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Macrophage-derived VEGF-C decreases hematogenous metastatic dissemination by normalizing the tumor vasculature

Breast cancer (BC) cells spread to secondary organs by exploiting lymphatic and blood vessels. Pro-angiogenic perivascular tumor-associated macrophages (TAMs) promote tumor cell intravasation and spreading to secondary organs by multiple mechanisms, including fueling tumor vessel abnormalization. Here, we show that perivascular TAMs expressing lymphangiogenic vascular endothelial growth factor (VEGF)-C normalize the tumor vasculature. This effect limited pulmonary metastases while enhancing lymph node metastasis. In contrast, tumor cell-derived VEGF-C promotes vascular abnormalization and pulmonary metastases. In human breast cancer, expression of VEGF-C in TAMs inversely correlated with both malignant grade and occurrence of three-cell complexes composed of a perivascular macrophage, a tumor cell, and an endothelial cell (collectively defined as tumor microenvironment of metastasis, or TMEM), which are known to facilitate hematogenous cancer cell spreading. Conversely, tumor cell-derived VEGF-C was associated with increased tumor grade and density of TMEM complexes. Our study reveals opposing effects of VEGF-C on BC metastasis that are dependent on the cellular source.