Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics

TLDR

Lymphatic metastasis is a major cause of mortality in solid tumors, yet it remains unclear whether cancer cells reach lymph nodes via intratumor lymphatic vessels. The study aimed to investigate the role of functional lymphatics in mouse tumors with normal or elevated VEGF‑C expression. Using mouse tumors engineered to express varying levels of VEGF‑C, the authors assessed lymphangiogenesis and lymphatic function through multiple functional assays and immunohistochemistry. Despite VEGF‑C–induced increases in lymphatic surface area and metastasis, the tumors lacked functional lymphatics, indicating that functional lymphatics at the tumor margin alone suffice for metastasis and represent a therapeutic target.

Abstract

Lymphatic metastasis contributes to mortality from solid tumors. Whether metastasizing cancer cells reach lymph nodes via intratumor lymphatic vessels is unknown. Here, we examine functional lymphatics associated with mouse tumors expressing normal or elevated levels of vascular endothelial growth factor-C (VEGF-C), a molecule that stimulates lymphangiogenesis. Although VEGF-C overexpression increased lymphatic surface area in the tumor margin and lymphatic metastasis, these tumors contained no functional lymphatics, as assessed by four independent functional assays and immunohistochemical staining. These findings suggest that the functional lymphatics in the tumor margin alone are sufficient for lymphatic metastasis and should be targeted therapeutically.