Genetic and Pharmacologic Inhibition of Complement Impairs Endothelial Cell Function and Ablates Ovarian Cancer Neovascularization
| Autor: | Matthew Guerra, John D. Lambris, Robert A. DeAngelis, You-Qiang Wu, Selene Nunez-Cruz, Denise C. Connolly, Nathalie Scholler, Phyllis A. Gimotty, George Coukos |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Male
Vascular Endothelial Growth Factor A Cancer Research medicine.medical_specialty Angiogenesis medicine.medical_treatment Complement C5a Mice Transgenic Complement factor I Biology Peptides Cyclic lcsh:RC254-282 C5a receptor Mice Immune system Lymphocytes Tumor-Infiltrating Internal medicine medicine Animals Humans Protein Isoforms Complement Activation Ovarian Neoplasms Neovascularization Pathologic Endothelial Cells Complement C3 Complement System Proteins lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Complement system Endothelial stem cell Endocrinology Cytokine Cell Transformation Neoplastic Myeloid-derived Suppressor Cell Cancer research Female Research Article |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 14, Iss 11, Pp 994-1004 (2012) |
| ISSN: | 1522-8002 1476-5586 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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