Preclinical and clinical studies positively correlate the expression of
vascular endothelial growth factor (
VEGF)-C in
tumors and the incidence of
lymph node metastases. However, how
VEGF-C regulates individual steps in the transport of
tumor cells from the primary
tumor to the draining lymph nodes is poorly understood. Here, we image and quantify these steps in
tumors growing in the tip of the mouse ear using intravital microscopy of the draining lymphatic vessels and lymph node, which receives spontaneously shed
tumor cells. We show that
VEGF-C overexpression in
cancer cells induces
hyperplasia in peritumor lymphatic vessels and increases the volumetric flow rate in lymphatics at the base of the ear by 40%. The increases in lymph flow rate and peritumor lymphatic surface area enhance the rate of
tumor cell delivery to lymph nodes, leading to a 200-fold increase in
cancer cell accumulation in the lymph node and a 4-fold increase in
lymph node metastasis. In our model,
VEGF-C overexpression does not confer any survival or growth advantage on
cancer cells. We also show that an anti-
VEGF receptor (VEGFR)-3 antibody reduces both lymphatic
hyperplasia and the delivery of
tumor cells to the draining lymph node, leading to a reduction in
lymph node metastasis. However, this treatment is unable to prevent the growth of
tumor cells already seeded in lymph nodes. Collectively, our results indicate that
VEGF-C facilitates
lymphatic metastasis by increasing the delivery of
cancer cells to lymph nodes and
therapies directed against
VEGF-C/VEGFR-3 signaling target the initial steps of
lymphatic metastasis.