Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma

English, W. R., Lunt, S. J., Fisher, M., Lefley, D. V., Dhingra, M., Lee, Y. C., Bingham, K., Hurrell, J. E., Lyons, S. K., Kanthou, C., Tozer, G. M. (May 2017) Differential Expression of VEGFA Isoforms Regulates Metastasis and Response to Anti-VEGFA Therapy in Sarcoma. Cancer Res, 77 (10). pp. 2633-2646. ISSN 1538-7445 (Electronic)0008-5472 (Linking)

URL: https://www.ncbi.nlm.nih.gov/pubmed/28377452
DOI: 10.1158/0008-5472.CAN-16-0255

Abstract

Elevated plasma concentrations of soluble VEGFA isoforms are associated with poor prognosis in parallel with improved response to treatment with the anti-VEGFA antibody bevacizumab. To uncover the underlying mechanism to these observations, we administered anti-VEGFA therapy to mice bearing luminescent mouse fibrosarcomas expressing single VEGFA isoforms or their wild type counterparts expressing all isoforms (fs120, fs164, fs188 or fsWT). Expression of the more soluble isoforms conferred an advantage for lung metastasis from subcutaneous tumors (fs120/164 versus fs188/WT); fs120 cells also produced more lung colonies than fs188 cells when injected intravenously. Metastasis from subcutaneous fs120 tumors was more sensitive than fs188 to treatment with the anti-VEGFA antibody B20-4.1.1. Despite elevated plasma levels of VEGFA in fs120 tumor-bearing mice and a dependence on VEGF receptor 1 activity for metastasis to the lung, B20-4.1.1 did not affect survival in the lung on intravenous injection. B20-4.1.1 inhibited subcutaneous tumor growth and decreased vascular density in both fs120 and fs188 tumors. However, migration of fs120, but not fs188 cells in vitro was inhibited by B20-4.1.1. The greater survival of fs120 cells in the lung was associated with VEGFR1-dependent accumulation of CD11b positive myeloid cells and higher expression of the VEGFR1 ligand, PlGF2, by the fs120 cells in vitro and in the plasma and lungs of fs120 tumor-bearing mice. We conclude that soluble VEGFA isoform expression increases fibrosarcoma metastasis through multiple mechanisms that vary in their sensitivity to anti-VEGF/VEGFR inhibition, with VEGFA-targeted therapy suppressing metastasis through effects on the primary tumor rather than the metastatic site.

Item Type: Paper
Subjects: diseases & disorders > cancer > metastasis
diseases & disorders > cancer > cancer types > sarcoma
CSHL Authors:
Communities: CSHL labs > Lyons lab
CSHL Cancer Center Program > Cancer Genetics
Depositing User: Matt Covey
Date: 15 May 2017
Date Deposited: 12 May 2017 20:31
Last Modified: 12 Jun 2018 16:19
Related URLs:
URI: http://repository.cshl.edu/id/eprint/34712

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