Activation of the VEGFC/VEGFR3 pathway induces tumor immune escape in colorectal cancer.

Colorectal cancer (CRC) is a major cause of cancer-related death in Western countries and is associated with increased numbers of lymphatic vessels (LVs) and tumor-associated macrophages (TAMs). The VEGFC/VEGFR3 pathway is regarded as the principal inducer of lymphangiogenesis and it contributes to metastases; however, no data are available regarding its role during primary CRC development. We found that both VEGFC and VEGFR3 were upregulated in human non-metastatic CRC, with VEGFR3 expressed on both LVs and TAMs. With the use of three different preclinical models of CRC, we also discovered that the VEGFC/VEGFR3 axis can shape both lymphatic endothelial cells (LECs) and TAMs to synergistically inhibit anti-tumor immunity and promote primary CRC growth. Therefore, VEGFR3-directed therapy could be envisioned for the treatment of non-metastatic CRC.

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