Cancer is the major cause of death in children between the ages of 1 and 15 years. Neuroblastoma (NBL), the second most common solid tumor in childhood, accounts for 10percent of all juvenile cancer. Hematogenous dissemination of NBL with local invasion into bone marrow, leptomeninges and other organs is largely refractory to conventional radiation and chemotherapy. They are interested in the role of insulin-like growth factor (IGF)-I and II and the type I IGF receptor (IGF-IR) in the carcinogenic and metastatic potential of NBL. In the work, they utilize cell lines established from different human NBL tumors. The SH-SY5& NBL line was subcloned from a tumor of a 4 year old girl one month prior to her death. They find that SH-SY5Y cells secrete IGF-II which acts via IGF-IR to promote both autocrine growth and resistance to programed cell death. The most recent studies demonstrate IGF-I and II are also potent NBL motility factors. IGF treatment of SH-SY5Y cells results in redistribution of the actin cytoskeleton with the formation of rapidly moving membrane reffles. Ruffling is followed by protrusion of lamellipodia which adhere to specific extracellular matrix molecules and form stable adhesion foci. They have developed a novel hypothesis centered on understanding the mechanism which underlies NBL motility. They believe IGFs bind to IGF-IR, stimulating receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) phosphorylation, and activation of phsophatidylinositol-3 kinase (PI-3K). The results in the activation of a GTP-binding protein rac which, in turn, promotes actin polymerization followed by membrane ruffling and protrusion of the leading tumor edge. Protruding membranes form lamellipodia which adhere to the extracellular matrix and are stabilized by focal adhesions. Repetition of the cycle coupled with release of old adhesions allows continued lamellipodial advance and NBL migration. The purpose of the current proposal is to test the initial components of the hypothesis. They have 4 aims: 1) Characterize the morphological effects of IGF-I on NBL; 2) Determine the role of IGF-IR signaling cascades in IGF-I mediated morphological changes; 3) Determine the role of PI-3K in IGF-I mediated morphological changes and rac activation; 4) Examine the role of rac in IGF-I mediated membrane ruffling, lamellipodial formation and cellular motility. Results gained from these studies are of definite clinical importance. Therapies aimed at interrupting IGF mediated NBL motility may alter NBL metastatic potential. Strategies include inhibiting both the ligand and receptor, using neutralizing antibodies, blocking antibodies, or medified oligonucleotides. Clearly, anti-growth factory therapy, targeted at specific genes, has both theoretical and practical appear in the treatment of NBL.
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