Dissociation between resistance to apoptosis and the transformed phenotype in IGF-I receptor signaling

Programmed Cell Death (PCD) is known to play an important role in both the development and the growth rate of human tumors. It has in fact been suggested that suppression of the apoptotic pathway is a requirement for the establishment of the transformed phenotype. In order to elucidate the relationship between resistance to apoptosis and transformation, we have asked in this investigation whether or not the two processes can be directly correlated. For this purpose, we have used mouse embryo fibroblasts (MEF) expressing either the wild-type or several mutants of the type 1 insulin-like growth factor receptor (IGF-IR). The wild-type IGF-IR has both transforming and anti-apoptotic activities, and we have asked whether these two activities can be or not separated in mutant receptors. Using this well-defined system, our results show that certain mutants of the IGF-IR that have strong anti-apoptotic and mitogenic activities, are incapable of transforming MEF (colony formation in soft agar). We have, instead, a good correlation between mitogenic and anti-apoptotic activities, suggesting the possibility that the two processes may share similar signaling pathways from the IGF-IR. On the other hand, our results indicate that transformation requires an additional signal, above and beyond the mitogenic and survival signals. Our conclusion is that, at least in this system, the establishment of the malignant phenotype and resistance to apoptosis can be dissociated, implying the possibility of separate targeting. J. Cell. Biochem. 72:294–310, 1999. © 1999 Wiley-Liss, Inc.