determine its potential prognostic value in AML, we analyzed its expression on blasts from 76 patients at diagnosis. Moreover, since leukemic stem cells play a critical role in the resistance to chemotherapeutic drugs and may be responsible for relapse, we compared the growth potential and activated cellular pathways of CD133+ and CD133- cells from 20 AML patients. Methods: First, bone marrow samples were collected at diagnosis from 76 AML patients (median age: 65, range: 1–84). CD133 expression was evaluated on blasts cells and CD34+ cells using 6-color flow cytometry (FC) and the monoclonal antibody AC133. The mean fluorescence intensity ratio (MFIR) was calculated by dividing the MFI of CD133 by the MFI of its isotypic control. Second, purified CD34+, CD34+CD133+ and CD34+CD133- cells were isolated from 20 AML bone marrows using the magnetic separation system Minimacs (Miltenyi Biotec). These fractions were submitted to an in vitro colony forming assay during 14 days. Finally, the level of expression of survival proteins involved in the PI3K/AKT, Mitogen-Activated Protein Kinase (MAPK) and Bcl-2 pathways, as well as CXCR4 and Focal Adhesion Kinase (FAK) migration proteins, was analyzed by FC in these fractions. Results: The level of CD133 expression on blasts cells was significantly different between AML patients with favorable (n=12), intermediate (n=38) and unfavorable karyotypes (n=23) (p=0.007). In particular, it was significantly higher in patients with unfavorable karyotype than in patients with intermediate karyotype (p=0.032) or favorable karyotype (p=0.005). Moreover, when considering NPM1 and FLT3 mutation status in patients with intermediate karyotype, the level of CD133 expression was significantly higher in patients with an intermediate molecular profile than in patients with a favorable molecular profile (p=0.004). Most interestingly, we showed that the level of CD133 expression has an impact on overall survival in multivariate analysis, independently of leukocytosis, karyotype and achievement of complete remission after induction therapy (p=0.04). Second, in 20 patients, we found that AML progenitor cells (AML CFU) were present in all sorted fractions, but the CD34+CD133+ fraction gave rise to larger and more numerous colonies (74.9±39.6) than the CD34+CD133- fraction (11,25±6). Moreover, the CD34+CD133+ fraction was the only one able to form secondary colonies (52.1±31.8). Finally, we found that the expression of PI3K (mean percentage of positive cells: 78±20.1), pAKT (80±19.8), pERK (80.1±19), CXCR4 (71.6±22.7), pFAK (81.2±19.8), Bcl-2 (72.9±26.1), Bcl-xL (45.7±24.8), and pBad (63.9±36.1) was significantly upregulated in CD34+CD133+ cells compared to CD34+CD133- cells, whereas Bax was downregulated. Discussion: CD133 is known to be expressed in hematopoietic progenitors, but its role in the resistance to chemotherapy is not well studied. In our work, the level of expression of CD133 on AML blasts appeared as an independent immunophenotypic prognostic factor, encouraging its further evaluation in a larger number of cases. We also showed that CD133+ cells have greater replicative properties than CD133- cells, and exhibit activation of various signaling pathways. Since CD133+ cells might escape from apoptosis through activation of PI3K/AKT and ERK, these proteins could represent potential therapeutic targets. In conclusion, our results revealed that CD133+ cells exhibit more aggressive behavior than CD133- ones, and that CD133+ AML progenitors might contribute to resistance to chemotherapy through preferential activation of PI3K/AKT, MAPK and Bcl-2 survival response. Disclosures: No relevant conflicts of interest to declare.
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Abd El Atti, Rasha M., and Riham M. Abu-Zeid. "CD133 and FGF7." Egyptian Journal of Pathology 32, no. 1 (July 2012): 142–49. http://dx.doi.org/10.1097/01.xej.0000417559.72626.ac.
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Lisyaniy, N. I., D. N. Stanetskaya, A. N. Lisyaniy, and L. N. Belskaya. "CONTENT OF STEM TUMOR CD133+ CELLS IN BRAIN NEOPLASMS OF DIFFERENT HISTOLOGICAL TYPE." Experimental Oncology 39, no. 3 (September 22, 2017): 219–23. http://dx.doi.org/10.31768/2312-8852.2017.39(3):219-223.
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Today, there are conflicting data on the content of cancer stem cells responsible for recurrence and resistance to chemotherapy in tumors of human brain. The aim of the study was to analyze the content of CD133+ cells in different brain tumors by immunofluorescence assay and immunohistochemical method. Materials and Methods: The samples of different brain tumors removed during neurosurgical operations were studied for CD133 expression. Results: Immunofluorescence assay of tumor imprints revealed CD133+ cells in 40–85% of tumors regardless of histological type. In malignant tumors, the count of CD133+ cells was higher than in benign tumors. Immunohistochemical method used for detection of CD133+ cells was less sensitive than immunofluorescence technique. The number of CD133+ cells may vary even in tumors of the same histological type. In 20–30% of malignant tumors (glioblastomas, medulloblastomas), the content of CD133+ cells was very low or not detected at all. Conclusions: In tumors of the brain of different genesis and degree of anaplasia CD133+ cells are found out. In malignant tumors (glioblastomas and medulloblastomas), CD133+ cells are much more frequently detected than in benign brain tumors. The content of CD133+ cells in brain tumors is highly variable being small and some malignant tumors, indicating low predictive and diagnostic value of cancer stem cell content in clinical practice.
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Goto, Shinji, Tsuyoshi Kawabata, and Tao-Sheng Li. "Enhanced Expression of ABCB1 and Nrf2 in CD133-Positive Cancer Stem Cells Associates with Doxorubicin Resistance." Stem Cells International 2020 (August 12, 2020): 1–13. http://dx.doi.org/10.1155/2020/8868849.
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The precise mechanism about drug resistance of cancer stem cells (CSCs) has not yet been completely understood. Based on the expression of CD44 and CD133, two well-recognized cell surface markers for CSC identification, we tried to separate HCT8 colorectal cancer cells into different subpopulations and then investigated how the expression of CD44 and CD133 associated with doxorubicin (DXR) resistance. Interestingly, DXR resistance was observed in CD44+CD133+ (P<0.01vs. all other subpopulations), but not in CD44+CD133- cells. CD44+CD133+ cells also showed an enhanced expression of ABCB1 and drug efflux ability (P<0.001vs. all other subpopulations), but verapamil, an inhibitor of ABCB1, only partially mitigated the DXR resistance. Independent on the accumulation of DXR, lower level of reactive oxygen species and higher expression of Nrf2 were detected in CD44+CD133+ than CD44+CD133- cells (P<0.05). Unexpectedly, silencing CD133 by siRNA only partially enhanced the cytotoxicity of DXR, but did not obviously change the expression of ABCB1 and the accumulation of DXR in CD44+CD133+ cells. Complex mechanisms, including drug excretion and redox regulation, are likely involved in the DXR resistance of CD133-positive cells, suggesting the difficulty of drug resistance problem in cancer chemotherapy.
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Han, Susu, Tao Huang, Xing Wu, Xiyu Wang, Shanshan Liu, Wei Yang, Qi Shi, Hongjia Li, and Fenggang Hou. "Prognostic Value of CD133 and SOX2 in Advanced Cancer." Journal of Oncology 2019 (January 1, 2019): 1–12. http://dx.doi.org/10.1155/2019/3905817.
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Background. The prognostic value of CD133 and SOX2 expression in advanced cancer remains unclear. This study was first conducted to investigate the association between CD133 or SOX2 positivity and clinical outcomes for advanced cancer patients.Methods. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated to evaluate the correlation between CD133 or SOX2 positivity and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), cancer-specific survival (CSS), or recurrence-free survival (RFS) from multivariable analysis. Trial sequential analysis (TSA) was also performed.Results. 13 studies with 1358 cases (CD133) and five studies with 433 cases (SOX2) were identified. CD133 positivity was correlated with worse CSS and OS, but there was no correlation between CD133 positivity and DFS. SOX2 positivity was associated with poor DFS and RFS but was not linked to PFS. Stratified analysis by study source showed that only CD133 positivity can decrease OS for Chinese patients. Stratified analysis by treatment regimens indicated that CD133 positivity was linked to poor OS in patients treated with adjuvant therapy. TSA showed that additional studies were necessary.Conclusions. CD133 and SOX2 might be associated with worse prognosis in advanced cancer. More prospective studies are strongly needed.Impact. CD133 and SOX2 may be promising targeted molecular therapy for advanced cancer patients.
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Leung, Carmen O. N., Wen Deng, Tian-Min Ye, Hextan Y. S. Ngan, Sai Wah Tsao, Annie N. Y. Cheung, Niu Ziru, Dominic C. K. Yuen, Ronald T. K. Pang, and William S. B. Yeung. "MicroRNA-135a-induced formation of CD133+ subpopulation with cancer stem cell properties in cervical cancer." Carcinogenesis 41, no. 11 (May 16, 2020): 1592–604. http://dx.doi.org/10.1093/carcin/bgaa025.
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Abstract Cancer stem cells (CSCs) play significant roles in tumor initiation. MicroRNA-135a (miR-135a) induced the formation of a CD133+ subpopulation from a human papillomavirus-immortalized cervical epithelial cell line. Compared with the CD133− cells, the CD133+ cells expressed higher levels of miR-135a and OCT4, exhibited significantly higher tumorsphere forming capacity and the time required for tumorsphere formation was shortened in the second generation. Serum induction suppressed the expression of CD133, OCT4 and miR-135a, but increased expression of involucrin in the miR-135a-induced CD133+ cells. The miR-135a-induced CD133+ cells were tumorigenic in a limiting dilution approach in vivo. The cells expressed significantly higher level of active β-catenin and OCT4 than the CD133− counterpart. Wnt3a enhanced the expression of OCT4 and CD133 in cervical cancer cells but failed to enhance CD133 transcription in normal cervical cells. Wnt3a stimulation also increased tumorsphere size and self-renewal of miR-135a-induced CD133+ subpopulation. Wnt/β-catenin inhibition suppressed tumorsphere formation while Wnt3a partially nullified the inhibitory effect. Taken together, miR-135a induced the formation of a subpopulation of cells with CSC properties both in vitro and in vivo and the Wnt/β-catenin signaling pathway is essential to maintain its tumorigenicity.
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Baljevic, Muhamed, Sergey V. Shmelkov, Daniel J. Nolan, Andrea T. Hooper, Adilia Hormigo, Rajiv Iyer, Philip H. Gutin, and Shahin Rafii. "Endothelial Progenitor Cell Marker CD133 Identifies Tumor Endothelium." Blood 112, no. 11 (November 16, 2008): 5449. http://dx.doi.org/10.1182/blood.v112.11.5449.5449.
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Abstract CD133, a pentaspan surface antigen, is considered a marker of tissue-specific stem cells, including hematopoietic stem cells and endothelial progenitors. We and others have previously shown that CD133 expression is high on endothelial progenitor cells; that it is downregulated during their differentiation and that it is not found on mature endothelium. In addition, CD133+ cells in brain tumors were shown to exhibit features of cancer stem cells. Recent report showed that CD133+ tumor cells are located in perivascular niches in astrocytomas and glioblastomas. It was also demonstrated that in glioblastomas, CD133+ cancer stem cells are tightly associated with tumor vasculature and that signals from endothelial cells are the key factors in self-renewal and proliferation of cancer stem cells. However, the contribution of CD133+ endothelial progenitor cells to tumor angiogenesis remains unknown. We sought to investigate the role of CD133+ cells in human brain tumors and their relation to endothelial progenitor cells and to the mature endothelium. To this end we examined tumor samples resected from patients with glioblastomas. Histological and immunohistochemical analyses revealed that CD133+ cells in these tumors are predominantly endothelial cells as demonstrated by co-staining with CD31 and CD133. We further analyzed a population of endothelial cells using multicolor flow cytometry analysis and we demonstrated that on average 60% of endothelial cells, as defined by the expression of CD31 and VE-cadherin, also express CD133. However, we also found significant heterogeneity between glioblastomas obtained from different patients. Additionally, CD133 was not expressed on CD45−CD31+ subpopulation in meningiomas. Taken together, we demonstrated that high percentage of endothelial cells in glioblastomas expresses CD133, while CD133 could also be found on other cell types within the tumor. Furthermore, our data suggest that tumor vasculature might be enriched with bone marrow derived hemangiogenic progenitors.
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Gong, Lei, Zhuqingqing Cui, Xin Yu, Yuhua Wei, Jirun Peng, and Xisheng Leng. "Hexokinase II in CD133+ and CD133- Hepatoma BEL-7402 Cells." Pathology & Oncology Research 18, no. 2 (September 10, 2011): 377–81. http://dx.doi.org/10.1007/s12253-011-9455-y.
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Mehra, N., M. Penning, J. Maas, N. Van Daal, and E. Voest. "Endothelial progenitor marker CD133 mRNA expression in peripheral blood mononuclear cells predicts outcome of cancer patients." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 10087. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.10087.
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10087 Background: We examined whether expression of CD133, a surface molecule expressed on progenitors of hematopoietic and endothelial lineages, is increased in the peripheral blood mononuclear cells (PBMC’s) of cancer patients. Furthermore we correlated CD133 mRNA expression with tumor prognostication factors and overall survival. Methods: PBMC’s were isolated from the blood of 130 advanced cancer patients (43 renal cell carcinoma, 27 colorectal cancer, 34 prostate cancer, 27 head and neck cancer). Clinicopathological parameters were obtained. Median follow-up time was 16 months after inclusion (range 3–33 months). For the quantification of CD133 mRNA we used a real-time detection and quantification method based on nucleic acid sequence-based amplification (NASBA). Also U1A DNA was quantified as internal control for input and isolation. CD133 mRNA copy numbers were expressed as copies per 10.000 cells, as determined by U1A DNA. Results: Patients with metastasized disease have a significant increase in CD133 mRNA as compared to patients without metastasis. This increase is strongest in patients with bone metastasis. Subgroup analysis in patients with bone involvement show that CD133 mRNA also correlates with PSA (n=34)and inversely with hemoglobin (n=50). CD133 mRNA expression is an independent predictor for overall survival in Cox’s multivariate analysis (variables in the model included age, hemoglobin, metastasis, previous treatment and CD133 as categorical variable). A CD133 mRNA cut-off value was established by Receiver Operating Characteristic analysis of CD133 expression in relationship to survival (sensitivity 64% and specificity 71%). Cancer patients with more than 200 copies of CD133 mRNA, demonstrate a decreased survival compared to patients with lower CD133 expression (median survival 8 and 15.4 months, respectively). In patients with bone metastasis the median survival of high and low expressers is 6.3 months and 21.9 months, respectively. Conclusions: mRNA expression of stem-cell marker CD133 is increased in cancer patients with metastasized disease and an independent prognostic factor for overall survival. Increased CD133 mRNA expression may reflect an activated angiogenic state in these cancer patients. [Table: see text]
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Takahashi, Masaya, Yoshikazu Matsuoka, Keisuke Sumide, Ryusuke Nakatsuka, Tatsuya Fujioka, Hirao Kohno, Yutaka Sasaki, et al. "CD133 Is a Positive Marker Of Human Cord Blood-Derived CD34-Negative Hematopoietic Stem Cells." Blood 122, no. 21 (November 15, 2013): 1177. http://dx.doi.org/10.1182/blood.v122.21.1177.1177.
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Abstract Background We have previously identified very primitive human cord blood (CB)-derived CD34-negative (CD34-) severe combined immunodeficiency (SCID)- repopulating cells (SRCs) using the intra-bone marrow injection (IBMI) method (Blood 2003:101;2924). A series of our studies suggests that the identified CD34- SRCs are a distinct class of primitive hematopoietic stem cell (HSC) and that they are at the apex of human HSC hierarchy. Recently, we developed a high-resolution purification method for primitive CD34- SRCs using 18 lineage (Lin)-specific antibodies, which can enrich CD34- SRC at 1/1,000 level (Exp Hematol 2011: 39:203). In the present study, we tried to identify the positive marker of CD34- SRCs in order to further purify and characterize the CD34- SRCs (HSCs). Materials and Methods First, we extensively analyzed candidate positive markers, including known HSC markers and various adhesion molecules by FACS using highly purified CB-derived 18Lin-CD34+/- cells. Finally, we identified CD133 as a positive marker of human CB-derived CD34- SRCs. Then, CB-derived 18Lin- CD34+/-CD133+/- cells were sorted by FACS, and hematopoietic stem/progenitor cell (HSPC) capacities of these four fractions of cells were extensively investigated. HSPC capacities were evaluated using (1) colony-forming cell (CFC) assays, (2) measurement of maintenance/production of CD34+ cell capacities in co-cultures with human bone marrow-derived mesenchymal stromal cells (BM-MSCs) (Blood 2010:24:162), (3) SRC activities using NOG mice, (4) limiting dilution analyses (LDA) to determine the SRC frequency in the 18Lin-CD34-CD133+ fractions, and (5) comparison of gene expression profiles between 18Lin-CD34+/-CD133+/- cells by real-time RT-PCR. Results Seventy-five percent of 18Lin-CD34+ and 13.5% of 18Lin-CD34- cells highly expressed CD133. In the CFC assays, the plating efficiencies of 18Lin-CD34+CD133+, CD34+CD133-, CD34-CD133+ and CD34-CD133- cells were 57%, 65%, 39% and 19%, respectively. Interestingly, most of 18Lin-CD34-CD133+/- cells formed erythroid-bursts (71% and 73%) and erythro/megakaryocytes-containing mixed colonies (25% and 27%). On the contrary, they formed few granulocyte/macrophage colonies (4.2% and 0%). Then, we co-cultured these four fractions of cells with human BM-MSCs. One thousand of 18Lin-CD34+/-CD133+/- cells were seeded into each well and cells were co-cultured for 7 days in the presence of SCF+TPO+FL+IL-3+IL-6 +G-CSF. Both the 18Lin-CD34-CD133+/- cells produced CD34+ cells. However, the percentage and absolute number of CD34+ cells produced from 18Lin-CD34-CD133+ cells (31.7 % and 3.2 x 104 cells) were greater than those of 18Lin-CD34-CD133- cells (13.2 % and 0.4 x 104 cells). In addition, both the 18Lin-CD34- CD133+/- cells generated higher percentages (13.5 % and 11.5%) of CD41+ cells compared to those of the 18Lin- CD34+CD133+/- (1.8% and 4.2%) cells. Collectively, 18Lin-CD34+/-CD133+/- cells showed different in vitro lineage differentiation potentials. Then, these four fractions of cells were transplanted into NOG mice by IBMI. We performed primary and secondary transplantations for up to 36 weeks. In the results, all of the mice received 18Lin-CD34+CD133+ cells (n = 5) or 18Lin-CD34-CD133+ cells (n = 9) showed primary and secondary human CD45+ cell repopulations. However, neither 18Lin-CD34+CD133- cells nor 18Lin-CD34-CD133- cells showed human cell repopulations (n = 6 in each group). These results clearly demonstrated that the CD133 expression clearly segregated SRC activities in the 18Lin-CD34+/- cells. Moreover, LDA demonstrated that the frequency of SRCs in the 18Lin-CD34-CD133+ fraction was 1/142. Interestingly, HSC self-renewal maintenance genes, such as Notch1, HoxB4, HoxA9, and Bmi-1, were highly expressed in both 18Lin-CD34+/-CD133+ cells. Conclusion These results clearly demonstrated that CD133 is a positive marker of human CB-derived CD34- SRCs (HSCs). Furthermore, CD133 segregated SRC activities of 18Lin-CD34- as well as 18Lin-CD34+ cells in its positive fractions. More importantly, these findings suggest that number of CD133+ cells in cord blood units is a more appropriate marker to detect/predict HSC potentials in cord blood stem cell transplantation in comparison to currently used CD34+ cell numbers. Disclosures: No relevant conflicts of interest to declare.
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Finney, Marcie R., Matthew Joseph, Daniel G. Winter, Omar Masari, Margaret Kozik, Laura R. Fanning, Ying Huang, et al. "In Vitro Characteristics of Umbilical Cord Blood Derived Mononuclear Cells, CD133+ Cells and Endothelial Generating Cells and Their Effectiveness In Vivo in Mediating Neovascularization in a Murine Model of Hind-Limb Ischemia." Blood 104, no. 11 (November 16, 2004): 3922. http://dx.doi.org/10.1182/blood.v104.11.3922.3922.
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Abstract Recent reports have studied the use of various cell populations from bone marrow, peripheral blood and umbilical cord blood (UCB) in mediating therapeutic angiogenesis. We sought to investigate the surface phenotype of UCB derived-mononuclear cells (MNC), CD133+ cells and endothelial generating cells (EGC) using flow cytometry and in vitro functional migration studies. A murine hind-limb injury ischemia model was used to assess in vivo efficacy of the different cell populations. METHODS: Mononuclear cells were isolated by density centrifugation. CD133+ cells were isolated from UCB MNC by magnetic separation (Miltenyi). EGC were derived by adherence of the CD133- cells overnight on fibronectin-coated tissue culture plates in EGM2 media (Clonetics). Surface phenotype was determined by flow cytometry for stem cell markers, CD133 and CD34, stromal markers CD73 and CD105, KDR (VEGFR2), and the receptor for SDF-1, CXCR4. Modified Boyden chambers (Neuroprobe) were used to observe chemotactic migration of MNC, CD133, EGC or the combination of CD133 and EGC towards SDF-1 (100ng/mL) compared to control wells containing media alone. In the in vivo studies, 40 NOD.SCID mice underwent right femoral artery ligation. Mice were randomized into five study groups: Cytokines (EGM2 media, n=5), MNC (n=5), CD133 (n=5), EGC (n=7), or CD133 and EGC (1:2 ratio, n=4). Laser Doppler blood flow measurements were recorded weekly for four weeks and the ratio of ischemic/non-ischemic leg was calculated. At day 28, tissue samples were harvested for histological studies. RESULTS: Surface phenotype by flow cytometry showed an average purity of 78.67% +/− 2.41% for the selection of CD133. In addition, an enhancement of the expression of CXCR4 was seen in the EGC population after overnight exposure to fibronectin and EGM2 media. Surface Phenotype of UCB MNC, CD133 and EGC MNC CD133 EGC CD34 4.03 87.42 3.40 CD133 3.19 78.67 5.06 CD73 5.07 N/A 7.15 CD105 6.74 22.74 33.78 KDR 7.14 3.59 37.65 CXCR4 28.54 8.66 64.57 The in vitro functional migration assays showed increased migration of MNC, EGC, and CD133 with EGC to SDF-1, where the CD133 cells alone showed no increased migration compared to control media. In the in vivo murine model of hind-limb ischemia, the blood flow ratio of ischemic/non-ischemic limb was used to estimate the rate of blood flow recovery. The rates of blood flow recovery were 0.0198 (CD133), 0.02 (CD133 and EGC), 0.0163 (MNC), 0.016 (EGC) and 0.0123 (cytokines). The rates were significantly different between CD133 and cytokines (p=0.011) and between CD133 and EGC compared to cytokines (p=0.011). The difference between MNC and cytokines (p=0.156) and between EGC and cytokines (p=0.176) was not significant. Histological studies are ongoing. CONCLUSION: Surface phenotype of UCB-derived MNC, CD133, and EGC were compared by flow cytometry. The in vitro functional chemotactic capacity toward SDF-1 of these cell types was determined by migration assays. The infusion of CD133+ or the combination of CD133 and EGC cells augmented the rate of blood flow recovery in the in vivo murine hind-limb model of ischemia compared to the crude MNC prep or the ECG alone.
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Pelagiadis, Iordanis, Helen Dimitriou, and Maria Kalmanti. "CD133 Immunomagnetic Separation: How Effective Is the Method for CD133+ Cell Isolation from Umbilical Cord Blood?." Blood 110, no. 11 (November 16, 2007): 4917. http://dx.doi.org/10.1182/blood.v110.11.4917.4917.
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Abstract Umbilical cord blood (UCB) is a rich source of stem cells. Characterisation of stem cell subpopulations residing in UCB requires specific stem cell markers and reliable and reproducible protocols. We assessed the feasibility of CD133 positive cells’ isolation using immunomagnetic cell sorting protocols. The separation was based on the manufacturer’s instructions (Myltenyi Biotec). We compared these results with the corresponding ones of CD34 isolation. Two additional protocols were also applied to increase the efficiency of the CD133+ yield. The first one included an extra-labeling of the selected CD133 subpopulation from the first column with CD133 microbeads before their application to the second column. The second protocol was an indirect labelling procedure, using CD133-PE monoclonal antibody and either anti-PE microbeads or goat anti-mouse IgG microbeads as well as a combination of them. The CD133 isolation was performed in 18 UCB samples, while the CD34 in 17 samples. The volume of the samples used for CD133+ isolation was 38.5 ± 2.1ml and the respective one for the CD34+ protocol was 40.4 ± 2.8ml. The mononuclear cell fraction had 1.29 ± 0.16 x108 cells and 0.53 ± 0.06% of them expressed CD133. The corresponding values for samples used for CD34 isolation were 2.8 ± 0.3 x108 mononuclear cells and 1.64 ± 0.15% CD34. Following the manufacturer’s instructions for CD133 isolation, the number of cells obtained was 21.33 ± 3.3x104 (median 18 x104) and CD133 expression ranged from 10–85% (median=60%). Concerning the CD34 isolation, the number of cells obtained was 54.3 ± 2.1x104 and 93 ± 1.25% expressed CD34. Applying the extra-labeling method, the number of cells obtained was 8±4 x104 and these cells were CD133+ at a percentage of 32.2±4.1%. Applying the indirect immunomagnetic separation the results were as follow: using anti-PE microbeads only, 3 ± 3 x104 cells were retrieved and the percentage of CD133+ was 13.8±9.7. With the use of goat anti-mouse IgG microbeads the cell number obtained was 13±1 x104 of which CD133+ were just 2.0± 2%. In the combination method, the cells initially isolated with anti-PE microbeads and subsequently with goat anti-mouse IgG microbeads were 20 x 104, of which only 18.5% were CD133+. Finally, labeling the cells initially with anti-PE microbeads and consecutively with goat anti-mouse IgG microbeads followed by column isolation yielded 16x104 cells and 19.1% CD133 positive. In conclusion CD34 isolation by the immunomagnetic method results in highly pure CD34+ population confirming the reliability and reproducibility of the method. On the other hand, with the currently available CD133 isolation kit, efficient and reproducible yield of pure CD133 positive population is not feasible.
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Pötgens, Andy J. G., Ulrike Schmitz, Peter Kaufmann, and Hans-Georg Frank. "Monoclonal Antibody CD133–2 (AC141) Against Hematopoietic Stem Cell Antigen CD133 Shows Crossreactivity with Cytokeratin 18." Journal of Histochemistry & Cytochemistry 50, no. 8 (August 2002): 1131–34. http://dx.doi.org/10.1177/002215540205000814.
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CD133 is an antigen expressed on hematopoietic progenitor cells and on some epithelial cells. We previously reported that a commercially available antibody against CD133, CD133–2/AC141, also reacted with an intracellular protein in placental trophoblasts. Here we show by 2D electrophoresis and mass spectroscopy that this reactivity is with cytokeratin 18, a cytokeratin present in most simple epithelia. Immunohistochemistry (IHC) with CD133–2/AC141 on a trophoblast cell line displayed a staining pattern typical for the cytoskeleton. Cryostat sections of stratified epithelia lacking cytokeratin 18 did not react with CD133–2/AC141. In conclusion, care must be taken not to misinterpret staining patterns using CD133–2/AC141 in IHC.
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Zhou, Xuefeng, Haidan Chen, Qilong Wang, Li Zhang, and Jinping Zhao. "Knockdown of Mgat5 inhibits CD133+ human pulmonary adenocarcinoma cell growth in vitro and in vivo." Clinical & Investigative Medicine 34, no. 3 (June 1, 2011): 155. http://dx.doi.org/10.25011/cim.v34i3.15188.
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Purpose: In spite of many therapeutic advances, the prognosis of lung cancer remains poor. Therefore, understanding the molecular mechanisms underlying cancer progression, invasion and metastasis is needed. Accumulating evidence indicate that N-acetylglucosaminyltransferase V (Mgat5 or GnT-V) is involved in cancer develpement. The purpose of this study was to characterize the expression and function of Mgat5 in CD133+ pulmonary adenocarcinoma cells. Methods: CD133+ pulmonary adenocarcinoma cells were separated by magnetic activated cell sorting (MACS) from excised pulmonary adenocarcinoma specimens from 10 patients. Expression of Mgat5 in CD133+ cells was detected by fluorescent quantitative RT-PCR (FQRT-PCR) and Western blot. Subsequently, CD133+ cells were transfected with specific siRNA of Mgat5 to evaluate the effects of Mgat5 inhibition on cancer cell growth in vivo and in vitro. Results: Expression of Mgat5 was 1.2-fold and 1.4-fold higher in CD133+cells than in CD133– cells detected by FQRT-PCR and Western Blot, respectively (p < 0.05). The L-PHA binding assay also showed higher reactivity in CD133+ cells than in CD133- cells. In addition, Mgat5-specific siRNA efficiently knocked down the expression of Mgat5 in CD133+ cells. Interestingly, downregulation of Mgat5 resulted in significant inhibition of cancer cell growth in vitro and in vivo. Conclusion: Mgat5 is expressed at a relatively high level in CD133+ lung adenocarcinoma cells, and knockdown of Mgat5 in CD133+ cells inhibits cancer cell growth both in vitro and in vivo. These findings suggest Mgat5 may play an important role during oncogenesis, identifying a potential therapeutic target for pulmonary adenocarcinoma.
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Vora, P., C. Venugopal, C. Choksi, M. Qazi, J. Adams, M. London, M. Subapanditha, et al. "PS2 - 172 Preclinical Validation of a Novel CD33/CD3 Bispecific T-Cell Engager (BiTE) Antibody to Target Patient-Derived Glioblastoma Cells." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 43, S4 (October 2016): S13—S14. http://dx.doi.org/10.1017/cjn.2016.367.
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Glioblastoma (GBM), an aggressive primary adult brain tumor, is feared for its near uniformly fatal prognosis. Despite the use of aggressive treatment including surgical resection, radiotherapy and chemotherapy, the outcome of patients with GBM has failed to improve significantly. Numerous studies have implicated CD133+GBM subpopulation as driver of chemo- and radio-resistance. CD133 expression correlates with disease progression, recurrence, and poor overall survival of GBM patients. Here, we describe the preclinical evaluation of a recombinant CD133xCD3 bispecific T-cell engager (BiTE) antibody that redirects human polyclonal T cells to CD133+GBM cells, inducing very potent anti-tumor response. CD133-specific BiTE was constructed; with one arm recognizing the tumor antigen (CD133) while the second is specific to CD3 antigen. Using CD133high and CD133low primary GBM lines, we validated the binding of BiTEs to CD133+GBMs and CD3+T cells. In order to test the ability of BiTEs to functionally elicit CD133-specific cytotoxic responses in vitro, we performed killing assays. We observed CD133-specific BiTE mediated T cell activation and redirection to kill CD133-expressing GBM cells in a co-culture of T cells and GBM cells. The killing was more efficient in CD133high GBMs compared to CD133low GBMs, validating its specificity to target CD133+BTICs. Treatment with BiTEs yielded significant reductions in brain tumor burden in vivo. These data offers compelling evidence that BiTE-mediated cytotoxicity against treatment-resistant CD133+GBMs could provide a very potent, specific and can be a novel therapeutic strategy for GBM patients.
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You, Changxuan, Yu Yang, and Beili Gao. "Imperatorin Targets MCL-1 to Sensitize CD133+ Lung Cancer Cells to γδ-T Cell-Mediated Cytotoxicity." Cellular Physiology and Biochemistry 49, no. 1 (2018): 235–44. http://dx.doi.org/10.1159/000492874.
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Background/Aims: CD133+ cancer cells display low sensitivity to anti-cancer treatment; thus, combination treatment with adjuvant drugs is required to improve the efficiency of cancer therapy. The aim of this study was to explore the effect of imperatorin, a linear furanocoumarin compound, on γδ T cell-mediated cytotoxicity against CD133+ lung cancer cells. Methods: CD133+ and CD133- subgroups from A549 and PC9 lung cancer cells were sorted by using flow cytometry. The cytotoxicity of γδ T cells against cancer cells was evaluated by measuring lactate dehydrogenase release. The concentration of tumor necrosis factor-related apoptosis-inducing ligand in the co-culture system was determined by using an enzyme-linked immunosorbent assay. Mitochondrial membrane potential, expression of death receptor 4 (DR4) and DR5 on the cell surface, and rate of apoptosis were measured by flow cytometry. Cytochrome c release and cellular protein expression were detected by western blot analysis. Results: Compared with CD133- cells, CD133+ cells were resistant to γδ T cell-mediated cytotoxicity. However, imperatorin significantly increased the sensitivity of CD133+ lung cancer cells to γδ T cell treatment in vitro and in vivo. Mechanically, we found that myeloid cell leukemia 1 (MCL-1), an important anti-apoptotic protein belonging to the Bcl-2 family, was overexpressed in CD133+ A549 and PC9 cells compared to their corresponding CD133- cells. Co-treatment with imperatorin and γδ T cells suppressed the expression of MCL-1, and thus promoted the mitochondrial apoptosis mediated by γδ T cells in CD133+ A549 and PC9 lung cancer cells. Conclusion: Up-regulated MCL-1 in CD133+ lung cancer cells is responsible for their resistance to γδ T cells. Furthermore, the combination of γδ T cells with imperatorin sensitized CD133+ lung cancer cells to γδ T cell-mediated cytotoxicity by targeting MCL-1.
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Inoue, Y., K. Tanaka, S. Saigusa, T. Yokoe, H. Yasuda, Y. Toiyama, C. Miki, H. Yanagi, and M. Kusunoki. "Evaultion of CD133, VEGF, or EGFR as predictive markers of distant recurrence after preoperative chemoradiotherapy in rectal cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 4050. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.4050.
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4050 Background: CD133 has been postulated to be a colon cancer stem cells (CSCs) marker. Recent investigations suggest that CSCs might contribute to cancer recurrence and resistance to conventional therapies. This study aimed to evaluate the role of CD133 in residual cancer cells after chemoradiotherapy (CRT) for rectal cancer. Methods: Forty patients with rectal cancer underwent CRT followed by surgery. Total RNAs of rectal cancer cells before (n=30) and after (n=40) CRT were isolated. Residual cancer cells after CRT were collected from formalin-fixed paraffin-embedded (FFPE) specimens using microdissection. Intratumoral CD133, vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) were measured using real-time reverse transcription polymerase chain reaction. Immunohistochemical staining of CD133 after CRT was also investigated. Results: CD133 in residual cancer cells was higher than in stromal cells on post-CRT specimens (p<0.0001). CD133 was increased in post-CRT specimens (p=0.0184), while VEGF and EGFR were decreased during CRT (p<0.0001 and p=0.0002, respectively). There were positive correlations between CD133 and VEGF (p=0.0392) or EGFR (p<0.0001) in pre-CRT specimens. Any correlations were not found in post-CRT specimens. Patients who developed distant recurrence had a higher post-CRT CD133 compared with those patients without recurrence (p=0.0136). Elevated post-CRT CD133 was associated with poor disease free survival (p=0.0168). Immunohistochemically, cytoplasmic and apical/endoluminal membranous CD133 staining was observed in residual cancer cells after CRT. Conclusions: CD133 in residual cancer cells after CRT may indicate a treatment resistant phenotype in putative CSCs. Elevated CD133 but not VEGF or EGFR on FFPE specimens may be a predictive marker of distant recurrence and poor survival after preoperative CRT in rectal cancer. No significant financial relationships to disclose.
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Schwartz, John D., Francis Dumler, Jason M. Hafron, George D. Wilson, Stacy C. Wolforth, Michele T. Rooney, Wei Li, and Ping L. Zhang. "CD133 Staining Detects Acute Kidney Injury and Differentiates Clear Cell Papillary Renal Cell Carcinoma from Other Renal Tumors." ISRN Biomarkers 2013 (June 2, 2013): 1–8. http://dx.doi.org/10.1155/2013/353598.
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CD133 has recently been characterized as a progenitor cell marker in the kidney. However, the expression of this marker has not been thoroughly investigated in kidney injury and variants of renal tumors for pathology practice. We quantified CD133 expression in kidney biopsies from patients with acute renal failure and compared staining intensity with serum creatinine levels. CD133 expression levels were also evaluated in several subtypes of renal neoplasms. Normal adult renal parenchyma showed CD133 expression in parietal epithelium and in less than 5% of the epithelial cells in proximal and distal nephron tubules. However, CD133 was diffusely upregulated in the injured proximal and distal tubular epithelium and the CD133 expression scores in renal tubules were significantly correlated with serum creatinine levels. Amongst the renal tumors, CD133 was diffusely expressed in clear cell papillary renal cell carcinoma but was only focally present in other types of renal tumors. In summary, CD133 is a useful marker to detect renal tubular injury and to differentiate clear cell papillary renal cell carcinoma from other tumor types.
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Simbulan-Rosenthal, Cynthia M., Yogameenakshi Haribabu, Sahar Vakili, Li-Wei Kuo, Havens Clark, Ryan Dougherty, Ryyan Alobaidi, Bonnie Carney, Peter Sykora, and Dean S. Rosenthal. "Employing CRISPR-Cas9 to Generate CD133 Synthetic Lethal Melanoma Stem Cells." International Journal of Molecular Sciences 23, no. 4 (February 20, 2022): 2333. http://dx.doi.org/10.3390/ijms23042333.
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Malignant melanoma is a lethal skin cancer containing melanoma-initiating cells (MIC) implicated in tumorigenesis, invasion, and drug resistance, and is characterized by the elevated expression of stem cell markers, including CD133. The siRNA knockdown of CD133 enhances apoptosis induced by the MEK inhibitor trametinib in melanoma cells. This study investigates the underlying mechanisms of CD133’s anti-apoptotic activity in patient-derived BAKP and POT cells, harboring difficult-to-treat NRASQ61K and NRASQ61R drivers, after CRISPR-Cas9 CD133 knockout or Dox-inducible expression of CD133. MACS-sorted CD133(+) BAKP cells were conditionally reprogrammed to derive BAKR cells with sustained CD133 expression and MIC features. Compared to BAKP, CD133(+) BAKR exhibit increased cell survival and reduced apoptosis in response to trametinib or the chemotherapeutic dacarbazine (DTIC). CRISPR-Cas9-mediated CD133 knockout in BAKR cells (BAKR-KO) re-sensitized cells to trametinib. CD133 knockout in BAKP and POT cells increased trametinib-induced apoptosis by reducing anti-apoptotic BCL-xL, p-AKT, and p-BAD and increasing pro-apoptotic BAX. Conversely, Dox-induced CD133 expression diminished apoptosis in both trametinib-treated cell lines, coincident with elevated p-AKT, p-BAD, BCL-2, and BCL-xL and decreased activation of BAX and caspases-3 and -9. AKT1/2 siRNA knockdown or inhibition of BCL-2 family members with navitoclax (ABT-263) in BAKP-KO cells further enhanced caspase-mediated apoptotic PARP cleavage. CD133 may therefore activate a survival pathway where (1) increased AKT phosphorylation and activation induces (2) BAD phosphorylation and inactivation, (3) decreases BAX activation, and (4) reduces caspases-3 and -9 activity and caspase-mediated PARP cleavage, leading to apoptosis suppression and drug resistance in melanoma. Targeting nodes of the CD133, AKT, or BCL-2 survival pathways with trametinib highlights the potential for combination therapies for NRAS-mutant melanoma stem cells for the development of more effective treatments for patients with high-risk melanoma.
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Ohtsubo, Shin, Masakazu Ishikawa, Naosuke Kamei, Yasumu Kijima, Osami Suzuki, Toru Sunagawa, Yukihito Higashi, Haruchika Masuda, Takayuki Asahara, and Mitsuo Ochi. "The therapeutic potential of ex vivo expanded CD133+ cells derived from human peripheral blood for peripheral nerve injuries." Journal of Neurosurgery 117, no. 4 (October 2012): 787–94. http://dx.doi.org/10.3171/2012.7.jns111503.
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Object CD133+ cells have the potential to enhance histological and functional recovery from peripheral nerve injury. However, the number of CD133+ cells safely obtained from human peripheral blood is extremely limited. To address this issue, the authors expanded CD133+ cells derived from human peripheral blood using the serum-free expansion culture method and transplanted these ex vivo expanded cells into a model of sciatic nerve defect in rats. The purpose of this study was to determine the potential of ex vivo expanded CD133+ cells to induce or enhance the repair of injured peripheral nerves. Methods Phosphate-buffered saline (PBS group [Group 1]), 105 fresh CD133+ cells (fresh group [Group 2]), 105 ex vivo expanded CD133+ cells (expansion group [Group 3]), or 104 fresh CD133+ cells (low-dose group [Group 4]) embedded in atelocollagen gel were transplanted into a silicone tube that was then used to bridge a 15-mm defect in the sciatic nerve of athymic rats (10 animals per group). At 8 weeks postsurgery, histological and functional evaluations of the regenerated tissues were performed. Results After 1 week of expansion culture, the number of cells increased 9.6 ± 3.3–fold. Based on the fluorescence-activated cell sorting analysis, it was demonstrated that the initial freshly isolated CD133+ cell population contained 93.22% ± 0.30% CD133+ cells and further confirmed that the expanded cells had a purity of 59.02% ± 1.58% CD133+ cells. However, the histologically and functionally regenerated nerves bridging the defects were recognized in all rats in Groups 2 and 3 and in 6 of 10 rats in Group 4. The nerves did not regenerate to bridge the defect in any of the rats in Group 1. Conclusions The authors' results show that ex vivo expanded CD133+ cells derived from human peripheral blood have a therapeutic potential similar to fresh CD133+ cells for peripheral nerve injuries. The ex vivo procedure that can be used to expand CD133+ cells without reducing their function represents a novel method for developing cell therapy for nerve defects in a clinical setting.
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Gemei, Marica, Rosa Di Noto, Peppino Mirabelli, and Luigi Del Vecchio. "Cytometric Profiling of CD133+ Cells in Human Colon Carcinoma Cell Lines Identifies a Common core Phenotype and Cell Type-specific Mosaics." International Journal of Biological Markers 28, no. 3 (July 2013): 267–73. http://dx.doi.org/10.5301/jbm.5000020.
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In colorectal cancer, CD133+ cells from fresh biopsies proved to be more tumorigenic than their CD133– counterparts. Nevertheless, the function of CD133 protein in tumorigenic cells seems only marginal. Moreover, CD133 expression alone is insufficient to isolate true cancer stem cells, since only 1 out of 262 CD133+ cells actually displays stem-cell capacity. Thus, new markers for colorectal cancer stem cells are needed. Here, we show the extensive characterization of CD133+ cells in 5 different colon carcinoma continuous cell lines (HT29, HCT116, Caco2, GEO and LS174T), each representing a different maturation level of colorectal cancer cells. Markers associated with stemness, tumorigenesis and metastatic potential were selected. We identified 6 molecules consistently present on CD133+ cells: CD9, CD29, CD49b, CD59, CD151, and CD326. By contrast, CD24, CD26, CD54, CD66c, CD81, CD90, CD99, CD112, CD164, CD166, and CD200 showed a discontinuous behavior, which led us to identify cell type-specific surface antigen mosaics. Finally, some antigens, e.g. CD227, indicated the possibility of classifying the CD133+ cells into 2 subsets likely exhibiting specific features. This study reports, for the first time, an extended characterization of the CD133+ cells in colon carcinoma cell lines and provides a “dictionary” of antigens to be used in colorectal cancer research.