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1
Haiko, Paula, Taija Makinen, Salla Keskitalo, Jussi Taipale, Marika J. Karkkainen, Megan E. Baldwin, Steven A. Stacker, Marc G. Achen, and Kari Alitalo. "Deletion of Vascular Endothelial Growth Factor C (VEGF-C) and VEGF-D Is Not Equivalent to VEGF Receptor 3 Deletion in Mouse Embryos." Molecular and Cellular Biology 28, no. 15 (June 2, 2008): 4843–50. http://dx.doi.org/10.1128/mcb.02214-07.
Анотація:
ABSTRACT Lymphatic vessels play an important role in the regulation of tissue fluid balance, immune responses, and fat adsorption and are involved in diseases including lymphedema and tumor metastasis. Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) is necessary for development of the blood vasculature during early embryogenesis, but later, VEGFR-3 expression becomes restricted to the lymphatic vasculature. We analyzed mice deficient in both of the known VEGFR-3 ligands, VEGF-C and VEGF-D. Unlike the Vegfr3 −/− embryos, the Vegfc −/−; Vegfd −/− embryos displayed normal blood vasculature after embryonic day 9.5. Deletion of Vegfr3 in the epiblast, using keratin 19 (K19) Cre, resulted in a phenotype identical to that of the Vegfr3 −/− embryos, suggesting that this phenotype is due to defects in the embryo proper and not in placental development. Interestingly, the Vegfr3 neo hypomorphic mutant mice carrying the neomycin cassette between exons 1 and 2 showed defective lymphatic development. Overexpression of human or mouse VEGF-D in the skin, under the K14 promoter, rescued the lymphatic hypoplasia of the Vegfc +/− mice in the K14-VEGF-D; Vegfc +/− compound mice, suggesting that VEGF-D is functionally redundant with VEGF-C in the stimulation of developmental lymphangiogenesis. Our results suggest VEGF-C- and VEGF-D-independent functions for VEGFR-3 in the early embryo.
2
Jantus-Lewintre, Eloisa, Marta Usó, Elena Sanmartin, Sandra Gallach, Rafael Sirera, Ana Blasco, Cristina Hernando, et al. "Ratios between VEGF ligands and receptors in tumor and stroma have impact on the outcome in resectable NSCLC." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): e22147-e22147. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e22147.
Анотація:
e22147 Background: In tumor angiogenesis there is a complex interplay between endothelial, stromal and tumor cells. Some key regulators of this process are the members of the vascular endothelial growth factor (VEGF) family of ligands and receptors and the neuropilins (NRP). This study analyzes the correlations between the expression of these angiogenic factors in tumor cells and tumor stroma, and their prognostic role in tissue samples from resected non-small cell lung cancer (NSCLC) patients. Methods: Representative tumor and stroma areas from FFPE tissue samples of 125 early-stage NSCLC patients were carefully micro-dissected. RNA isolated from the samples was retrotranscripted and preamplified. RTqPCR was performed using hydrolysis probes (TaqMan, Applied Biosystems) and relative quantification was calculated using GAPDH and CDKN1B as endogenous controls. Results were normalized against a human cDNA (Clontech) as a reference. All statistical analyses were considered significant at p<0.05. Results: Paired Wilcoxon test revealed differences between tumor and stroma gene expression for VEGFB (p<0.0001), VEGFC (p<0.0001), VEGFR-1 (p<0.0001), VEGFR-2 (p=0.020), VEGFR-3 (p< 0.0001), NRP-1 (p=0.001) and NRP-2 (p< 0.0001). Survival analyses showed that those patients with higher levels of the Ratio Stromal-VEGFA/ Tumoral-VEGFR-2 had worse time to progression (TTP) (median 26.23 months vs NR, p=0.013) and overall survival (OS) (median 29.50 months vs NR, p=0.001). Similarly, those patients with higher levels of the Ratio Stromal-VEGFC/Tumoral-VEGFR-3 had worse TTP (median 23.30 vs 70.53 months, p=0.015) and OS (median 37.20 months vs NR, p=0.023). Conclusions: Our results show significant differences in the expression of VEGF family members between tumor and stromal cells. This may indicate the importance of the tumor-stroma interaction when trying to understand the angiogenic process. Furthermore, the combination of the ligands expression in stroma and their receptors in tumor may have a prognostic value in NSCLC patients. Supported by grants PS09-01149 and RD06/0020/1024 from ISCIII.
3
Morfoisse, Florent, Fabienne De Toni, Jeremy Nigri, Mohsen Hosseini, Audrey Zamora, Florence Tatin, Françoise Pujol, et al. "Coordinating Effect of VEGFC and Oleic Acid Participates to Tumor Lymphangiogenesis." Cancers 13, no. 12 (June 8, 2021): 2851. http://dx.doi.org/10.3390/cancers13122851.
Анотація:
In cancer, the lymphatic system is hijacked by tumor cells that escape from primary tumor and metastasize to the sentinel lymph nodes. Tumor lymphangiogenesis is stimulated by the vascular endothelial growth factors-C (VEGFC) after binding to its receptor VEGFR-3. However, how VEGFC cooperates with other molecules to promote lymphatics growth has not been fully determined. We showed that lymphangiogenesis developed in tumoral lesions and in surrounding adipose tissue (AT). Interestingly, lymphatic vessel density correlated with an increase in circulating free fatty acids (FFA) in the lymph from tumor-bearing mice. We showed that adipocyte-released FFA are uploaded by lymphatic endothelial cells (LEC) to stimulate their sprouting. Lipidomic analysis identified the monounsaturated oleic acid (OA) as the major circulating FFA in the lymph in a tumoral context. OA transporters FATP-3, -6 and CD36 were only upregulated on LEC in the presence of VEGFC showing a collaborative effect of these molecules. OA stimulates fatty acid β-oxidation in LECs, leading to increased AT lymphangiogenesis. Our results provide new insights on the dialogue between tumors and adipocytes via the lymphatic system and identify a key role for adipocyte-derived FFA in the promotion of lymphangiogenesis, revealing novel therapeutic opportunities for inhibitors of lymphangiogenesis in cancer.
4
Secker, Genevieve A., and Natasha L. Harvey. "Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update." International Journal of Molecular Sciences 22, no. 14 (July 20, 2021): 7760. http://dx.doi.org/10.3390/ijms22147760.
Анотація:
The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.
5
ZHAO, JIANFENG, YU GENG, HAIRONG HUA, BIYUN CUN, QIANBO CHEN, XIAOTING XI, LIUSHU YANG, and YAN LI. "Fenofibrate inhibits the expression of VEGFC and VEGFR-3 in retinal pigmental epithelial cells exposed to hypoxia." Experimental and Therapeutic Medicine 10, no. 4 (August 21, 2015): 1404–12. http://dx.doi.org/10.3892/etm.2015.2697.
6
Verbiest, Annelies, Benoit Beuselinck, Gabrielle Couchy, Sylvie Job, Aurelien De Reynies, Clément Meiller, Maarten Albersen, et al. "Metastatic clear cell renal cell carcinoma: Proangiogenic gene expression and outcome on sunitinib." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e16085-e16085. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e16085.
Анотація:
e16085 Background: Clear cell renal cell carcinomas (ccRCC) are hypervascular tumors that respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. They can be divided into 4 mRNA-expression based subgroups (ccrcc 1-4) with different outcomes on sunitinib. We hypothesized that the expression of proangiogenic genes is predictive for response to sunitinib. Methods: Retrospective series of metastatic ccRCC-patients treated with sunitinib as first line targeted therapy (n = 104). We studied expression of genes involved in angiogenesis and the immune-suppressive microenvironment (qRT-PCR) and mutational status of Von Hippel Lindau and Polybromo (PBRM) 1 (sequencing) on primary tumor samples. Outcome parameters were response rate (Response Evaluation Criteria in Solid Tumors), progression free survival (PFS) and overall survival (OS). Gene expression levels were tested in multivariate analysis (MV) against the IMDC risk criteria, presence of bone metastases and sarcomatoid dedifferentiation ≥25%. Results: Expression of Hypoxia Inducible Factor (HIF) 2A, Platelet Derived Growth Factor Receptor B, VEGFC, VEGFR1 and VEGFR2 was significantly correlated with PFS on MV and expression of HIF1A, HIF2A and VEGFR2 with OS. VEGFR2-expression was also correlated with partial response (p = 0.03) and anti-correlated with early progressive disease (p = 0.008). HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3-expression was higher in ccrcc2-tumors compared to others. Expression of genes involved in angiogenesis and in the immune-suppressive microenvironment was not directly correlated nor anti-correlated. In tumors with a bi-allelic PBRM1-inactivation, HIF2A, VEGFA, VEGFR1 and VEGFR2-expression were higher compared to tumors with 1 or 2 functional PBRM1-alleles. This did not translate in different outcome on sunitinib. Conclusions: Tumoral expression of genes involved in the HIF-VEGF-VEGFR proangiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in metastatic ccRCC. Expression of these genes was high in the molecular ccrcc2-subgroup, known to be sensitive to sunitinib. These findings could be used for patient selection in future clinical trials.
7
De Alarcon, Pedro, Manu Gnanamony, and Jessica Garcia. "An in Vitro Study on the Role of Angiogenesis in Iron Deficiency Induced Reactive Thrombocytosis." Blood 132, Supplement 1 (November 29, 2018): 2450. http://dx.doi.org/10.1182/blood-2018-99-115378.
Анотація:
Abstract Introduction: Iron deficiency (ID) is one of the recognized causes of reactive thrombocytosis in children. Factors that are commonly associated with megakaryopoiesis such as thrombopoietin (TPO), interleukin 6 (IL-6) and IL-11 are not altered in patients with iron deficiency and thrombocytosis suggesting the role of alternate mechanisms in controlling this process. We have previously shown using an ID rat model that ID increased the number of megakaryocytes in the bone marrow. We have also shown an increase in VEGFR (FLT1) and CXCR4 staining in bone marrow slides of ID rats. This data suggests that angiogenesis plays a vital role in the development of reactive thrombocytosis in response to ID. In this report, we have expanded our study to identify specific angiogenic signaling molecules associated with ID and used functional assays to validate it. Methods: For this study, we used the megakaryoblast cell line MEG-01 as an in vitro model of megakaryopoiesis. MEG-01 cells were adapted to grow in chemically defined serum free medium containing iron (iron replete media). For iron deficiency, serum free iron free media was mixed with iron replete media at a 1% v/v concentration (iron deplete media). For our experiments, MEG-01 cells were grown in both iron replete and depleted media for 7 days. Cell viability was measured using the trypan blue exclusion assay. Messenger-RNA expression of iron-related markers (TFR1, TFR2, FLT1, FLT3, FTL, FTH1, TF, HMOX1 and HMOX2) and angiogenic markers (VEGFA, VEGFB, VEGFC, PDGF, ANGPTL1, ANGPTL2, FGF2) was studied using real time PCR. We performed functional validation of angiogenesis with an in vitro tube formation assay using human umbilical vein endothelial (HUVEC) cells. For statistical analysis of the data we performed the t test using graph pad prism software and we considered p<0.05 as statistically significant. Results: In low iron conditions, MEG-01 cells showed a significant increase in FLT1 (4 fold) and FLT3 (3 fold) expression using real time PCR (p<0.001). Iron deficiency also induced a 2 fold increase in the mRNA expression of angiogenic molecules VEGFB, VEGFC, FGF2 and PDGFA (p<0.001). Using the tube formation assay, we also show that conditioned media collected from iron deficient MEG-01 cells induced increased vessel formation in endothelial cells. Conclusion: In this study, we were able to validate our earlier in vivo findings on iron deficiency induced reactive thrombocytosis. We show that cells adapt to low iron conditions by upregulating FLT1, FLT3 and FTL. We also show that several markers in the angiogenesis pathway like VEGFB, VEGFC, FGF2 and PDGFA are upregulated in response to iron deficiency. We were also able to show that an increase in these angiogenic molecules induced increased vessel formation in endothelial cells. This report, along with our previous findings, points to the importance of the angiogenic pathway in reactive thrombocytosis induced by iron deficiency. Disclosures No relevant conflicts of interest to declare.
8
Baker, A. F., T. Dragovich, A. Cui, D. Laheru, C. Campen, D. D. Von Hoff, and M. Hidalgo. "Plasma IL-6 level and survival of pancreatic cancer patients treated with a VEGFR inhibitor, vatalanib (PTK/ZK)." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e15514-e15514. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15514.
Анотація:
e15514 Background: Use of anti-angiogenesis drugs in pancreatic cancer has not yet resulted in significant clinical improvements and it is unknown if there are subsets of patients with pancreatic cancer that may benefit from this therapeutic approach. We have reported on a phase II trial of PTK/ZK (VEGFR inhibitor) in patients (n=65) who have failed or progressed on gemcitabine. The 6- month OS met the primary endpoint of 29 % and there were 2 partial responses. We investigated some of the plasma proteins relevant for angiogenesis in correlation with clinical outcomes on this trial. Methods: Plasma samples were obtained prior to and after 4 weeks of therapy with PTK/ZK, aliquoted and frozen until assayed. Patient plasma was assayed for: VEGFA, VEGFC, VEGFR1, VEGFR2, FGFb, PDGFBB, OPN, ANG2, IL-6, and sIL-6R (SearchLight, Pierce Biotechnology Multiplex ELISA and IL-6 and sIL-6R using R&D Systems).The Spearmen correlation was utilized to look for correlations and changes from baseline compared to post-treatment levels. The correlation of baseline levels with survival were analyzed using the Cox proportional hazard model. Results: Thirty eight paired patient samples were assayed. A significant correlation of baseline values was found between VEGF-C and VEGFR1 (p=0.0496), VEGF-C and VEGF (0.0092), PDGFB and ANG2 (p=0.0003), IL-6 and ANG2 (p=0.0089), and FGFb and OPN (p=0.0281). A correlation in post-treatment change was observed between VEGF-C and PDGFB (p=0.0008), FGFb and OPN (p=0.0374), PDGFB and ANG2 (p=0.0005), IL-6 and ANG-2 (p=0.0464), and VEGF and IL-6 (p=0.0546). Lower baseline IL-6 levels correlated with longer survival (p=0.0227). A post-treatment decrease in plasma IL-6 levels was significantly associated with improvement in survival (p=0.0457). IL-6 mediates multiple effects including angiogenic and pro-survival signaling and has been proposed as a potential prognostic factor in different malignancies. Conclusions: Of all angiogenesis markers analyzed only a post-treatment decrease in plasma IL-6 correlated with improved survival on study. IL-6 warrants further investigation as a potential marker of sensitivity to anti-angiogenesis therapy, especially in patients with pancreatic cancer. Supported by: 1P50 CA95060; 1PO1CA109552–01A1 [Table: see text]
9
Matas-Céspedes, Alba, Vanina Rodriguez, Susana Kalko, Eva Gine, Elias Campo, Gael Roue, Armando Lopez-Guillermo, Dolors Colomer, and Perez-Galan Patricia. "Follicular Dendrytic Cells Deliver Angiogenesis Signaling To Follicular Lymphoma Cells That Is Hampered By The Pan-PI3K Inhibitor NVP-BKM120." Blood 122, no. 21 (November 15, 2013): 3072. http://dx.doi.org/10.1182/blood.v122.21.3072.3072.
Анотація:
Abstract Follicular Lymphoma (FL) is the paradigm of a neoplasia depending on the microenvironment for proliferation and survival. In the lymphoid follicle, FL cells are surrounded by follicular dendrytic cells (FDCs) that function as antigen presenting cells delivering survival and proliferation signaling. FDCs together with macrophages are associated to poor FL survival. Our aim was to uncover the signaling pathways underlying FL-FDC crosstalk and its validation as new targets for therapy using specific inhibitors. Global gene expression profiling of FL-FDC co-cultures yield a marked modulation of FL transcriptome by FDCs. The Principal Component Analysis (PCA) showed that HK-cocultured FL cells clustered together,independently of the patient origin. Then, pathways assignmentwas performed by DAVID and GSEA softwares, both of themuncovering an overrepresentation on genes related toangiogenesis. In the DAVID analysis, we found significant(False Discovery Rate (FDR)<5%,) angiogenesis–related GOterms such as, blood vessel development, blood vessel morphogenesis, VEGFR signaling pathway, sprouting angiogenesis, positive regulation of angiogenesis, patterning of blood vessels among others. In the GSEA analysis, our dataset was interrogated for enrichment of genesets belonging to C2 data base together with custom-derived ones. In accordance with DAVID results, genesets related to angiogenesis were enriched (FDR< 5%) in HK-cocultured FLcells, such as HumanAngiogenesis, Weston_VEGFA_targtes, PID_VEGFR1_2 and PID_lymphangiogenesis. As PI3K pathway is known to play a determinant role in angiogenesis, we explored if NVP-BKM120, a pan-PI3K inhibitor in clinical trials for solid tumors, could interfere with this signaling. First, by using Taqman Angiogenesis Array®containing 94 probes against genes related to angiogenesis, we analyzed if the modulation of genes in FL cells cocultured with HK could be inhibited by NVP-BKM120. Effectively, we found a group of genes that were positively regulated by HK and inhibited by NVP-BKM120, among them ANGPT1, CXCL12, EPHB2, VEGFA, VEGFC, ADAMST1, NRP1, NRP2, HSPG2,COL4A1, PDGFRA and PDGFRB. In addition, by ELISA analysis of cell culture supernatants, we found that NVP-BKM120 reduced VEGFA and VEGFC secretion of FL cells alone or co-cultured with HK. Then, we analyzed if this reduction of proangiogenic factors effectively reduced angiogenesis. To this aim we performed HUVEC tube formation assay with the supernatants of FL cells co-cultured or not with HK, in the presence or absence of the PI3K inhibitor. We demonstrated that, as expected, supernatants derived fromFL-HK-cocultures increased the number of tubes formed, and NVP-BKM120 reduced these numbers. Then, we investigated the impact of NVP-BKM120 treatment on FL cell signalling and proliferation. NVP-BKM120 efficiently blocks both constitutive activation of PI3K/AKT pathway in FL cells and that derived from B-cell receptor stimulation or HK co-culture, reducing cell proliferation of FL cells and inducing apoptosis in a portion of FL cell lines and primary cells. NVP-BKM120 also impedes signaling and migration induced by the chemokine SDF1α. In vivo, NVP-BKM120 significantly (p<0.05) reduces tumor outgrowth in subcutaneous and systemic FL mouse models. We isolated RNA from mouse tumors and run TaqmanAngiogenesis array as before. NVP-BKM120 downmodulated the expresion of genes related to angiogenesis already found in vitro such a VEGFA, HSPGB2, NRP2 ,PDGFRA and PDGFRB, but also novel genes, including SERPINC1, FST,PDGFB, TGFB1, TNF, VEGFB, COL18A1, ANGPT4 and PECAM(CD31). In addition, the reduction on VEGFA and CD31 was also validated by IHC in these tumors. These results warrant further investigation of pan-PI3K inhibitors for FL therapy in the context of microenvironment survival signaling inhibition. Disclosures: Lopez-Guillermo: Roche: Membership on an entity’s Board of Directors or advisory committees.
10
Weidenaar, Alida C., Hendrik J. M. de Jonge, Vaclav Fidler, Arja ter Elst, Tiny Meeuwsen, Jenny Douwes, Jessica C. A. Bouma, Karel Hählen, Willem A. Kamps, and Evelina S. de Bont. "Addition of PTK787/ZK 222584 Can Lower the Dosage of Amsacrine To Achieve Equal Amounts of AML Cell Death." Blood 110, no. 11 (November 16, 2007): 4199. http://dx.doi.org/10.1182/blood.v110.11.4199.4199.
Анотація:
Abstract Acute myeloid leukemia (AML) is a disease with a poor prognosis. At this moment conventional chemotherapy is the gold standard for the treatment of AML. It is demonstrated that AML cells express VEGFA and VEGFC as well as KDR (VEGFR2), the main receptor for downstream effects, resulting in an autocrine pathway for cell survival. The present study investigates the role of PTK787/ZK 222584, a potent inhibitor of VEGF receptor tyrosine kinases, upon leukemic cell death, and the possibility of an additional effect upon cell death achieved by a conventional chemotherapeutic drug Amsacrine. In 3 AML-cell lines and 33 pediatric AML patient samples we performed total cell kill assays to determine the percentage of cell death achieved by PTK787/ZK 222584 (5–100 μM) and/or Amsacrine (0.001–2 μg/ml). Both drugs induced AML cell death. The LC50 values (drug concentration needed to kill 50% of the leukemic cells) for HL-60, TF-1 and THP-1 were 27 μM, 49 μM and 24 μM respectively. An excellent survival was seen on a KDR-negative cell line demonstrating that the cell death induced by PTK787/ZK 222584 is not a toxic effect. The primary blasts were overall 5–10 times more sensitive to PTK787/ZK 222584 than the cell lines, with a median LC50 value of 5.1 μM. Patient samples with a LC50 value below the median did not differ from patients above the median regarding age, sex, FAB classification or WBC count. With a response surface analysis we investigated the additional effect of PTK787/ZK 222584 upon cell death achieved by Amsacrine; we estimated the concentration combinations resulting in the same cell survival. We could show that, in cell lines as well as in primary AML blasts, the concentration of Amsacrine can be lowered and replaced for a certain dose of the potentially less toxic VEGFR inhibitor to achieve the same percentage of leukemic cell death. This study shows that PTK787/ZK 222584 might have more clinical potential in AML when combined with chemotherapy, e.g. Amsacrine. In addition, it is known from literature that topoisomerase inhibitors, e.g. Amsacrine, can cause treatment related AMLs. Moreover, many survivors of childhood or adolescent cancer experience treatment related cardiovascular complications that can impair their quality of life years after treatment. Therefore, reduction of complications and long-term effects of chemotherapy is warranted and might be achieved by lowering dosages of Amsacrine and replace it by other drugs with a lower toxicity profile, such as PTK787/ZK 222584.
11
Wu, Yu, Xinyi Chen, and Yuhuan Zheng. "The Role of Tumor Associated Macrophages in Multiple Myeloma and Its Pathophysiological Effect on Myeloma Cells Survival, Apopotosis and Angiogenesis." Blood 126, no. 23 (December 3, 2015): 4204. http://dx.doi.org/10.1182/blood.v126.23.4204.4204.
Анотація:
Abstract Objective The aim of this study is to explore the role of tumor associated macrophages (TAMs) in the prognosis, early treatment response of multiple myeloma and to investigate the role of TAMs on the proliferation, apoptosis£¬oncogene expression and chemotaxis of myeloma cells. Methods 1 In vivo we retrospectively collected and analyzed 240 patients initially diagnosed wih multiple myeloma and their bone marrow biopsy tissue from Jan, 2009 to June, 2014 in West China Hospital, Sichuan University, China. All the patients enrolled in this study were followed up till April, 2015. We observed and quantified the involvement of macrophage (M¦µ), classic activated macrophage (M1 M¦µ) and alternatively activated macrophage (M2 M¦µ) in bone marrow by immunohistochemical staining of anti-CD68 monoclonal antibody, anti-iNOS monoclonal antibody and anti-CD163 monoclonal antibody, respectively. We analyzed the relation between macrophage involvement with International Staging System (ISS) and the clinical response as well. The effect of different type macrophage involvement on prognosis, progression-free survival and overall survival were estimated. Time-to-event data were analyzed with the Kaplan-Meier method, and the differences were calculated using the Log-rank and Breslow tests. Cox proportional-hazards models were used to estimate hazard ratios and 95% confidence intervals for the main comparisons. 2 In vitro we induced human peripheral blood mononuclear cell£¨PBMC£© and human monocytic THP-1 cells to M2 macrophages with M-CSF or PMA in the presence of IL-4/13 in vitro. Macrophages were identified by morphology and flow cytometry. Two myeloma cell lines (RPMI 8226 and U266) were cocultured with M2 macrophages by using a transwell system. We measured myeloma cells proliferation through CCK-8 method and the pro-inflammatory cytokines expression (TNF-¦Á and IL-6) by ELISA. Real time PCR was applied to measure chemokines (CCL2 and CCL3), chemokine receptors (CCR2, CCR1, CCR5), vascular endothelial growth factor (VEGFA, VEGFB and VEGFC), VEGF receptors (VEGFR1-3), proto-oncogene serine/threonine-protein kinase Pim (PIM1-3). In addition, flow cytometry was used to analyze the apoptosis of myeloma cells induced by dexamethasone. Results 1 patients with high M2 macrophage involvement (>40/hp) in bone marrow showed poorer response (including complete response and partial response after 3 cycles of chemotherapy) to Dexamethasone-containing regimen (23.9% versus 73%, P=5x10-13). On the contrary, the patients with high M1 macrophage involvement demonstrated much better response to regimen than low M1 macrophage (69.6 versus 40.6%, P=5x10-5). 2 Both progression-free survival and overall survival were significantly shorter with high M2 macrophage involvement than low involvement (median progression-free survival, 12.9 months vs. 39 months; hazard ratio for progression, 1.77, 95% confidence interval [CI], 1.14 to 2.74; P=0.01; and overall survival, 4.9 months vs. 59.2 months; hazard ratio for death, 2.63; 95% CI, 1.75 to 3.95; P<0.001). 3 In vitro M2 macrophage stimulate myeloma cell proliferation. 4 In vitro M2 macrophage protect myeloma cells from dexamethasone induced apoptosis. 5 In vitro M2 macrophage promote myeloma cells secreting higher level of IL-6, TNF-¦Á and higher expression of CCL2, CCL3, CCR2, CCR5, VEGFA, VEGFR-1,-2, PIM-1, PIM-2 compared with the non-macrophage coculture system. Conclusion TAMs are associated with early clinical response and prognosis. Notably, M2 macrophages involvement has been shown strongly negatively associated with progression-free survival and overall survival. M2 macrophages promote myeloma cells proliferation and protect from apoptosis through a very complex mechanism involving pro-inflammatory cytokines IL-6 and TNF-¦Á, chemokines and related receptors such as CCL2, CCL3, CCR2 and CCR3, VEGF, VEGFR and PIM1, PIM2. Figure 1. Kaplan-Meier Analysis of PFS and OS in multiple myeloma patients in total Macrophage subgroups (A), M1 subgroups (B) and M2 subgroups(C). Figure 1. Kaplan-Meier Analysis of PFS and OS in multiple myeloma patients in total Macrophage subgroups (A), M1 subgroups (B) and M2 subgroups(C). Figure 2. Macrophages promote myeloma cells proliferation. Figure 2. Macrophages promote myeloma cells proliferation. Disclosures No relevant conflicts of interest to declare.
12
Kampen, Kim R., Frank J. G. Scherpen, Steven M. Kornblau, and Evelina SJM de Bont. "p53 Suppression Mediates Blasts Survival, Proliferation and CD34 Maintenance in Pediatric Acute Myeloid Leukemia." Blood 124, no. 21 (December 6, 2014): 897. http://dx.doi.org/10.1182/blood.v124.21.897.897.
Анотація:
Abstract Aberrations in the DNA damage responses contributes to the uncontrolled proliferation and therapy resistance in many cancers. Acute myeloid leukemia (AML) presents enhanced DNA damage as compared to MDS characterized by induced levels γ-2HAX and phosphorylated ATM that correlated with AML blast percentages (Boehrer et al. Oncogene 2009). The low incidence of p53 mutations (7% in adult AML, The Cancer Genome Atlas Research Network, N Engl J Med 2013) in AML indicates downstream suppression of DNA damage control system proteins, as was proposed previously by overexpression of MDM2 and BCL-2 (Wojcik et al. Neoplasma 2005). However, the role of p53 and downstream effectors regulating the DNA damage pathway in CD34+ AML blasts is still relatively unclear. Surprisingly, using RPPA analysis, we found a common significant increase in p53 phosphorylation at serine 15 in pediatric AML as compared to CD34+ NBM (AML n=31 and NBM n=10, Mann-Whitney U, P = 0.003). Therefore, we challenged to target p53 using a shRNA approach. In the sh-p53 model, primary pediatric AML samples transduced with sh-p53 showed a significant increase in AML proliferation over time as compared to scrambled control (paired-samples t-test, P = 0.005). The overall AML cell viability was significantly improved in sh-p53 AML cultures (paired-samples t-test P = 0.001). DNA cell cycle analysis revealed that sh-p53 AML cultures contained significant increased percentages of cells in S and G2/M phases of the cell cycle as compared to their scrambled controls (paired samples t-test, P = 0.015). The CD34+ leukemic population was maintained in p53 knockdown cultures and thereby outcompeted scrambled control cultures. Knockdown of p53 in primary pediatric AML samples resulted in a higher proliferation rate, repressed differentiation and prolonged survival of AML blasts, especially in MLL-rearranged AML. Interestingly, we previously showed that MLL-rearranged AML samples express significantly higher BCL-2 peptide phosphorylation as compared to NBM (Kampen et al. Leukemia 2014). Growth factors are extrinsic cues that can regulate BCL-2 expression (Pidgeon et al. Br J Cancer 2001). Growth factors like VEGF, have been shown to be involved in leukemia pathogenesis in the bone marrow where leukemic stem cells are preserved in tightly controlled niches (Kampen et al. Cell Mol Life Sci 2013). Accordingly, we found that FGF and VEGFC stimulation of CD34+ AML blasts both significantly accelerated BCL-2 mRNA expression by 28-fold and 2-fold, indicating that indeed the niche is important for inhibiting pro-apoptotic p53-dependent signals further downstream the pathway, which protects AML CD34+ blasts (Student’s t-test, both P < 0.001), where p53 and p21 mRNA expression remained unchanged. The availability of VEGFR-2 and FGFR1 previously highlighted their therapeutic targeting potential in AML (Kampen et al. Leukemia 2006, Kentsis et al, Nature Med 2012). This study presents the effect of p53 suppression on AML blast proliferation, survival and maintenance in pediatric AML and indicates the importance of exploring extrinsic factors that contribute to DNA damage control system suppression in vivo for therapeutic interventions. Disclosures No relevant conflicts of interest to declare.
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Peng, Min, Hui Li, Huan Cao, Yamei Huang, Weiping Yu, Chuanlai Shen, and Jinyang Gu. "Dual FGFR and VEGFR inhibition synergistically restrain hexokinase 2-dependent lymphangiogenesis and immune escape in intrahepatic cholangiocarcinoma." Journal of Gastroenterology, July 11, 2023. http://dx.doi.org/10.1007/s00535-023-02012-8.
Анотація:
Abstract Background Therapies for cholangiocarcinoma are largely limited and ineffective. Herein, we examined the role of the FGF and VEGF pathways in regulating lymphangiogenesis and PD-L1 expression in intrahepatic cholangiocarcinoma (iCCA). Methods The lymphangiogenic functions of FGF and VEGF were evaluated in lymphatic endothelial cells (LECs) and iCCA xenograft mouse models. The relationship between VEGF and hexokinase 2 (HK2) was validated in LECs by western blot, immunofluorescence, ChIP and luciferase reporter assays. The efficacy of the combination therapy was assessed in LECs and xenograft models. Microarray analysis was used to evaluate the pathological relationships of FGFR1 and VEGFR3 with HK2 in human lymphatic vessels. Results FGF promoted lymphangiogenesis through c-MYC-dependent modulation of HK2 expression. VEGFC also upregulated HK2 expression. Mechanistically, VEGFC phosphorylated components of the PI3K/Akt/mTOR axis to upregulate HIF-1α expression at the translational level, and HIF-1α then bound to the HK2 promoter region to activate its transcription. More importantly, dual FGFR and VEGFR inhibition with infigratinib and SAR131675 almost completely inhibited lymphangiogenesis, and significantly suppressed iCCA tumor growth and progression by reducing PD-L1 expression in LECs. Conclusions Dual FGFR and VEGFR inhibition inhibits lymphangiogenesis through suppression of c-MYC-dependent and HIF-1α-mediated HK2 expression, respectively. HK2 downregulation decreased glycolytic activity and further attenuated PD-L1 expression. Our findings suggest that dual FGFR and VEGFR blockade is an effective novel combination strategy to inhibit lymphangiogenesis and improve immunocompetence in iCCA.
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Zhou, Jie, Yaomin Hu, Wende Zhu, Chuansheng Nie, Wenxiu Zhao, Alexander T. Faje, Kay E. Labelle, et al. "Sprouting Angiogenesis in Human Pituitary Adenomas." Frontiers in Oncology 12 (May 5, 2022). http://dx.doi.org/10.3389/fonc.2022.875219.
Анотація:
IntroductionAngiogenesis in pituitary tumors is not fully understood, and a better understanding could help inform new pharmacologic therapies, particularly for aggressive pituitary tumors.Materials and Methods219 human pituitary tumors and 12 normal pituitary glands were studied. Angiogenic genes were quantified by an angiogenesis qPCR array and a TaqMan probe-based absolute qPCR. Angiogenesis inhibition in pituitary tumors was evaluated in vitro with the endothelial tube formation assay and in vivo in RbΔ19 mice.Results71 angiogenic genes, 40 of which are known to be involved in sprouting angiogenesis, were differentially expressed in pituitary tumors. Expression of endothelial markers CD31, CD34, and ENG was significantly higher in pituitary tumors, by 5.6, 22.3, and 8.2-fold, respectively, compared to in normal pituitary tissue. There was no significant difference in levels of the lymphatic endothelial marker LYVE1 in pituitary tumors compared with normal pituitary gland tissue. Pituitary tumors also expressed significantly higher levels of angiogenesis growth factors, including VEGFA (4.2-fold), VEGFB (2.2), VEGFC (19.3), PGF (13.4), ANGPT2 (9.2), PDGFA (2.7), PDGFB (10.5) and TGFB1 (3.8) compared to normal pituitary tissue. Expression of VEGFC and PGF was highly correlated with the expression of endothelial markers in tumor samples, including CD31, CD34, and ENG (endoglin, a co-receptor for TGFβ). Furthermore, VEGFR inhibitors inhibited angiogenesis induced by human pituitary tumors and prolonged survival of RbΔ19 mice.ConclusionHuman pituitary tumors are characterized by more active angiogenesis than normal pituitary gland tissue in a manner consistent with sprouting angiogenesis. Angiogenesis in pituitary tumors is regulated mainly by PGF and VEGFC, not VEGFA and VEGFB. Angiogenesis inhibitors, such as the VEGFR2 inhibitor cabozantinib, may merit further investigation as therapies for aggressive human pituitary tumors.
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"OK-432 suppresses lymphorrhea after urological tumorectomy by regulating Akt/NFκB mediated VEGFC/VEGFR-3 signaling". Frontiers in Medical Science Research 5, № 8 (2023). http://dx.doi.org/10.25236/fmsr.2023.050804.