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可治疗的疾病发展到弥漫性无法治愈的疾病了解有限。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，以提高这种疾病的诊断和治疗。与前列腺癌进展相关的一种机制是细胞与细胞外基质（ECM）相互作用的改变。我们一直在关注肌外基质蛋白的细胞受体-肌外基质糖酐（DG）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，其表达在晚期癌（包括前列腺癌）中减少或消除。我们还知道，DG细胞外部分的适当碳水化合物修饰（部分由LARGE蛋白介导）对于其结合ECM配体的能力是必要的，我们在这里表明，这在人类前列腺癌细胞系和临床标本中被破坏。然而，这对疾病进展的影响以及是否可以区分侵袭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，我们汇集了基于细胞的检测，前列腺癌动物模型和临床标本评估的组合，以解决这一假设，具体目的如下：DG低糖基化及其对前列腺癌进展的影响2)研究DG功能缺失对前列腺癌小鼠模型肿瘤进展和转移的影响；3)确定的预后意义？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定义一个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：了解前列腺癌进展的生物学机制对于开发治疗和诊断前列腺癌的新方法至关重要。在这一建议中，我们关注的是胞外基质蛋白的受体糖酐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.