The type I insulin-like growth factor receptor regulates cancer metastasis independently of primary tumor growth by promoting invasion and survival.
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.
Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA. sachd003@umn.edu
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Sachdev
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Zhang
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Gaillard-Kelly
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D000818:Animals; D023102:Anoikis / Q000187:drug effects; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D015151:Immunoblotting; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D014183:Transplantation, Heterologous; D047368:Tumor Burden / Q000187:drug effects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D017526:Receptor, IGF Type 1; C545477:AVE1642