RETRACTED: Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment.
Tumors induce new blood vessel growth primarily from host organ microvascular endothelial cells (EC), and microvasculature differs significantly between the lung and liver. Vascular endothelial growth factor (VEGF or VEGF-A) promotion of tumor angiogenesis is thought to be mediated primarily by VEGF receptor-2 (VEGFR-2). In this study, VEGFR-2 antibody (DC101) inhibited growth of RenCa renal cell carcinoma lung metastases by 26%, whereas VEGFR-1 antibody (MF-1) had no effect. However, VEGFR-2 neutralization had no effect on RenCa liver metastases, whereas VEGFR-1 neutralization decreased RenCa liver metastases by 31%. For CT26 colon carcinoma liver metastases, inhibition of both VEGFR-1 and VEGFR-2 was required to induce growth delay. VEGFR-1 or VEGFR-2 inhibition decreased tumor burden not by preventing the establishment of micrometastases but rather by preventing vascularization and growth of micrometastases by 55% and 43%, respectively. VEGF induced greater phosphorylation of VEGFR-2 in lung ECs and of VEGFR-1 in liver ECs. EC proliferation, migration, and capillary tube formation in vitro were suppressed more by VEGFR-2 inhibition for lung EC and more by VEGFR-1 inhibition for liver EC. Collectively, our results indicate that liver metastases are more reliant on VEGFR-1 than lung metastases to mediate angiogenesis 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.
Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Yoon-Jin
YJ
Lee
Daniel L
DL
Karl
Ugwuji N
UN
Maduekwe
Courtney
C
Rothrock
Sandra
S
Ryeom
Patricia A
PA
D'Amore
Sam S
SS
Yoon
D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D015153:Blotting, Western; D002292:Carcinoma, Renal Cell / Q000556:secondary; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000473:pathology; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006394:Hemangiosarcoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D006801:Humans; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000473:pathology; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D009928:Organ Specificity; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000276:immunology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000276:immunology*
D057134:Antibodies, Neutralizing; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2