title: Colon cancer-derived myofibroblasts increase endothelial cell migration by glucocorticoid-sensitive secretion of a pro-migratory factor.
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.
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Oncology & Experimental Cancer Research, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Drebert
authors.affiliation: University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: MacAskill
authors.affiliation: Edinburgh Phenotypic Assay Centre, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Dahlia
authors.initials: D
authors.lastname: Doughty-Shenton
authors.affiliation: Cancer Research Institute Ghent (CRIG), Ghent, Belgium; Receptor Research Laboratories, Nuclear Receptor Lab (NRL), VIB Department of Medical Protein Research, Ghent University, Ghent, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Oncology & Experimental Cancer Research, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: Marc
authors.initials: M
authors.lastname: Bracke
authors.affiliation: University/BHF Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom. Electronic address: Patrick.hadoke@ed.ac.uk.
authors.forename: Patrick W F
authors.initials: PWF
authors.lastname: Hadoke
authors.affiliation: Laboratory of Experimental Cancer Research, Department of Radiation Oncology & Experimental Cancer Research, Ghent University, Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
authors.forename: Ilse M
authors.initials: IM
authors.lastname: Beck
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000072645:Cancer-Associated Fibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017077:Culture Media, Conditioned / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005938:Glucocorticoids / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic / Q000187:drug effects; D019899:Paracrine Communication / Q000187:drug effects; D012259:Ribonuclease, Pancreatic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D046509:Tissue Culture Techniques; D059016:Tumor Microenvironment; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism
chemical_list: C485792:ANGPTL2 protein, human; D020533:Angiogenesis Inhibitors; D000091302:Angiopoietin-Like Protein 2; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D017077:Culture Media, Conditioned; D005938:Glucocorticoids; D003907:Dexamethasone; C046366:angiogenin; D012259:Ribonuclease, Pancreatic; D014568:Urokinase-Type Plasminogen Activator
keywords: Angiogenesis; Cancer; Endothelial cell; Glucocorticoid; Myofibroblast