Osteopontin & Tumor Progression in Head and Neck Cancers

骨桥蛋白（OPN）是一种分泌型磷蛋白，与骨发育和骨形成有关。 几种实体瘤的进展。在以前的项目中，我们已经确定OPN作为一种分泌性标志物， 肿瘤缺氧和一个强大的预后指标，为头颈部（H&N）癌症。因此，这是一种自然的 该项目的重点是OPN对H&N癌症中肿瘤进展的作用。主要 本课题的目的是系统研究骨桥蛋白及其结构域对肿瘤的作用 H&N肿瘤的侵袭和转移，并探索使用OPN阻断靶向OPN的可能性， 抗体作为一种新的抗癌疗法。具体来说，我们将产生表达全长 OPN、其单个结构域或其在H&N中四环素可调控启动子下的突变构建体 已知具有最小基础OPN表达的癌细胞系。我们将确定OPN的影响 在体外和体内常氧和缺氧条件下，其结构域对细胞侵袭和转移的影响。我们将使用 分子工具来探索OPN在H&N癌症中增强肿瘤侵袭的机制。在 同时，我们将评估使用结构域阻断OPN及其结构域表达的影响， 特异性抗体（ABS）对裸鼠移植瘤侵袭、生长和转移的影响， 使用OPN阻断ABS进行新的治疗。二硝基苯甲酰胺类化合物（DNBMs）是一种新的 这是一种高效的缺氧细胞毒素，将在项目2中详细研究。因为我们发现， OPN显著增强H&N癌细胞在缺氧条件下的侵袭和转移，我们假设， 靶向骨桥蛋白和缺氧可能比单独靶向单个组分更好。因此，最后 该项目的具体目的是评估OPN abs与PR-104 +放射联合治疗肿瘤的疗效 与单独的每种治疗相比，生长和转移。概括而言，建议的目标如下： 旨在回答有关OPN增强 H&N癌症中的恶性肿瘤表型，并确定针对此的最佳方法 蛋白质临床应用

Osteopontin (OPN) is a secreted phosphoprotein that has been implicated in the development and progression of several solid tumors. In the previous project, we have identified OPN as a secreted marker for tumor hypoxia and a powerful prognostic marker for head and neck (H&N) cancers. It is therefore a natural progression for this project to focus on the role of OPN on tumor progression in H&N cancers. The major goal of this project is to systematically investigate the effect of OPN and its individual domains on tumor invasion and metastasis in H&N cancers and to explore the possibility of targeting OPN using OPN blocking antibodies as a novel anticancer therapy. Specifically, we will generate stable cell lines expressing full-length OPN, its individual domains or its mutant constructs under a tetracycline-regulatable promoter in an H&N cancer cell line that is known to have minimal basal OPN expression. We will determine the impact of OPN and its domains on cell invasion and metastasis under normoxia and hypoxia in vitro and in vivo. We will use molecular tools to explore the mechanisms by which OPN enhances tumor invasion in H&N cancers. At the same time, we will evaluate the impact of blocking the expression OPN and its domains using domain- specific antibodies (abs) on tumor invasion, growth and metastasis in nude-mouse xenografts and to explore the use of OPN blocking abs for novel therapy. Dinitrobenzamide mustards (DNBMs) constitute a new and highly potent class of hypoxic cytotoxins that will be studied in detail in Project 2. Since we have found that OPN significantly enhances H&N cancer cell invasion and metastasis under hypoxia, we hypothesize that targeting both OPN and hypoxia may be better than targeting individual component alone. Therefore, the last specific aim of the project will evaluate the efficacy of combining OPN abs with PR-104 + radiation on tumor growth and metastasis in comparison to each treatment alone. In summary, the proposed aims are intended to answer the fundamental questions about the mechanisms by which OPN enhances the malignant tumor phenotype in H&N cancers and to identify the optimal approach to target this protein for clinical use.