Role of Dystroglycan in Prostate Cancer Progression

描述(申请人提供)：我们目前对前列腺癌是如何从一种局部的、可治疗的疾病进展到播散性的不可治愈的疾病有一个有限的了解。我们的长期目标是了解前列腺癌进展和转移的生物学机制，以改善这种疾病的诊断和治疗。前列腺癌进展的一个机制是细胞与细胞外基质(ECM)相互作用的改变。我们一直在关注营养不良多糖(DG)，一种ECM蛋白的细胞受体在这一过程中的作用。研究表明，DG参与了正常上皮的发育和功能，在包括前列腺癌在内的晚期癌症中，DG的表达降低或消除。我们还知道，对DG胞外部分进行适当的碳水化合物修饰是其与ECM配体结合的能力所必需的，这部分是由大蛋白介导的，我们在这里证明了这一点在人类前列腺癌细胞系和临床标本中被破坏。然而，这对疾病进展的后果以及这是否可以区分攻击性和惰性病例尚不清楚。根据我们的初步数据，我们假设DG的不适当糖基化会导致ECM的结构和功能紊乱，从而导致前列腺癌的进展。在这里，我们结合了基于细胞的分析、前列腺癌的动物模型和临床标本的评估来解决这一假说，具体目的如下：1)评估？DG低糖基化的原因及其对前列腺癌进展的影响；2)在前列腺癌的小鼠模型中确定？DG功能丧失对肿瘤进展和转移的影响；3)确定？DG糖基化状态和在人类前列腺癌中大量表达的预后意义。这些研究的成功完成将确定前列腺癌进展的新的致病机制和疾病生物标记物。公共卫生相关性：了解推动前列腺癌进展的生物学机制对于开发治疗和诊断这种疾病的新方法至关重要。在这项提案中，我们关注的是细胞外基质蛋白的受体--营养不良糖蛋白是如何参与这一过程的。

DESCRIPTION (provided by applicant): We currently have a limited understanding of how prostate cancer progresses from a localized, treatable disease to a disseminated incurable one. Our long term goal is to understand the biological mechanisms underlying prostate cancer progression and metastasis in order to improve diagnosis and treatment of this disease. One mechanism that has been implicated in prostate cancer progression is alteration of cellular interactions with the extracellular matrix (ECM). We have been focusing on the role of dystroglycan (DG) a cellular receptor for ECM proteins in this process. DG has been shown to be involved in the development and function of normal epithelia and its expression is reduced or eliminated in advanced carcinomas, including prostate cancer. It is also known that appropriate carbohydrate modification of the extracellular portion of DG, which is in part mediated by the LARGE protein, is necessary for its ability to bind its ECM ligands, and we show here that this is disrupted in human prostate cancer cell lines and clinical specimens. However, the consequences of this for disease progression and whether this can distinguish aggressive from indolent cases is not yet known. Based on our preliminary data, we hypothesize that inappropriate glycosylation of DG results in structural and functional perturbations of the ECM that contribute to prostate cancer progression. Here we have brought together a combination of cell-based assays, animal models of prostate cancer, and evaluation of clinical specimens to address this hypothesis with the following specific aims: 1) Evaluate cause of ?DG hypo-glycosylation and its effects on prostate cancer progression; 2) Determine the effects of loss of DG function on tumor progression and metastasis in a mouse model of prostate cancer; 3) Determine the prognostic significance of ?DG glycosylation status and LARGE expression in human prostate cancer. The successful completion of these studies will define a novel pathogenic mechanism and disease biomarker underlying prostate cancer progression. PUBLIC HEALTH RELEVANCE: Understanding the biological mechanisms driving prostate cancer progression is essential for developing new ways to treat and diagnose this disease. In this proposal, we are focusing on how dystroglycan, a receptor for extracellular matrix proteins, is involved in this process.