The Role of Osteopontin in Cancer Progression and Bone Metastasis

描述(申请人提供)：这个项目的长期目标是阐明骨桥蛋白(OPN)刺激的信号通路，它在提高细胞存活率的同时也刺激癌细胞转移。骨桥蛋白与黏附受体如整合素和CD44的相互作用介导了许多细胞过程，包括细胞黏附、迁移、增殖和生存。随着最近的研究发现OPN在乳腺癌、前列腺癌和胰腺癌中的过度表达，OPN在癌症进展中的作用越来越引起人们的兴趣；OPN也可能是一个潜在的转移预后指标。在阐明OPN在癌症中的作用时，一个关键的步骤是它被证明增加了PKB/Akt的激活，PKB/Akt是调节细胞生存和发展的重要分子。Akt的结构性激活在许多类型的人类癌症中经常被观察到，其致病作用以及参与其生存和发展的信号通路(S)尚不清楚。这一建议旨在通过首先阐明整合素aVp3和细胞表面受体CD44在通过Akt调控癌细胞生存和进展中的作用，从而更全面地破译OPN在癌细胞生存和转移中的作用。包括siRNA在内的特异性细胞受体抑制剂和抑制抗体将用于确定OPN介导的Akt激活的启动过程中涉及的分子相互作用。前列腺癌细胞(PCS)具有表达OPN和转移到包括下颌骨在内的骨结构的能力，因此被选为模型系统。OPN与其细胞表面受体结合的下游效应将集中在Akt细胞生存机制中的两个重要调节因子整合素连接激酶(ILK)和PI3-激酶的细胞信号变化上。OPN介导的Akt细胞的存活和转移将通过使用ILK和PI3-K的特异性分子抑制剂来进一步阐明，同时还将研究OPN对其激酶活性的影响。这一建议旨在通过检验OPN与其细胞受体的协同作用通过激活在癌细胞的生存、迁移、肿瘤生长和转移事件中起关键作用的PI3-K/Akt和ILK/Akt通路来引起下游细胞信号变化的总体假说来阐明转移和生存机制。骨桥蛋白是一种细胞外基质蛋白，作为细胞黏附、迁移、增殖和生存的重要介质，与肿瘤的发展密切相关。进一步研究骨桥蛋白在癌症中的作用可能会增加对癌症进展机制的了解，从而为临床医学打开新的大门，从而提供更多的治疗靶点。

DESCRIPTION (provided by applicant): The long-term objective of this project is to elucidate the signaling pathways stimulated by osteopontin (OPN) which increase cell survival while also stimulating cancer cell metastasis. Osteopontin interaction with adhesion receptors such as integrins and CD44 mediates many cellular processes, including cell adhesion, migration, proliferation, and survival. The role of OPN in cancer progression is of increasing interest as recent studies have noted that OPN is overexpressed in breast, prostate, and pancreatic cancers; OPN may also be a potential prognostic indicator of metastasis. A key step in elucidating the role of OPN in cancer came when it was shown to increase the activation of PKB/Akt, an important molecule for regulating cell survival and progression. Constitutive activation of Akt is frequently observed in many types of human cancers, the causative role of this kinase as well as the signaling pathway(s) involved in their survival and progression is unknown. This proposal aims to more fully decipher the role of OPN in cancer cell survival and metastasis by first elucidating the roles of the integrin aVp3 and the cell surface receptor CD44 in the regulation of cancer cell survival and progression through Akt. Specific cell receptor inhibitors including SiRNA, and inhibiting antibodies will be used to determine the molecular interactions involved in the initiation of OPN mediated Akt activation. Prostate cancer cells (PCS) have been chosen as a model system due to there ability to express OPN and metastasize to osseous structures, including the mandible. The down stream effects of the engagement of OPN and its cell surface receptors will focus on the cell signaling changes of integrin linked kinase (ILK) and PI3-kinase, two important regulators in the Akt cell survival mechanism. OPN mediated Akt cell survival and metastasis will be further elucidated via using specific molecular inhibitors to ILK and PI3-K while also investigating the role of OPN on their kinase activity. This proposal aims to elucidate metastatic and survival mechanisms by testing the over all hypothesis that the synergistic activity of OPN on its cellular receptors elicits the down stream cell signaling changes via activating the PI3-kinase/Akt and ILK/Akt pathways which play a crucial role in the survival, migration, tumor growth, and metastatic events of cancer cells. Osteopontin is an extracellular matrix protein which has been implicated in the progression of cancer as an important mediator of cell adhesion, migration, proliferation, and survival. Further investigation into the role of osteopontin in cancer may open new doors in clinical medicine by increasing the knowledge of the mechanisms involved in cancer progression and thus providing additional therapeutic targets.