Tumors must invade lymph nodes to become metastatic, but how the tumor cells make this trip is not completely clear. On page 1089, Hirakawa and colleagues show that a tumor-derived growth factor stimulates the formation of new lymphatic vessels in the nearby lymph node, even before any tumor cells arrive. This suggests that the tumor may instruct the lymph node to prepare for its arrival.
Hirakawa et al. now show that expression of VEGF-A by skin cells causes mice to develop cancer more rapidly in response to a chemical carcinogen. Both blood vessel and lymphatic vessel growth were increased in VEGF-A–expressing skin tumors, a result that was consistent with their earlier observations that VEGF-A could induce the proliferation of lymphatic endothelial cells in culture.
VEGF-A induced active lymphatic proliferation both within the tumor and in the nearby lymph node, possibly explaining the increased metastasis of VEGF-A–expressing tumors. Lymphatic growth in the lymph node began—to the authors' surprise—before tumor cells arrived on the scene, suggesting that VEGF-A expression may help initiate tumor metastasis.
The angiogenic activity of VEGF-A was previously thought to be restricted to the immediate tumor vicinity. The authors now suggest that VEGF-A is drained from the tumor through both preexisting lymphatic vessels and the lymphatic vessels it helped construct. They are now investigating relative timing to see if tumor-localized lymphangiogenesis might be a prerequisite for node-localized lymphangiogenesis.