The IGF-I/IGF-I receptor pathway: Implications in the Pathophysiology of Thyroid Cancer.
The biological actions of the insulin-like growth factor(IGF)-I are mediated by its activation of the IGF-I receptor (IGF-I R), a transmembrane tyrosine kinase linked to the Akt and ras-raf-MAPK cascades. A functional IGF-I R is required for the cell to progress through the cell cycle. Most importantly, cells lacking this receptor cannot be transformed by any of a number of dominant oncogenes, a finding that proves that the presence of the IGF-I R is important for the development of a malignant phenotype. Consistent with this role, it has been well established that IGF-I can protect cells from apoptosis under a variety of circumstances. For example, IGF-I prevents apoptosis induced by overexpression of c-myc in fibroblasts, by interleukin-3 withdrawal in interleukin-3-dependent hemopoietic cells, etoposide, a topoisomerase I inhibitor, anti-cancer drugs, UV-B irradiations, and serum deprivation. While the anti-apoptotic effect of IGF-I has been clearly demonstrated, the molecular mechanisms by which IGF-I inhibits apoptosis induced by these various stimuli remain unknown. We have previously documented increased IGF-I and IGF-I receptor immunoreactivity in human thyroid carcinomas with a corresponding up-regulation of IGF-I mRNA. Immunoreactivity for IGF-I and IGF-I receptor positively correlated with tumor diameter, but not with the occurrence of lymph node metastases. Several recent studies have identified new signaling pathways emanating from the IGF-I receptor that affect cancer cell proliferation, adhesion, migration and apoptosis, which represent critical functions for cancer cell survival and metastasizing capacity. In this review, various aspects of the IGF-I/IGF-I R pathway and its relationship to thyroid cancer are discussed.
Ciampolillo
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A
Section of Internal Medicine, Endocrinology and Metabolic Disease, Department of Emergency and Organ Transplantation, University of Bari, School of Medicine, Piazza Giulio Cesare, 11, 70124 Bari, Italy. a.ciampolillo@endo.uniba.it.
De Tullio
C
C
Giorgino
F
F
D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*
D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1