Francesco Moccia1, Vittoria Fotia2, Richard Tancredi3, Matteo Giovanni Della Porta4, Vittorio Rosti5, Elisa Bonetti5, Valentina Poletto5, Sergio Marchini6, Luca Beltrame6, Giulia Gallizzi7, Gian Antonio Da Prada8, Paolo Pedrazzoli9, Alberto Riccardi10, Camillo Porta9, Alberto Zambelli11, Maurizio D'Incalci12. 1. Laboratory of General Physiology, Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy. 2. PhD Program in Experimental Medicine, University of Pavia, Pavia, Italy. 3. Medical Oncology Unit, IRCCS Fondazione Salvatore Maugeri, Pavia, Italy. 4. Cancer Center - IRCCS Humanitas Research Hospital Department of Biomedical Sciences, Humanitas University Rozzano - Milan, Italy. 5. Center for the Study of Myelofibrosis S.C. Research and Experimental Laboratory Biotechnology Area IRCCS Policlinico San Matteo Foundation, Pavia, Italy. 6. Dept. of Oncology, IRCCS-Mario Negri Institute for Pharmacological Research, Milano, Italy. 7. Oncology Unit Ospedale SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy. 8. Medical Oncology Unit, IRCCS Salvatore Maugeri Foundation, Pavia, Italy. 9. Medical Oncology, IRCCS San Matteo University Hospital Foundation, Pavia, Italy. 10. Medical Oncology Unit, IRCCS Salvatore Maugeri Foundation, Pavia, Italy; Department of Internal Medicine, University of Pavia, Pavia, Italy. 11. Unit of Medical Oncology, Azienda Ospedaliera Papa Giovanni XXIII, Bergamo, Italy. 12. Dept. of Oncology, IRCCS-Mario Negri Institute for Pharmacological Research, Milano, Italy. Electronic address: maurizio.dincalci@marionegri.it.
Abstract
BACKGROUND: Neovascularisation supports the metastatic switch in many aggressive solid cancers. Tumour neovessels are mostly lined by endothelial cells sprouting from nearby capillaries, but they could also be contributed by circulating endothelial progenitor cells (EPCs). However, scant information is available about tumour-derived EPCs. METHODS: We carried out the first thorough, unbiased comparison of phenotype, function and genotype of normal versus tumour-derived endothelial colony forming cells (ECFCs), a truly endothelial EPC subtype. We used healthy donors-derived ECFCs (N-ECFCs) as control for breast cancer (BC)- and renal cell carcinoma (RCC)-derived ECFCs. RESULTS: We found that both BC- and RCC-ECFCs belong to the endothelial lineage. Normal and tumour-derived ECFCs did not differ in terms of proliferative and tubulogenic rates. However, RCC-ECFCs were more resistant to rapamycin-induced apoptosis, whereas BC-ECFCs were more sensitive as compared with N-ECFCs. Gene expression profiling revealed 382 differentially expressed genes (DEGs; 192 upregulated and 150 downregulated) and 71 DEGs (33 upregulated, 38 downregulated) when comparing, respectively, BC- and RCC-ECFCs with N-ECFCs. Nonetheless, BC- and RCC-derived ECFCs shared 35 DEGs, 10 of which were validated by qRT-PCR; such 35 DEGs are organised in a gene network centred on FOS. CONCLUSION: These results provide the first clear-cut evidence that BC- and RCC-derived ECFCs exhibit an altered gene expression profile as compared with N-ECFCs; yet, they share a common gene signature that could highlight novel and more specific targets to suppress tumour vascularisation.
BACKGROUND: Neovascularisation supports the metastatic switch in many aggressive solid cancers. Tumour neovessels are mostly lined by endothelial cells sprouting from nearby capillaries, but they could also be contributed by circulating endothelial progenitor cells (EPCs). However, scant information is available about tumour-derived EPCs. METHODS: We carried out the first thorough, unbiased comparison of phenotype, function and genotype of normal versus tumour-derived endothelial colony forming cells (ECFCs), a truly endothelial EPC subtype. We used healthy donors-derived ECFCs (N-ECFCs) as control for breast cancer (BC)- and renal cell carcinoma (RCC)-derived ECFCs. RESULTS: We found that both BC- and RCC-ECFCs belong to the endothelial lineage. Normal and tumour-derived ECFCs did not differ in terms of proliferative and tubulogenic rates. However, RCC-ECFCs were more resistant to rapamycin-induced apoptosis, whereas BC-ECFCs were more sensitive as compared with N-ECFCs. Gene expression profiling revealed 382 differentially expressed genes (DEGs; 192 upregulated and 150 downregulated) and 71 DEGs (33 upregulated, 38 downregulated) when comparing, respectively, BC- and RCC-ECFCs with N-ECFCs. Nonetheless, BC- and RCC-derived ECFCs shared 35 DEGs, 10 of which were validated by qRT-PCR; such 35 DEGs are organised in a gene network centred on FOS. CONCLUSION: These results provide the first clear-cut evidence that BC- and RCC-derived ECFCs exhibit an altered gene expression profile as compared with N-ECFCs; yet, they share a common gene signature that could highlight novel and more specific targets to suppress tumour vascularisation.
Authors: Anton G Kutikhin; Alexey E Tupikin; Vera G Matveeva; Daria K Shishkova; Larisa V Antonova; Marsel R Kabilov; Elena A Velikanova Journal: Cells Date: 2020-04-03 Impact factor: 6.600