title: Mechanisms by which IGF-I may promote cancer.
abstract: Multiple large case-control studies in the past five years have reported positive associations between high circulating levels of the insulin-like growth factor (IGF)-I and risk for different types of cancer. Correlations certainly do not prove causation, but the reproducibility of this finding implies this is a hypothesis worth further examination through more mechanistic studies. IGF-I binds to the IGF-I receptor, a tyrosine kinase receptor that transduces signals to the nucleus and mitochondrion primarily via the mitogen-activated protein kinase (MAPK) and PI3K/Akt pathways. Examples will be provided to illustrate how IGF-I signaling may contribute to each stage of cancer progression: malignant transformation, tumor growth, local invasion and distant metastases, and resistance to treatment. In addition to direct contributions to each of these stages, IGF-I may promote cancer indirectly, through interactions with oncogenes and tumor suppressors, interactions with other hormones (especially the sex steroids in breast and prostate cancers) and interactions with the IGF binding proteins (IGFBPs). Finally, circulating IGF-I may facilitate cancer development though it likely does not cause cancer to form. Prompted by the accumulating evidence, investigations are also being pursued to modulate the IGF system as a possible means of cancer prevention or treatment.
authors.affiliation: University of Pennsylvania School of Medicine, Division of Pediatric Endocrinology, The Children's Hospital of Philadelphia, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania, USA. grimberg@email.chop.edu
authors.forename: Adda
authors.initials: A
authors.lastname: Grimberg
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000097:blood / Q000209:etiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1 / Q000737:chemistry / Q000502:physiology; D012307:Risk Factors; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C494918:AKT1 protein, human