Author:

Keywords:

Angiogenesis, Cancer, Endothelial cell, Glucocorticoid, Myofibroblast, Science & Technology, Life Sciences & Biomedicine, Pharmacology & Pharmacy, TENASCIN-C, GROWTH-FACTOR, TUMOR ANGIOGENESIS, HEPATOCYTE GROWTH, RECEPTOR, MECHANISMS, PROSTAGLANDINS, PROLIFERATION, INHIBITION, MODULATOR, Angiogenesis Inhibitors, Angiopoietin-Like Protein 2, Angiopoietin-like Proteins, Angiopoietins, Animals, Cancer-Associated Fibroblasts, Cell Line, Transformed, Cell Movement, Cell Proliferation, Colonic Neoplasms, Culture Media, Conditioned, Dexamethasone, Endothelial Cells, Glucocorticoids, Human Umbilical Vein Endothelial Cells, Humans, Male, Mice, Inbred C57BL, Myofibroblasts, Neovascularization, Pathologic, Neovascularization, Physiologic, Paracrine Communication, Ribonuclease, Pancreatic, Signal Transduction, Stromal Cells, Time Factors, Tissue Culture Techniques, Tumor Microenvironment, Urokinase-Type Plasminogen Activator, 1115 Pharmacology and Pharmaceutical Sciences, Cardiovascular System & Hematology, 3214 Pharmacology and pharmaceutical sciences

Abstract:

Angiogenesis is important in cancer progression and can be influenced by tumor-associated myofibroblasts. We addressed the hypothesis that glucocorticoids indirectly affect angiogenesis by altering the release of pro-angiogenic factors from colon cancer-derived myofibroblasts. Our study shows that glucocorticoids reduced prostanoids, urokinase-type plasminogen activator (uPA) and angiopoietin-like protein-2 (ANGPTL2) levels, but increased angiogenin (ANG) in supernatant from human CT5.3hTERT colon cancer-derived myofibroblasts. Conditioned medium from solvent- (CMS) and dexamethasone (Dex)-treated (CMD) myofibroblasts increased human umbilical vein endothelial cell (HUVEC) proliferation, but did not affect expression of pro-angiogenic factors or tube-like structure formation (by HUVECs or human aortic ECs). In a HUVEC scratch assay CMS-induced acceleration of wound healing was blunted by CMD treatment. Moreover, CMS-induced neovessel growth in mouse aortic rings ex vivo was also blunted using CMD. The latter effect could be ascribed to both Dex-driven reduction of secreted factors and potential residual Dex present in CMD (indicated using a dexamethasone-spiked CMS control). A similar control in the scratch assay, however, revealed that altered levels of factors in the CMD, and not potential residual Dex, were responsible for decreased wound closure. In conclusion, our results suggest that glucocorticoids indirectly alter endothelial cell function during tumor development in vivo.