title: Insulin-like growth factor II overexpression in myoblasts induces phenotypic changes typical of the malignant phenotype.
abstract: The objective of this study was to examine the role of insulin-like growth factor II (IGF-II) in the pathogenesis of human rhabdomyosarcomas (RMS). We have demonstrated previously that RMS express high levels of IGF-II mRNA, secrete IGF-II peptide, and express both IGF-I and IGF-II receptors. Moreover, we showed that IGF-II functions as an autocrine 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 from skeletal myoblasts arrested along the normal myogenic pathway, autocrine production of IGF-II by RMS may be an etiological event in the development of this tumor. We have developed a model system which enabled us to study the effects of endogenous IGF-II overprotection in muscle 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 differentiation process. Expression of high IGF-II levels resulted in: (a) an increased proliferative rate; (b) impairment of the ability to differentiate into myoblasts; and (c) acquisition of the capability of anchorage-independent growth. No changes in the expression of IGF-I receptors were noted. We conclude that IGF-II overexpression in muscle myoblasts induces morphological and biological changes typical of the malignant phenotype and represents a fundamental event in the pathogenesis of RMS and possibly of other embryonal tumors.
authors.affiliation: Lombardi Cancer Center, Georgetown University Medical School, Washington, DC 20007, USA.
authors.forename: C P
authors.initials: CP
authors.lastname: Minniti
authors.forename: D
authors.initials: D
authors.lastname: Luan
authors.forename: C
authors.initials: C
authors.lastname: O'Grady
authors.forename: R G
authors.initials: RG
authors.lastname: Rosenfeld
authors.forename: Y
authors.initials: Y
authors.lastname: Oh
authors.forename: L J
authors.initials: LJ
authors.lastname: Helman
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D003402:Creatine Kinase / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009132:Muscles / Q000166:cytology / Q000378:metabolism*; D018008:Myogenin / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis; D013997:Time Factors; D014162:Transfection
chemical_list: C503799:MYOG protein, human; C503801:Myog protein, mouse; D018008:Myogenin; D012333:RNA, Messenger; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D003402:Creatine Kinase