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.

Even before metastasis, VEGF-A induces growth of new lymphatic vessels (red) in the draining lymph node.

Stimulation of lymphatic growth has for some time played second fiddle to angiogenesis. During angiogenesis, tumors produce factors such as vascular endothelial growth factor-A (VEGF-A) that induce vessel growth and thus greater nutrient supply. Recently, however, two relatives of VEGF-A, VEGF-C and VEGF-D, have been shown to induce lymphangiogenesis within tumors. Although earlier studies suggested that VEGF-A could also induce lymphangiogenesis, this had never been shown in a tumor model and remained controversial.

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.