Differential effects of VEGFR-1 and VEGFR-2 inhibition on tumor metastases based on host organ environment.

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.

• Authors: Yoon-Jin Lee, Daniel L Karl, Ugwuji N Maduekwe, Courtney Rothrock, Sandra Ryeom, Patricia A D'Amore, Sam S Yoon
• Journal: Cancer research (Cancer Res) Vol. 70 Issue 21 Pg. 8357-67 (Nov 01 2010) ISSN: 1538-7445 [Electronic] United States
• PMID: 20978198 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2010 AACR.

Chemical References

• Antibodies, Neutralizing
• RNA, Messenger
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factor Receptor-1
• Vascular Endothelial Growth Factor Receptor-2

Topics

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