Article: article from journal or magazin.
Genetic and pharmacologic inhibition of complement impairs endothelial cell function and ablates ovarian cancer neovascularization.
Publication types: Journal Article Publication Status: ppublish
Complement activation plays a critical role in controlling inflammatory responses. To assess the role of complement during ovarian cancer progression, we crossed two strains of mice with genetic complement deficiencies with transgenic mice that develop epithelial ovarian cancer (TgMISIIR-TAg). TgMISIIR-TAg mice fully or partially deficient for complement factor 3 (C3) (Tg(+)C3(KO) and Tg(+)C3(HET), respectively) or fully deficient for complement factor C5a receptor (C5aR) (Tg(+)C5aR(KO)) develop either no ovarian tumors or tumors that were small and poorly vascularized compared to wild-type littermates (Tg(+)C3(WT), Tg(+)C5aR(WT)). The percentage of tumor infiltrating immune cells in Tg(+)C3(HET) tumors compared to Tg(+)C3(WT) controls was either similar (macrophages, B cells, myeloid-derived suppressor cells), elevated (effector T cells), or decreased (regulatory T cells). Regardless of these ratios, cytokine production by immune cells taken from Tg(+)C3(HET) tumors was reduced on stimulation compared to Tg(+)C3(WT) controls. Interestingly, CD31(+) endothelial cell (EC) function in angiogenesis was significantly impaired in both C3(KO) and C5aR(KO) mice. Further, using the C5aR antagonist PMX53, tube formation of ECs was shown to be C5a-dependent, possibly through interactions with the VEGF(165) but not VEGF(121) isoform. Finally, the mouse VEGF(164) transcript was underexpressed in C3(KO) livers compare to C3(WT) livers. Thus, we conclude that complement inhibition blocks tumor outgrowth by altering EC function and VEGF(165) expression.
Animals, Cell Transformation, Neoplastic/genetics, Cell Transformation, Neoplastic/immunology, Complement Activation/immunology, Complement C3/deficiency, Complement C5a/antagonists & inhibitors, Complement C5a/immunology, Complement System Proteins/drug effects, Complement System Proteins/genetics, Endothelial Cells/drug effects, Endothelial Cells/immunology, Female, Humans, Lymphocytes, Tumor-Infiltrating/immunology, Male, Mice, Mice, Transgenic, Neovascularization, Pathologic/immunology, Ovarian Neoplasms/blood supply, Ovarian Neoplasms/genetics, Peptides, Cyclic/pharmacology, Protein Isoforms, Vascular Endothelial Growth Factor A/metabolism
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