VEGF-C expressing Tumor Associated Macrophages decrease hematogenous metastatic dissemination and normalizes the tumor vasculature

Expression of pro-lymphangiogenic vascular endothelial growth factor C (VEGF-C) in primary tumors correlates with the occurrence of proximal lymph node metastasis in most solid cancer types. However, the role of VEGF-C in regulating tumor cell dissemination to distant organs is currently unclear. Perivascular tumor-associated macrophages (TAMs) are key regulators of hematogenous cancer cell spreading, forming tumor microenvironment of metastasis (TMEM) doorways for breast cancer cells to intravasate tumor blood vessels and fuel distant metastases. Using an experimental breast cancer (BC) model, we show here that TAMs expressing VEGF-C decrease cancer cell dissemination to the lung while enhancing lymph node metastasis. These TAMs express podoplanin and LYVE-1 and associate with normalized tumor blood vessels expressing VEGFR3. Further clinical data reveal that VEGF-C+ TAMs correlate inversely with malignant grade and with the occurrence of TMEM complexes in a cohort of BC patients. Thus, our study displays an apparently paradoxical role of TAM-derived VEGF-C in redirecting cancer cells to preferentially disseminate to the lymph nodes, at least in part, by normalizing tumor blood vessels.