Inhibitors of the vascular endothelial growth factor (VEGF) pathway are approved for the treatment of several tumor types but their effectiveness is limited. The heterogeneity of tumor endothelial cells, determined by the dynamics of tumor vascularization not only requires sprouting angiogenesis but impinges on alternative mechanisms such as the recruitment of bone marrow (BM)-derived endothelial progenitor cells (EPCs). We focused on endothelial colony forming cells (ECFCs) the only EPC population truly belonging to the endothelial lineage by comparing normal vs tumor-derived ECFCs phenotype in two distinct, but hypervascularized cancers, such as renal cell carcinoma (RCC) and breast cancer (BC). ECFCs were successfully isolated from healthy donors (N-ECFCs), RCC patients (RCC-ECFCs) and BC patients (BC-ECFCs). ECFC colonies displayed the typical cobblestone-shaped monolayer, both normal and tumor derived ECFCs formed capillary-likes structures, and express classic endothelial markers. There was no difference in growth kinetics or tubulogenic rate between N-, RCC-, and BC-ECFCs. However, RCC-ECFCs were more resistant to rapamycin-induced apoptosis as compared to control cells, while BC-ECFCs were more sensitive. Genomic expression analysis identified a total of 382 differentially expressed genes (DEGs) between N- and BC-ECFCs and of 71 DEGs (33 up-regulated, 38 down-regulated) between N- and RCC-ECFCs. Nevertheless, we identified a common gene signature in BC- and RCC-derived ECFCs due to the presence of 35 DEGs that shared the same direction of regulation, i.e. all genes were either up-regulated or down-regulated in both groups. Ingenuity pathway analysis (IPA) unveiled interactions between these 35 DEGs there were centered on FOS, which plays a key role in the control of cell cycle and apoptosis. These findings provide the first strong molecular evidence that tumor microenviroment may also affect distant tissues and reprogram bone marrow derived-cells, such as ECFCs. However, the common signature identified in ECFCs isolated from patients suffering from two distinct tumor types might be relevant for carcinogenesis and could suggest new targets anti-angiogenic therapies.

27P * Common gene signature expressed by breast and kidney cancers-derived endothelial colony forming cells

DELLA PORTA, MATTEO GIOVANNI;Zambelli, Alberto;
2015

Abstract

Inhibitors of the vascular endothelial growth factor (VEGF) pathway are approved for the treatment of several tumor types but their effectiveness is limited. The heterogeneity of tumor endothelial cells, determined by the dynamics of tumor vascularization not only requires sprouting angiogenesis but impinges on alternative mechanisms such as the recruitment of bone marrow (BM)-derived endothelial progenitor cells (EPCs). We focused on endothelial colony forming cells (ECFCs) the only EPC population truly belonging to the endothelial lineage by comparing normal vs tumor-derived ECFCs phenotype in two distinct, but hypervascularized cancers, such as renal cell carcinoma (RCC) and breast cancer (BC). ECFCs were successfully isolated from healthy donors (N-ECFCs), RCC patients (RCC-ECFCs) and BC patients (BC-ECFCs). ECFC colonies displayed the typical cobblestone-shaped monolayer, both normal and tumor derived ECFCs formed capillary-likes structures, and express classic endothelial markers. There was no difference in growth kinetics or tubulogenic rate between N-, RCC-, and BC-ECFCs. However, RCC-ECFCs were more resistant to rapamycin-induced apoptosis as compared to control cells, while BC-ECFCs were more sensitive. Genomic expression analysis identified a total of 382 differentially expressed genes (DEGs) between N- and BC-ECFCs and of 71 DEGs (33 up-regulated, 38 down-regulated) between N- and RCC-ECFCs. Nevertheless, we identified a common gene signature in BC- and RCC-derived ECFCs due to the presence of 35 DEGs that shared the same direction of regulation, i.e. all genes were either up-regulated or down-regulated in both groups. Ingenuity pathway analysis (IPA) unveiled interactions between these 35 DEGs there were centered on FOS, which plays a key role in the control of cell cycle and apoptosis. These findings provide the first strong molecular evidence that tumor microenviroment may also affect distant tissues and reprogram bone marrow derived-cells, such as ECFCs. However, the common signature identified in ECFCs isolated from patients suffering from two distinct tumor types might be relevant for carcinogenesis and could suggest new targets anti-angiogenic therapies.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11699/64343
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