Faculty Collaboration Database

RETRACTED: Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment. Cancer Res 2010 Nov 01;70(21):8357-67

Date

10/28/2010

Pubmed ID

20978198

Pubmed Central ID

PMC2970713

DOI

10.1158/0008-5472.CAN-10-1138

Scopus ID

2-s2.0-78449290379 (requires institutional sign-in at Scopus site)   58 Citations

Abstract

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.

Author List

Lee YJ, Karl DL, Maduekwe UN, Rothrock C, Ryeom S, D'Amore PA, Yoon SS

Author

Ugwuji N. Maduekwe MD Associate Dean, Associate Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antibodies, Neutralizing
Blotting, Western
Carcinoma, Renal Cell
Cell Adhesion
Cell Movement
Cell Proliferation
Cells, Cultured
Colonic Neoplasms
Endothelium, Vascular
Female
Fluorescent Antibody Technique
Hemangiosarcoma
Humans
Immunoenzyme Techniques
Kidney Neoplasms
Liver Neoplasms
Lung Neoplasms
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Metastasis
Neovascularization, Pathologic
Organ Specificity
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factor Receptor-1
Vascular Endothelial Growth Factor Receptor-2