INSULIN-LIKE GROWTH-FACTOR-II OVEREXPRESSION IN MYOBLASTS INDUCES PHENOTYPIC CHANGES TYPICAL OF THE MALIGNANT PHENOTYPE

The objective of this study was to examine the role of insulin-like gr owth factor it (IGF-II) in the pathogenesis of human rhabdomyosarcomas (RMS). We have demonstrated previously that RMS express high levels o f lGF-II mRNA, secrete IGF-II peptide, and express both IGF-I and IGF- II receptors. Moreover, we showed that IGF-II functions as an autocrin e growth and motility factor in RMS. Since IGF-II is expressed at high levels in fetal muscle cells and RMS are tumors thought to derive fro m skeletal myoblasts arrested along the normal myogenic pathway, autoc rine production of IGF-II by RMS may be an etiological event in the de velopment of this tumor. We have developed a model system which enable d us to study the effects of endogenous IGF-II overprotection in muscl e myoblasts. Human cDNA for pre-prohormone IGF-II was transfected into mouse myoblasts in order to achieve high, constant expression of this growth factor, which is normally down-regulated at the end of the dif ferentiation process. Expression of high IGF-II levels resulted in: (a ) an increased proliferative rate; (b) impairment of the ability to di fferentiate into myoblasts; and (c) acquisition of the capability of a nchorage-independent growth. No changes in the expression of IGF-I rec eptors were noted. We conclude that IGF-II overexpression in muscle my oblasts induces morphological and biological changes typical of the ma lignant phenotype and represents a fundamental event in the pathogenes is of RMS and possibly of other embryonal tumors.