IGFS MEDIATE MOTILITY IN HUMAN NEUROBLASTOMA CELLS

描述：(改编自研究人员的摘要)癌症是 1至15岁儿童的死因。 神经母细胞瘤(NBL)是儿童第二常见的实体瘤， 占所有青少年癌症的10%。血源性传播 局部侵犯骨髓、软脑膜和其他器官的NBL 在很大程度上对常规放射和化疗无效。他们是 对胰岛素样生长因子-I和IGF-II的作用感兴趣 I型胰岛素样生长因子受体(IGF-IR)在肺癌致癌和转移潜能中的作用 NBL.在这项工作中，他们利用了从不同人类建立的细胞系 NBL肿瘤。SH-SY5&NBL系是从一个4岁的肿瘤中亚克隆的 女孩在她死前一个月。他们发现SH-SY5Y细胞分泌 IGF-II通过IGF-IR促进自分泌生长和抵抗 到程序化的细胞死亡。最近的研究表明IGF-I和IGF-II 也是强大的NBL运动因子。胰岛素样生长因子对SH-SY5Y细胞的作用 导致肌动蛋白细胞骨架的重新分布 快速移动的膜洗涤。褶皱之后是突出的 粘着特定细胞外基质分子的片状脂体和 形成稳定的粘连灶。 他们提出了一种新的假说，以理解 支持NBL运动的机制。他们认为IGF与IGF-IR结合， 刺激受体自磷酸化，胰岛素受体底物-1 磷脂酰肌醇-3激酶(IRS-1)的磷酸化和活化 (PI-3K)。导致GTP结合蛋白Rac的激活， 反过来，促进肌动蛋白聚合，随后是膜褶皱和 肿瘤前缘的突起。凸出的膜形成 粘附胞外基质的片状脂体，并通过 灶性粘连。循环的重复伴随着旧的释放 粘连可以持续推进椎板和NBL的移行。这个 当前提案的目的是测试 假设。它们有四个目的：1)表征形态效应 IGF-I对NBL的作用；2)确定IGF-IR信号通路在IGF-I中的作用 3)确定PI-3K在IGF-I中的作用 介导的形态变化和RAC的激活；4)检测 Rac在IGF-I介导的膜褶皱、片脂形成和细胞周期中的作用 细胞的运动性。 这些研究的结果具有一定的临床意义。 旨在阻断IGF介导的NBL运动的治疗可能改变NBL 转移潜能。策略包括抑制配体和 受体，使用中和抗体、封闭抗体或中介 寡核苷酸。显然，抗生长工厂疗法的目标是 特定的基因，在治疗中既有理论又有实践 Nbl.

DESCRIPTION: (adapted from the investigator's abstract) 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.