Vascular endothelial growth factor receptors (VEGFR) have important roles in
cancer, affecting blood and lymphatic vessel functionality as well as
tumor cells themselves. We compared the efficacy of a VEGFR
tyrosine kinase inhibitor,
PTK787/
ZK222584 (PTK/ZK), which targets the three VEGFRs, with
blocking antibodies directed against
VEGFR-2 (DC101) or
VEGF-A (Pab85618) in a metastatic
melanoma model. Although all inhibitors exerted comparable effects on primary
tumor growth, only PTK/ZK significantly reduced
lymph node metastasis formation. A comparable decrease in lymphatic vessel density following blockade of
VEGFR-2 (DC101) or the three VEGFRs (PTK/ZK) was observed in the
metastases. However, the functionality of lymphatics surrounding the primary
tumor was more significantly disrupted by PTK/ZK, indicating the importance of multiple VEGFRs in the metastatic process. The antimetastatic properties of PTK/ZK were confirmed in a
breast carcinoma model. B16/BL6
tumor cells express
VEGF ligands and their receptors. Blockade of a
VEGFR-1 autocrine loop with PTK/ZK inhibited
tumor cell migration. Furthermore, the
tumor cells also showed enhanced sensitivity to
platinum-based
chemotherapy in combination with PTK/ZK, indicating that autocrine VEGFRs are promoting
tumor cell migration and survival. In summary, our results suggest that, in addition to blocking angiogenesis, combined inhibition of the three VEGFRs may more efficiently target other aspects of
tumor pathophysiology, including lymphatic vessel functionality,
tumor cell dissemination, survival pathways, and response to chemotherapeutic compounds.