The type I insulin-like growth factor receptor (IGF1R) regulates multiple aspects of malignancy and is the target of several drugs currently in clinical trials. Although the function of IGF1R in proliferation and survival is well studied, the regulation of metastasis by IGF1R is not as clearly delineated. Previous work showed that disruption of IGF1R signaling by overexpression of a dominant-negative IGF1R inhibited metastasis. To establish a clinically applicable approach to inhibition of metastasis by targeting IGF1R, we examined the effect of an inhibitory antibody against IGF1R, EM164 and its humanized version, AVE1642, on metastasis of cancer cells. EM164 and AVE1642 did not affect primary tumor growth of MDA-435A/LCC6 cells but inhibited metastasis of these cells. Consistent with this inhibition in the formation of metastatic nodules, disruption of IGF1R also resulted in a decreased number of circulating tumor cells in blood of tumor-bearing mice. Disruption of IGF1R with a dominant-negative construct or antibody inhibited invasion across Matrigel in vitro. When tumor cells were directly injected into the circulation through the lateral tail vein of mice, IGF1R disruption also resulted in significant reduction of pulmonary nodules, suggesting that regulation of invasion is not the only function of IGF1R signaling. Further, disruption of IGF1R rendered cells more susceptible to anoikis. Thus, IGF1R regulated metastasis independently of tumor growth. The multiple phenotypes regulated by IGF1R must be considered during development of this therapeutic strategy as inhibition of metastasis independent of inhibition of tumor growth is not easily assessed in phase II clinical trials.
Bibliographical noteFunding Information:
We acknowledge ImmunoGen Inc. for providing us with EM164 and the isotype-matched control antibody (anti-CD20), sanofi-aventis for AVE1642 (the humanized version of EM164), and the National Cell Culture Center (NCCC), a division of Biovest International, Fridley, MN, USA, for producing supernatant containing scFv-Fc from NSO 3b1Fc 1F12 cells in spinner cultures. We thank Nicole Kirchoff and the staff of the Comparative Pathology Shared Resource of the Masonic Cancer Center, University of Minnesota. We thank Sarah Thuriot and Alissa Pelzer for assistance with the care of the mice. We also thank Michael Franklin for editorial assistance. This work was supported by NIH R01 CA074285 (D Yee), NIH P30 CA077598PHS Cancer Center Support Grant P30 CA77398 from the National Cancer Institute and the Prospect Creek Foundation.
Copyright 2010 Elsevier B.V., All rights reserved.
- Antibodies against IGF1R
- Cancer metastasis
- Circulating tumor cells
- Type I IGF receptor