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Vascular Endothelial Growth Factor Secretion by Tumor-infiltrating Macrophages Essentially Supports Tumor Angiogenesis, and IgG Immune Complexes Potentiate the Process

BioCrystal Ltd. Research Laboratories, Westerville, Ohio 43082-8888

Tumor growth requires neoangiogenesis. Members of the vascular endothelial growth factor (VEGF) family play an important role as angiogenic promoters in malignant tumors. Tumor cells and stromal cells are sources of VEGF in the tumor. We tested the relevance of the tumor-infiltrating macrophage (TIM) contribution as a source of VEGF in the tumor environment and the role of the local immune complexes in inducing the TIM release of VEGF. Colon and breast carcinoma biopsies were studied with immunoperoxidase staining of CD11b, sialyl-Tn (sTn) antigen (Ag), and immunoglobulin (IgG). The presence of TIM containing phagosomes positive for both IgG and sTn Ag was observed in all tumors, showing that TIMs endocytosed local immune complexes. Reverse transcription-PCR analysis of macrophage (MO) mRNA showed VEGF-A and -B, but not VEGF-C or -D. That pattern was not modified by the presence of tumor cells. In vitro, the interaction of tumor cells and MO promoted the secretion of MO VEGF. The MO secretion of VEGF was augmented when tumor cells were added to cocultures containing MOs and polymorphonuclear cells. Immune complexes formed with tumor sTn Ag and IgG induced a 5-fold increase of MO VEGF secretion. In vivo, TIMs and neoangiogenesis were associated. In vivo experiments with severe combined immunodeficient and athymic nude (nu/nu) mice showed increased number of TIMs, increased tumor angiogenesis, and faster tumor growth in mice with significant serum anti-sTn IgG. This study demonstrates that VEGF secreted by TIMs represents an essential support for tumor angiogenesis and growth, certainly influenced by the humoral antitumor immune response.

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