Role of Dystroglycan in Prostate Cancer Progression

描述（由申请人提供）：我们目前对前列腺癌如何从局部的、可治疗的疾病进展为播散性不可治愈的疾病的了解有限。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。与前列腺癌进展有关的一种机制是细胞与细胞外基质（ECM）相互作用的改变。我们一直专注于肌营养不良蛋白聚糖（DG）的ECM蛋白的细胞受体在这一过程中的作用。DG已被证明参与正常上皮细胞的发育和功能，并且其表达在晚期癌（包括前列腺癌）中减少或消除。它也是已知的，适当的碳水化合物修饰的DG，这是在部分介导的LARGE蛋白，其结合其ECM配体的能力是必要的，我们在这里显示，这是在人前列腺癌细胞系和临床标本中断。然而，这对疾病进展的后果以及这是否可以区分侵袭性病例和惰性病例尚不清楚。基于我们的初步数据，我们假设DG的不适当糖基化导致ECM的结构和功能扰动，从而导致前列腺癌进展。在这里，我们汇集了基于细胞的测定，前列腺癌的动物模型，和临床标本的评价的组合，以解决这一假设与以下具体目标：1）评估的原因？DG低糖基化及其对前列腺癌进展的影响; 2）确定DG功能丧失对前列腺癌小鼠模型中肿瘤进展和转移的影响; 3）确定DG功能丧失对前列腺癌的预后意义？人前列腺癌中DG糖基化状态和LARGE表达。这些研究的成功完成将确定一种新的致病机制和前列腺癌进展的疾病生物标志物。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。在这个提议中，我们专注于肌营养不良蛋白聚糖，细胞外基质蛋白的受体，是如何参与这一过程。

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.