The Roles of Osteonectin and Osteoactivin in Gliomas

项目描述（由申请人提供）：本项目的主要目的是验证两个骨相关基因在胶质瘤侵袭的病理过程中发挥重要作用的假设，骨连接素是一种在多种晚期人类癌症中过表达的分泌性细胞外基质蛋白，骨激活素是一种在多种癌症中也过表达的结构无关的跨膜蛋白。近年来，虽然许多基因改变失调的细胞生长和死亡过程参与肿瘤的启动已经被阐明，但在肿瘤侵袭、转移和血管生成的复杂而关键的过程中进展较少。侵袭在胶质瘤的病理生理中尤为重要，因为正常大脑的肿瘤细胞浸润阻碍了根治性切除。有了这个重点，我们的初步结果表明，骨连接素和骨激活素可以介导关键的肿瘤细胞行为。我们已经证明骨连接素和骨激活素的表达可以诱导自发转移和肿瘤细胞沿穿透血管侵入大脑。

DESCRIPTION (provided by applicant): The primary goal of this project is to test the hypothesis that two bone-related genes - osteonectin, which is a secreted extracellular matrix protein over-expressed in a wide range of advanced human cancers, and osteoactivin, which is a structurally unrelated transmembrane protein also over-expressed in several cancers - play important roles in the pathological process of glioma invasion. Although many of the genetic alterations that dysregulate the cell processes of growth and death involved in tumor initiation have been elucidated in recent years, less progress has been made in the complex but critical processes of tumor invasion, metastasis, and angiogenesis. Invasion is particularly important in the pathophysiology of gliomas as tumor cell infiltration of normal brain prevents curative resection. With this emphasis, our preliminary results suggest that osteonectin and osteoactivin can mediate critical tumor cell behaviors. We have shown that the expression of osteonectin and osteoactivin can induce spontaneous metastases and tumor cell invasion into the brain along penetrating blood vessels. Hypothesis: We hypothesize that osteonectin and osteoactivin expression can induce glioma invasion through the modification of tumor microenvironment, and that these mechanisms can be targeted to inhibit glioma invasion. To firmly establish the role of osteonectin and osteoactivin in the pathophysiology of gliomas and elucidate the mechanism by which osteonectin and osteoactivin functions to lay the foundation for the development of novel therapeutics directed towards osteonectin and osteoactivin, we will focus our studies on the following two Specific Aims: 1) Define the contributions of osteonectin and osteoactivin to the invasive phenotype of glioma. 2) Validate osteonectin and osteoactivin as potential therapeutic targets in glioma invasion. It is hoped that these studies will provide the basis of novel therapeutic interventions for patients with malignant gliomas.