Academic literature on the topic 'MSC, Tumor Immunology, Mesenchymal Stem Cell'
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Journal articles on the topic "MSC, Tumor Immunology, Mesenchymal Stem Cell"
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Wirths, Stefan, Hans-Joerg Buehring, Lothar Kanz, Joerg T. Hartmann, and Hans-Georg Kopp. "Mesenchymal Stem Cell Differentiation Markers Shared with Soft Tissue Sarcomas." Blood 112, no. 11 (November 16, 2008): 4755. http://dx.doi.org/10.1182/blood.v112.11.4755.4755.
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Abstract Malignant tumors are hypothesized to harbor small populations of self-renewing cancer stem cells. Targeting these cells may be the decisive step to overcome treatment resistance and achieve tumor eradication in cancer patients. Advanced soft tissue sarcomas (STS) are rare tumors with a dismal prognosis and a small number of systemic treatment options. STS may originate from mesenchymal stem cells (MSC); the latter have mainly been isolated from adult bone marrow (BM) as non-hematopoietic, self-renewing cells whose in vitro progeny comprises osteoblasts, chondroblasts, myocytes, and adipocytes. While in vitro expression profiles of MSC have been investigated extensively, the in vivo counterparts of MSC are still hypothetical. To target rare human cell BM populations including MSC, an exclusive antibody panel was developed. The target antigens include platelet-derived growth factor receptor-β (CD140b), HER-2/erbB2 (CD340), the recently described W8B2 antigen as well as several surface antigens identified by novel antibodies. To define the expression pattern of MSC-markers in STS, three STS cell lines were tested for expression of these antigens. In addition, snap-frozen primary STS sections were analyzed by immunohistochemistry using the same antibody panel. All cell lines revealed expression of selected markers including CD340, W8B2, and CD140b. Several MSC markers were restricted to a subpopulation of cells. In addition, leiomyosarcoma cells displayed a different expression pattern as compared to liposarcoma and Ewing’s sarcoma cells. Results of immunohistochemistry analysis of primary leiomyosarcoma tumor samples correlated strongly with expression patterns established by FACS analysis. However, important cytoarchitectural features regarding selected markers were revealed by immunohistochemistry: while primary leiomyosarcomas displayed uniform expression of W7C6, HEK3D6, CD10, and CD318, other markers such as CD34, W5C5, and 57D2 were expressed by tumor endothelia only. Moreover, a population of perivascular tumor cells was found to express the MSC-markers W4A5, W8B2, CD140b, W3D5, and W5C4. Novel MSC-markers are expressed by subpopulations in STS cell lines as well as in primary sarcoma tissue. Further studies on the functional significance of these phenotypical studies are underway and may help to identify novel specific targets recognizing the self-renewing STS-compartment.
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BISWAS, SUBIR, Gunjan Mandal, Sougata Roy Chowdhury, Suman Purohit, Kyle K. Payne, Carmen Maria Anadon Galindo, Arnab Gupta, Xiaoqing Yu, Jose R. Conejo-Garcia, and Arindam Bhattacharyya. "Mesenchymal stem cells educate breast tumor associated macrophages to acquire increased immunosuppressive features." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 135.25. http://dx.doi.org/10.4049/jimmunol.202.supp.135.25.
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Abstract Breast cancer metastasis is known to be extensively promoted by immunosuppression. Here we describe a novel mechanism by which mesenchymal stem cell (MSC)-derived exosomes drive an immunosuppressive program within the breast tumor microenvironment. Initial q-PCR and immunophenotyping of human breast tumor samples, and TCGA data analysis confirmed a positive correlation between infiltrations of MSC and M2 macrophage phenotype, therefore we hypothesized that MSC promote M2 macrophage differentiation in breast tumors. We then performed a series of experiments in vitro and in vivo, and found that MSC-derived exosomes significantly promote differentiation of macrophages into PD-L1 expressing ‘M2-like’ phenotype, while also enhancing malignant progression of breast tumors, in vivo. Additionally, we observed increased invasive potential of tumor cells with higher expression of mesenchymal markers when induced with MSC-derived exosomes. Importantly, our observation of a significantly higher TGF-β production by tumor associated macrophages in exosome-induced tumors, with stronger PD-1 expression by intra-tumoral T cells, suggests TGF-β driven PD-1 upregulation. Blocking of PD-L1 abrogates exosome-induced tumor growth signifying the PD-L1/PD-1 checkpoint pathway is vital to MSC-induced tumor progression. Together, infiltration of MSCs within breast tumors drives the increased invasive potential as well as immune-checkpoint-mediated immunosuppression through inducing PD-L1 expression by tumor associated macrophages and PD-1 expression by T cells. Targeting infiltration of MSCs into the breast tumor therefore is a potential approach to reduce breast tumor metastases and improve efficacy of immunotherapies.
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Ruvolo, Peter, Yihua Qiu, Vivian Ruvolo, Rui-Yu Wang, Zhihong Zeng, Jared Burks, Rongqing Pan, et al. "Role of Mesenchymal Stem Cell Galectin 3 in the AML Tumor Microenvironment." Blood 126, no. 23 (December 3, 2015): 1198. http://dx.doi.org/10.1182/blood.v126.23.1198.1198.
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Abstract Background: Mesenchymal stem cells (MSC) protect acute myeloid leukemia (AML) cells from chemotherapy. Galectin 3 (LGALS3) is a beta-galactoside binding protein that regulates cell adhesion, apoptosis, cell cycle, and mRNA processing. When secreted, LGALS3 can modulate receptor kinase activity, influence cell adhesion, and can suppress immune cells. MSC are a rich source of LGALS3. In the present study we address the role of MSC derived LGALS3 in the leukemia microenvironment. Methods: The expression of LGALS3 and 150 other proteins was examined by reverse phase protein array analysis (RPPA) in AML (N = 106) and healthy donor (N = 71) MSC. To examine the putative role of MSC-derived proteins in therapy resistance, RPPA was used to determine levels of the 151 proteins in MSC obtained at diagnosis and from relapsed/refractory patients relapse. In vitro studies were performed to examine the effects of hypoxia or co-culture with AML cell lines on LGALS3 expression by immunofluorescence (IF) microscopy and immunoblot analysis. MSC containing lentiviral control shRNA or LGALS3 shRNA were used to assess effects of LGALS3 on cell viability, apoptosis, and cell adhesion by flow cytometry assays and effects on survival signaling by immunoblot analysis. Results: LGALS3 levels were found to be higher in AML MSC compared to normal MSC (p = 0.0001). The increase in protein expression was not correlated with gene expression as mRNA levels were similar in AML and normal MSC, suggesting a post-translational mechanism. To identify MSC proteins associated with relapse or refractory status, RPPA was utilized to compare protein expression in MSC from newly diagnosed with those from relapsed and refractory (salvage) patients. RPPA identified LGALS3 as one of only three proteins increased in MSC from relapse/refractory patients. Pearson Correlation of LGALS3 with the other 150 proteins in AML MSC revealed that LGALS3 was negatively correlated with expression of integrin beta 3 and LYN. These 2 proteins were also among the 6 proteins found to have lower expression in salvage as compared to MSC from newly diagnosed patients. LGALS3 positively correlated with 13 proteins including phosphorylated beta-catenin which was also higher in salvage as compared to newly diagnosed AML MSC. . The LGALS3 promoter contains HIF1 alpha response elements. MSC from healthy donors grown in 1% oxygen displayed > 4 fold increase in LGALS3 protein after 24 hours. Hypoxic MSC exhibited a re-localization of LGALS3 from the nucleus to the cytoplasm. LGALS3 activates RAS signaling so hypoxia induced expression and nuclear export of the galectin would be expected to activate diverse survival signaling pathways and would also allow the molecule to be secreted where it could then suppress immune cells. Using in vitro co-culture experiments of MSC with human OCI-AML3 cells to mimic the leukemia microenvironment, LGALS3 levels were induced in MSC suggesting that cross talk from leukemia cells could contribute to the increased LGALS3 levels in MSC cells. The consequences of suppressing LGALS3 in normal MSC were tested using lentivral shRNA. Suppression of LGALS3 resulted in a 2-fold reduction of MYC and S473 phosphorylated AKT, and a 2-fold increase in PPP2R2A (an AKT phosphatase) compared to control shRNA. LGALS3 suppression rendered MSC less adherent to OCI-AML3 cells (~ 50% reduction in MSC with LGALS3 shRNA compared to control shRNA). Conclusions: The data presented here demonstrate that LGALS3 is elevated in AML MSC especially in relapse/refractory samples. Possible mechanisms of up-regulation of LGALS3 in AML MSC may be due to the hypoxic nature of the leukemia microenvironment and/or contact with AML cell. Hypoxia induced nuclear export of the galectin to the cytoplasm could contribute to MSC survival and anti-tumor functions (e.g. suppression of immune cells by secreted galectin). Knock down of LGALS3 in MSC suppresses AKT activation and MYC expression suggesting it has a key role in MSC cell survival. Experiments are underway to determine if MSC derived LGALS3 might impact AML cell homing (as a regulator of cell adhesion) and/or immune surveillance (as a suppressor of T and NK cells). The identification of LGALS3 as an important component of AML MSC suggests that this molecule could be a target in a tumor microenvironment based therapy concept of AML. Disclosures No relevant conflicts of interest to declare.
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Andreeff, Michael, Jennifer Dembinski, Brett M. Hall, Matus Studeny, Xiaoyang Ling, Maria Cabreira-Hansen, A. Kate Sasser, Teresa McQueen, Frederick Lang, and Frank C. Marini. "Mesenchymal Stem Cells Selectively Engraft into Tumor Stroma and Produce Potent Antitumor Proteins In Situ." Blood 108, no. 11 (November 16, 2006): 352. http://dx.doi.org/10.1182/blood.v108.11.352.352.
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Abstract The formation of stroma is essential for tumor growth and involves complex interactions between malignant tumor cells, and non-tumor stromal cells. We have previously demonstrated that mesenchymal stem cells (MSC) integrate into solid tumors as stromal elements (Cancer Res62:3603, 2002; JNCI96:1593, 2004,), suggesting the development of anti-cancer therapies based on the intratumoral production of agents by gene-modified MSC. However, no direct evidence has demonstrated this migration and selective engraftment into the tumor microenvironment. Therefore, we noninvasively visualized MSC using luciferase bioluminescence. MSC were labeled by a fiber modified Ad vector expressing firefly luciferase (AdLux-F/RGD) and these MSC-Lux were injected into normal (healthy) SCID mice or mice bearing established metastatic breast or ovarian tumors. Biodistributed MSC-Lux were imaged utilizing the Xenogen IVIS detection system. In normal mice, human MSC (hMSC) migrated to the lungs where they remained resident for 7–10 days. In animals bearing established metastatic lung tumors, IV injected hMSC again migrated to the lungs. However, in contrast to control mice, the Lux signal remained strong over a 15-day period with only a slight decrease over the first 10 days. After IP injection, hMSC-LUX were detected in the peritoneum, and after 7 days, no hMSC-LUX was detected in normal animals, while strong punctate regions of LUX-activity were observed in ovarian tumors. In contrast to SCID mice injected with hMSC, healthy Balb/C mice injected with Balb/C derived MSC-LUX initially migrated to the lungs and within 2.5 hrs had exited the lungs to remain liver and spleen resident for 5–7 days. When tumor cells were transduced with renilla luciferase constructs, the co-localization and dynamic interactions of firefly luciferase MSC and renilla luciferase tumors could be examined in detail. Mechanisms regulating the MSC-tumor interactions involve TGF-beta, HGF/c-Met, and EGFR and will be discussed. We then examined whether hMSC-producing interferon-beta (IFNb-MSC) could inhibit the growth of metastatic tumors in the lungs of SCID mice. When injected IV (4 doses of 106 MSC/week) into SCID mice bearing pulmonary metastases of carcinomas or melanomas, tumor growth was significantly inhibited as compared to untreated or vector-control MSC controls (p= 0.007), while recombinant IFNb protein (50,000 IU qod) was ineffective (p=0.14). IV injected IFNb-MSC prolonged the survival of mice bearing metastatic breast carcinomas (p=0.001) Intraperitoneal (IP) injections of IFN-MSC into mice carrying ovarian carcinomas resulted in doubling of survival in SKOV-3, and cures in 70% of mice carrying OVAR-3 tumors. MSC injected into the ipsilateral or contralateral carotid artery were found to localize to glioma xenografts in mice and IFNb-MSC significantly (p<0.05) prolonged survival of these mice. These data suggest that systemically administered gene-modified MSC selectively engraft into the tumor microenvironment and remain resident as part of the tumor architecture. MSC-expressing IFN-b inhibit the growth of melanomas, gliomas, metastatic breast and ovarian cancers in vivo and prolong the survival of mice bearing established tumors. Clinical trials are in preparation.
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Tolar, Jakub, Alma J. Nauta, Mark J. Osborn, Angela Panoskaltsis-Mortari, Ron T. McElmurry, Scott Bell, Lily Xia, et al. "Osteosarcoma Derived from Cultured Mesenchymal Stem Cells." Blood 108, no. 11 (November 16, 2006): 2554. http://dx.doi.org/10.1182/blood.v108.11.2554.2554.
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Abstract The beneficial effects of Mesenchymal Stem Cells (MSC) are being tested clinically in attempts to improve hematopoietic engraftment, to treat osteogenesis imperfecta, graft-versus-host disease and autoimmune diseases, and to deliver therapy for malignancies. In early reports, phase I clinical studies have not been associated with toxicities. To study the biodistribution of MSC, we labeled adult murine C57BL/6 MSC with firefly luciferase and DsRed2 fluorescent protein using non-viral Sleeping Beauty transposons, and co-infused labeled MSC with bone marrow into irradiated allogeneic recipients. Using in vivo whole body imaging, luciferase signals were shown to be increased between weeks 3 and 12. Unexpectedly, some mice with the highest luciferase signals died and all surviving mice developed foci of sarcoma in lungs. Two mice also developed sarcomas in their extremities. Infusion of MSC-derived sarcoma cells resulted in malignant lesions in secondary recipients. Common cytogenetic abnormalities were identified in tumor cells isolated from different animals. Mapping of the Sleeping Beauty transposition insertion sites did not identify an obvious transposon-related genetic abnormality. Importantly, the original MSC cultures not labeled with transposons, as well as cultured MSC independently isolated from the bone marrow of both BALB/c and C57BL/6 mice showed cytogenetic aberrations after several passages in vitro. Even though not all MSC cultures formed tumors upon in vivo injection, these data indicate that MSC transformation was neither strain-specific nor a rare event following ex-vivo expansion. Karyotype analyses using fluorescence in situ hybridization with spectral karyotyping (SKY) as well as combined binary ratio labeling of nucleic acid probes (COBRA) showed clonal evolution of transformed MSC suggesting that the critical transformation event(s) occurred before MSC infusion. Collectively, we describe cytogenetic instability of murine MSC isolated in two independent laboratories, their cellular transformation, and potential for sarcoma formation. While the growth characteristics of human and murine MSC are not identical and murine cells are more prone to undergo immortalization and transformation in culture than human cells, our study highlights the importance of quality control measures needed for ongoing and future clinical trials using human MSC.
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Fakiruddin, Kamal Shaik, Moon Nian Lim, Norshariza Nordin, Rozita Rosli, and Syahril Abdullah. "Chemo-Sensitization of CD133+ Cancer Stem Cell Enhances the Effect of Mesenchymal Stem Cell Expressing TRAIL in Non-Small Cell Lung Cancer Cell Lines." Biology 10, no. 11 (October 26, 2021): 1103. http://dx.doi.org/10.3390/biology10111103.
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Pre-clinical studies have demonstrated the efficacy of mesenchymal stem cells (MSCs) expressing tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or MSC-TRAIL against several tumors. However, due to the existence of cancer stem cells (CSCs), some tumors, including non-small cell lung cancer (NSCLC), exhibit TRAIL resistance. This study was designed to evaluate the capacity of using first-line chemotherapies including cisplatin, 5-fluorouracil (5-FU) and vinorelbine to act as a chemo-sensitizer on CD133+ (prominin-1 positive) CSCs derived from NSCLC cell lines (A549, H460 and H2170) for the purpose of MSC-TRAIL-induced inhibition. We showed that MSC-TRAIL was resistant to all three chemotherapies compared to the NSCLC cell lines, suggesting that the chemotherapies had little effect on MSC-TRAIL viability. Pre-treatment using either cisplatin or 5-FU, but not with vinorelbine, was able to increase the efficacy of MSC-TRAIL to kill the TRAIL-resistant A549-derived CSCs. The study also demonstrated that both 5-FU and vinorelbine were an effective chemo-sensitizer, used to increase the anti-tumor effect of MSC-TRAIL against H460- and H2170-derived CSCs. Furthermore, pre-treatment using cisplatin was noted to enhance the effect of MSC-TRAIL in H460-derived CSCs; however, this effect was not detected in the H2170-derived CSCs. These findings suggest that a pre-treatment using certain chemotherapies in NSCLC could enhance the anti-tumor effect of MSC-TRAIL to target the CSCs, and therefore the combination of chemotherapies and MSC-TRAIL may serve as a novel approach for the treatment of NSCLC.
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Giallongo, Cesarina, Nunziatina L. Parrinello, Daniele Tibullo, Claudia Bellofiore, Piera La Cava, Alessandra Romano, Annalisa Chiarenza, et al. "Mesenchymal STEM CELLS Favor Tumor Growth By Generating Granulocyte-like Myeloid Derived Suppressor CELLS in CML Patients." Blood 126, no. 23 (December 3, 2015): 4018. http://dx.doi.org/10.1182/blood.v126.23.4018.4018.
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Abstract INTRODUCTION. The complex interplay between cancer cells and immune system allows neoplastic cells to evade immune surveillance and expand. Recently, our and another group have demonstrated that a subpopulation of myeloid cells, defined as "granulocytic myeloid-derived suppressor cells" (G-MDSC), plays an important role for immune escape in chronic myeloid leukemia (CML) patients by reducing T cell activation. The aim of this study was to evaluate the influence of Mesenchymal stem cells (MSC) on generation of MDSCs by comparing CML MSCs (n=10) with healthy donors (HD) MSC (n=8). METHODS. G-MDSC (CD11b+CD33+CD14-HLADR- cells) were analyzed in peripheral blood (PB) of 20 healthy donors (HD) and 30 CML patients at diagnosis by cytofluorimetric analysis. Immuno-suppressive activity was tested through incubation of G-MDSC with autologous CFSE-labeled T cells and stimulation with phytohaemagglutinin (PHA). Controls included a positive T cell proliferation control (T cells plus PHA) and a negative one (T cells only). After three days, T cell proliferation was analyzed by flow cytometry. For G-MDSC generation, human peripheral blood mononucleated cells (PBMC) from HD were cultured alone and with MSC of CML (n=10) or HD (n=8) (1:100 ratio). After one week, G-MDSC were isolated using anti-CD66b magnetic microbeads and the phenotype was confirmed by cytofluorimetric analysis. Expression of ARG1, NOS2, PTGS2, TNFα, TGFβ, IL6, IL10, IL1β was also evaluated using real time PCR. RESULTS. Percentage of cells with a G-MDSC phenotype was greater in PB obtained from CML patients than HD (82.5±9.6% vs 56,2±5.4%, p<0.0001). G-MDSC were able to inhibit T cell proliferation compared to positive control (25±5% vs 48±7.6%, p=0.0057). To investigate if CML MSC may be involved in G-MDSC generation, we incubated HD PBMC with CML or HD MSC for one week. After magnetic isolation, we found that only CML MSC-educated G-MDSC acquired immune-suppressive ability, inhibiting T cell proliferation compared to G-MDSCs control (isolated from PBMC cultured in medium alone) (32±12% vs 63±5.9%, p=0.003). On the contrary, HD MSC-educated G-MDSC did not show any suppressive effect. We also found that CML MSC-educated G-MDSC expressed higher level of the following immune modulatory factors: TNFα (20.8±19.3, p=0.006), IL1β (47.3±25.2, p=0.001), PTGS2 (20.7±10.9, p=0.002) and IL6 (33.8±13.9, p=0.004) compared to HD MSC-educated G-MDSCs (arbitrarily 2-ΔΔCt value: 1). MSC WE also observed ane an up-regulation of PTGS2 (19±4.4, p=0.04), TGFβ (6±3, p=0.01) and IL6 (5±2.8, p=0.04) in CML MSCs at time 0 with a great variability among the patients (calculated value of 2-ΔΔCt in HD MSC was 1). After 48 h of co-culture with PBMC, CML MSC showed statistically significant up-regulation of ARG1 (23.5±11.9, p=0.02), TGFβ (4.8±3, p=0.04), IL10 (5.6±2.8, p=0.03) and IL6 (54.3±23, p=0.02) expression, suggesting that multiple mechanisms are involved in MDSC induction by CML MSC. CONCLUSION. Our work demonstrates that CML MSCs are able to activate MDSCs favoring cancer immune evasion in CML patients. Disclosures Palumbo: Novartis: Honoraria, Other: Advisory Board.
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Martiniello-Wilks, Rosetta, Stephen R. Larsen, Stephane Flamant, Jessamy C. Tiffen, Charles G. Bailey, and John E. J. Rasko. "Mesenchymal Stem Cells as Suicide Gene Therapy Vehicles for Organ-Confined and Metastatic Prostate Cancer (PCa)." Blood 110, no. 11 (November 16, 2007): 5148. http://dx.doi.org/10.1182/blood.v110.11.5148.5148.
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Abstract The efficacy of mesenchymal stem cells (MSC) is currently being examined as a clinical regenerative medicine for multiple sclerosis, cirrhosis, liver disease, tibial fractures, heart failure and graft versus host disease. MSC display an inherent tumor-tropic property that has been exploited for the targeted delivery of therapeutic genes to metastatic melanoma, glioma, breast and colon carcinoma in animal models. Advantages of using MSC include their ability for: self-renewal, ease of propagation and gene modification ex vivo; secretion of high levels of therapeutic protein; evasion of immune rejection; differentiation into connective tissue and tumor stroma; and long-term engraftment in vivo. This study explores the utility of MSC to deliver reporter or suicide genes to advanced Pca which is currently incurable using the syngeneic RM1 mouse model. Sca-1bright CD45− cells sorted from adherent bone marrow cells were shown to be true MSC by their ability to undergo tri-lineage differentiation in adipogeneic, osteogenic and chondrogenic media and their characteristic CD44+, CD90+, CD73+ and CD106+ phenotype. Lentiviral vectors showed sustained green fluorescent protein (GFP) reporter gene expression in MSC (MSC-GFP) for 50 passages by flow cytometry. When MSC-GFP (10e6 cells) were implanted into the mouse prostate with or without RM1 tumor cells on day 0, examination by full body fluorescence imaging (IVIS 100; Xenogen/Caliper) showed MSC persisted only within the tumor-bearing prostate (p<0.05; day 18). No MSC were detected in any other organ examined. To test their systemic homing ability, MSC-GFP (10e6 cells) were infused every second day (2–14) via the tail vein of mice in the presence or absence of RM1 lung pseudometastases. MSC persisted within the lungs of RM1 tumor-bearing mice alone (p<0.01) with no detectable MSC in any other organ examined (day 18). These results suggest MSC engraft organ-confined Pca and home to metastatic Pca. Gene directed enzyme prodrug therapy (GDEPT) describes the transfer of a suicide gene, not expressed in mammalian cells, into tumors using viral vectors. This renders tumors sensitive to prodrugs that are non-toxic to normal tissues. In our pre-clinical study, prostate tumors established from RM1 tumor cells stably transfected with fusion suicide gene cytosine deaminase/uracil phosphoribosyltransferase (CDUPRT) followed by systemic treatment with prodrug 5-fluorocytosine, showed significant reductions in prostate tumor growth and pseudometastases in the lungs (1). More recently, we stably transfected MSC with CDUPRT prior to implantation into established RM1 prostate tumors. In the presence of prodrug MSC-CDUPRT showed similar levels of Pca killing observed in the published experiment. In both experiments CDUPRT in the presence of prodrug significantly reduced (∼75%; p<0.05) the weight of RM1 prostate tumors compared to the control gene or no prodrug control mice. These results demonstrate that MSC can deliver suicide genes to developing Pca and efficiently convert prodrug to a toxic diffusible metabolite to suppress tumor growth. MSC implantation was well tolerated without observed toxicity and therefore show promise as a novel form of cell-directed suicide gene therapy.
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Khakoo, Aarif Y., Shibani Pati, Stasia A. Anderson, William Reid, Mohamed F. Elshal, Ilsa I. Rovira, Ahn T. Nguyen, et al. "Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma." Journal of Experimental Medicine 203, no. 5 (April 24, 2006): 1235–47. http://dx.doi.org/10.1084/jem.20051921.
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Emerging evidence suggests that both human stem cells and mature stromal cells can play an important role in the development and growth of human malignancies. In contrast to these tumor-promoting properties, we observed that in an in vivo model of Kaposi's sarcoma (KS), intravenously (i.v.) injected human mesenchymal stem cells (MSCs) home to sites of tumorigenesis and potently inhibit tumor growth. We further show that human MSCs can inhibit the in vitro activation of the Akt protein kinase within some but not all tumor and primary cell lines. The inhibition of Akt activity requires the MSCs to make direct cell–cell contact and can be inhibited by a neutralizing antibody against E-cadherin. We further demonstrate that in vivo, Akt activation within KS cells is potently down-regulated in areas adjacent to MSC infiltration. Finally, the in vivo tumor-suppressive effects of MSCs correlates with their ability to inhibit target cell Akt activity, and KS tumors engineered to express a constitutively activated Akt construct are no longer sensitive to i.v. MSC administration. These results suggest that in contrast to other stem cells or normal stromal cells, MSCs possess intrinsic antineoplastic properties and that this stem cell population might be of particular utility for treating those human malignancies characterized by dysregulated Akt.
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Chen, Xiao Chen, De Pei Wu, Feng Chen, and Wei Rong Chang. "Research on Biological Characteristics of Chronic Myelogenous Leukemia Patients’ Bone Marrow Mesenchymal Stem Cells." Blood 110, no. 11 (November 16, 2007): 4535. http://dx.doi.org/10.1182/blood.v110.11.4535.4535.
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Abstract Objective To isolate and culture bone marrow mesenchymal stem cells (MSC) from chronic myelogenous leukemia (CML) patients and examine their functional characteristics; To investigate their biological characteristics like proliferation, apoptosis and tumorigenicity;To observe their effects on proliferation and apoptosis of K562 cells. Methods Bone marrow was extracted from the anterior superior iliac spines of 20 patients with CML. MSC were isolated and cultured in vitro and subcultured for three to five generations. Cell morphology was observed under microscope. The ultrastructure was observed with electron microscope. The immunophenotype was detected by flow cytometry (FCM). Different agents were used to induce the MSC to differentiate into osteocyte and adipocyte, and Von Kossa staining, oil-red staining was used to examine the ability of differentiation. The growth curve, cell cycle and apoptosis were investigated. MSC were cultured in soft agar for 2 weeks to observe the clone growth. BALB/C nude mice were inoculated with MSC to observe the tumorigenicity. MSC and K562 cells were cocultured in vitro and coinjected into subcutaneous of BALB/C nude mice, to observe the effects of MSC on proliferation and apoptosis of K562 cells. Results Fibroblast-like, positive in CD44, CD73 and CD90,and negative in CD34, CD45 and HLA-DR, the CML derived MSC could differentiate into osteocyte and adipocyte. The MSC showed normal ultrastructure. After 2 weeks’ culture, no clone was formed from the MSC. Four weeks after, no tumor was seen in the mice inoculated with MSC. The population doubling time of P3 MSC is (32.61±1.54)h. The population doubling time of P4 MSC is (32.59±1.23)h, The population doubling time of P5 MSC is (32.41±0.75)h. To investigate the cell cycle of the third passage MSC by FCM, there were(93.67%±1.66%)cells in phase G0/G1,(6.33%±1.66%)in phase S+G2+M. There weren’t any apoptosis observed. K562 cells adhensively cultivated with MSC were accelerated and the population doubling time decreased([29.59±0.46]h vs [37.49±2.19]h, P<0.05),cells in G0/G1 decreased ([16.43%±1.67%] vs [32.23%±3.35%], P<0.01),cells in phase S increased ([69.63%±3.09%] vs [59.37%±4.40%], P<0.05),and those in G2/M increased([13.93%±1.45%] vs [8.40%±1.05%], P<0.01),compared with that cultivated in suspension. The apoptosis in both conditions were not observed. Coinjected with MSC, K562 cells developed tumors in 100% of the mice by (12.00±0.82)d compared to (15.50±0.58)d when implanted alone, indicating a statistically earlier onset of tumor growth in presence of MSC (P<0.01). The tumor volume and tumor weight were also increased when K562 cells coinjected with MSC compared with implanted alone (K562+MSC vs K562):tumor volume([75.70±7.30]mm2 vs [37.38±2.39]mm2, P<0.01),tumor weight([0.64±0.08]g vs [0.32±0.06]g, P<0.01). Conclusion MSC from the bone marrow of CML patients can be isolated and cultured;MSC derived from CML seem to have the abilities of powerful proliferation in vitro and multiple differentiation and have no tumorigenicity. The MSC can accelerate the proliferation of K562 cells both in vitro and vivo.
Dissertations / Theses on the topic "MSC, Tumor Immunology, Mesenchymal Stem Cell"
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Pérez, lanzón María. "Modeling Hormone Receptor Positive Breast Cancer in Immunocompetent Mice Blocking tumor-educated MSC paracrine activity halts osteosarcoma progression Organoids for Modeling Genetic Diseases. In: International Review of Cell and Molecular Biology A preclinical mouse model of osteosarcoma to define the extracellular vesicle-mediated communication between tumor and mesenchymal stem cells Failure of immunosurveillance accelerates aging The metabolomic signature of extreme longevity: Naked mole rats versus mice Lurbinectedin synergizes with immune checkpoint blockade to generate anticancer immunity Laminin-binding integrins are essential for the maintenance of functional mammary secretory epithelium in lactation Immunoprophylactic and immunotherapeutic control of hormone receptor-positive breast cancer." Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL019.
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Les progrès de la recherche sur le cancer du sein dépendent de la disponibilité d’outils appropriés, comme les lignées cellulaires qui peuvent être implantées chez des souris immunocompétentes. La souche de souris C57Bl/6 est la plus étudiée et c’est la seule pour laquelle certaines variantes génétiques sont disponibles. Étant donné qu'aucune lignée cellulaire de carcinome mammaire à récepteurs hormonaux positifs de souche C57Bl/6 n'est disponible, nous avons décidé d'établir des lignées cellulaires de ce type. Nous avons induit des cancers du sein chez des souris C57BL/6 femelles en utilisant un analogue synthétique de la progestérone combiné à un agent endommageant l'ADN. Des lignées cellulaires ont été établies à partir de ces tumeurs et sélectionnées pour leur positivité au niveau du double récepteur (estrogène + progestérone), ainsi que pour leur transplantabilité chez les femelles C57BL/6. Parmi plusieurs lignées, une lignée cellulaire, que nous avons appelée MD5, remplissait ces critères et a permis l'établissement de tumeurs mal différenciées et très prolifératives. Ces tumeurs ont réduit leur croissance (sans toutefois régresser) lors du traitement par des antagonistes des récepteurs d’œstrogènes, ainsi que par une chimiothérapie à base d'anthracylines. Cependant, ce dernier effet n'a pas été influencé par la déplétion des lymphocytes T et, en outre, ces tumeurs n'ont pas répondu au blocage de PD-1, ce qui suggère que les tumeurs MD5 sont immunologiquement froides. En conclusion, les cellules MD5, dérivées des animaux C57BL/6, constituent un modèle de cancer du sein à récepteurs hormonaux positifs de mauvais pronosticProgress in breast cancer research relies on the availability of suitable cell lines that can be implanted in immunocompetent laboratory mice. The best explored mouse strain, C57Bl/6, is also the only one for which multiple genetic variants are available. Driven by the fact that no hormone receptor-positive C57Bl/6-derived mammary carcinoma cell lines are available, we decided to establish such cell lines. Breast cancers were induced in female C57BL/6 mice using a synthetic progesterone analogue combined with a DNA damaging agent. Cell lines were established from these tumors and selected for dual (estrogen + progesterone) receptor positivity, as well as transplantability into C57BL/6 females. One cell line, which we called MD5,fulfilled these criteria and allowed for the establishment of poorly differentiated, highly proliferative, immune cold tumors. Such tumors reduced their growth (though did not regress) upon treatment with estrogen receptor antagonists, as well as with anthracyline-based chemotherapy. However, the latter effect was not influenced by T cell depletion and MD tumors failed to respond to PD-1 blockade, suggesting that they are immunologically cold. In conclusion, C57BL/6-derived MD5 cells constitute a model of poor prognosis hormone receptor-positive breast cancer
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Montaini, Gianni. "Meccanismi cellulari e molecolari coinvolti nell’evasione dall’immunosorveglianza nei carcinomi testa-collo a cellule squamose (Cellular and molecular mechanisms of immunosurveillance escape in Head Neck Squamous Cell Carcinoma)." Doctoral thesis, 2019. http://hdl.handle.net/2158/1149324.
Full textAbstract:
In this study, we wanted to investigate more about the mechanisms involved in the immunosuppressive activity of tumor-MSCs.
First, we observed that T cells infiltrating HNSCC were enriched for Treg, however, most of the effector T cells were characterized by IFN-γ and TNF-α production.
Looking at the effect of these two cytokines on MSCs, we found out that upon inflammatory stimulation, MSCs upregulate the expression of immunosuppressive molecules such as IDO1, IL4I1 and PD-L1. Testing the functional role of anyone of these molecules, we discovered that IDO1 was the major player in MSCs’ mediated immunosuppression, but also IL4I1 and PD-L1 play a small part.
We also found out that, MSCs are able to attract (by the expression of numerous chemokines) and bind lymphocytes (by expressing CD106), nevertheless their inhibitory action does not seem to be due to cellular contact.
Our data together with the previous ones, consolidate the hypothesis that tumor-MSCs could promote tumor growth, directly or indirectly inhibiting the immune response.
Book chapters on the topic "MSC, Tumor Immunology, Mesenchymal Stem Cell"
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Regad, Tarik, and Morgan G. Mathieu. "Cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT): Tumor cell plasticity challenges immunotherapy." In Tumor Immunology and Immunotherapy, 401–14. Oxford University Press, 2014. http://dx.doi.org/10.1093/med/9780199676866.003.0027.
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