The Role of Osteopontin in Cancer Progression and Bone Metastasis

描述（由申请人提供）：本项目的长期目标是阐明骨桥蛋白（OPN）刺激的信号通路，这些信号通路在增加细胞存活的同时也刺激癌细胞转移。骨桥蛋白与粘附受体（如整合素和CD44）相互作用介导许多细胞过程，包括细胞粘附、迁移、增殖和存活。OPN在癌症进展中的作用越来越引起人们的兴趣，因为最近的研究表明，OPN在乳腺癌、前列腺癌和胰腺癌中过度表达；OPN也可能是转移的潜在预后指标。阐明OPN在癌症中的作用的关键一步是，它被证明可以增加PKB/Akt的激活，PKB/Akt是调节细胞存活和进展的重要分子。在许多类型的人类癌症中经常观察到Akt的组成性激活，但该激酶的致病作用以及参与其生存和进展的信号通路尚不清楚。本研究旨在通过阐明整合素aVp3和细胞表面受体CD44在Akt调控癌细胞存活和进展中的作用，更全面地揭示OPN在癌细胞存活和转移中的作用。特异性细胞受体抑制剂（包括SiRNA）和抑制抗体将用于确定OPN介导的Akt激活起始过程中涉及的分子相互作用。前列腺癌细胞（PCS）被选择作为模型系统，因为它能够表达OPN并转移到骨结构，包括下颌骨。OPN及其细胞表面受体参与的下游效应将集中在整合素连接激酶（integrin linked kinase， ILK）和pi3激酶的细胞信号变化上，这是Akt细胞存活机制中的两个重要调节因子。OPN介导的Akt细胞存活和转移将通过对ILK和PI3-K的特异性分子抑制剂进一步阐明，同时研究OPN对其激酶活性的作用。本研究旨在通过验证OPN对其细胞受体的协同活性，通过激活pi3 -激酶/Akt和ILK/Akt通路，引发下游细胞信号通路的变化，从而阐明转移和生存机制，这些通路在癌细胞的生存、迁移、肿瘤生长和转移事件中起着至关重要的作用。骨桥蛋白是一种细胞外基质蛋白，作为细胞粘附、迁移、增殖和存活的重要媒介，与癌症的进展有关。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，从而提供额外的治疗靶点。

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.