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Loss of Tumorigenicity and Metastatic Potential in Carcinoma Cells Expressing the Extracellular Domain of the Type 1 Insulin-Like Growth Factor Receptor

Departments of ¹ Medicine and ² Surgery, McGill University Health Center, ³ Royal Victoria Hospital, ⁴ Organelle Signaling Laboratory, and ⁵ the Lady Davis Institute, McGill University, Montreal, Quebec, Canada

The receptor for the type 1 insulin-like growth factor (IGF-IR) was identified as a major regulator of the malignant phenotype and a target for cancer therapy. In the present study, a novel IGF-IR mutant consisting of the entire extracellular domain of the receptor (IGFIR⁹³³) was genetically engineered and expressed in highly metastatic H-59 murine lung carcinoma cells. We show here that the cells expressed a truncated heterotetramer (ß^m---ß^m) that was secreted into the medium and could neutralize the effects of exogenous IGF-I, thus diminishing IGF-I-induced signaling and blocking IGF-I-mediated cellular functions such as cell proliferation, invasion, and survival. In vivo, tumor incidence and growth rate were markedly reduced in mice inoculated s.c. with H-59/IGFIR⁹³³ cells. Moreover, after the intrasplenic/portal inoculation of these cells, there was a 90% reduction in the incidence of hepatic metastases and a significant increase in the long-term, disease-free survival of the mice compared with controls. Our results identify the IGFIR⁹³³ as a potent antitumorigenic and antimetastatic agent with potential applications for cancer gene therapy.

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