erential Effects of VEGFR-1 and VEGFR-2 Inhibition on R or Metastases Based on Host Organ Environment

Downlo ors induce new blood vessel growth primarily from host organ microvascular endothelial cells (EC), and vasculature differs significantly between the lung and liver. Vascular endothelial growth factor (VEGF GF-A) promotion of tumor angiogenesis is thought to be mediated primarily by VEGF receptor-2 R-2). In this study, VEGFR-2 antibody (DC101) inhibited growth of RenCa renal cell carcinoma lung tases by 26%, whereas VEGFR-1 antibody (MF-1) had no effect. However, VEGFR-2 neutralization had ect on RenCa liver metastases, whereas VEGFR-1 neutralization decreased RenCa liver metastases by or CT26 colon carcinoma liver metastases, inhibition of both VEGFR-1 and VEGFR-2 was required uce growth delay. VEGFR-1 or VEGFR-2 inhibition decreased tumor burden not by preventing the ishment of micrometastases but rather by preventing vascularization and growth of micrometastases and 43%, respectively. VEGF induced greater phosphorylation of VEGFR-2 in lung ECs and of -1 in liver ECs. EC proliferation, migration, and capillary tube formation in vitro were suppressed more GFR-2 inhibition for lung EC and more by VEGFR-1 inhibition for liver EC. Collectively, our results te that liver metastases are more reliant on VEGFR-1 than lung metastases to mediate angiogenesis indica due to differential activity of VEGFRs on liver EC versus lung EC. Thus, therapies inhibiting specific VEGFRs should consider the targeted sites of metastatic disease. Cancer Res; 70(21); 8357–67. ©2010 AACR.