Role of Dystroglycan in Prostate Cancer Progression

我们目前对前列腺癌是如何从局部的、可治疗的 疾病变成了一种传播不治之症。我们的长期目标是了解生物机制 前列腺癌的潜在进展和转移，以改善诊断和治疗 疾病。前列腺癌进展的一个机制是细胞的改变 与细胞外基质(ECM)的相互作用。我们一直关注营养不良蛋白聚糖(DG)a的作用。 在这一过程中，细胞外基质蛋白的细胞受体。DG已被证明参与了开发和 在晚期癌症中，正常上皮的功能及其表达降低或消除，包括 前列腺癌。还已知对DG的胞外部分进行适当的碳水化合物修饰， 这部分是由大蛋白介导的，是其结合ECM配体的能力所必需的，而我们 这表明这在人类前列腺癌细胞系和临床标本中是被干扰的。然而， 这对疾病进展的后果，以及这是否可以区分侵略性和惰性病例 目前还不清楚。根据我们的初步数据，我们假设DG的不适当糖基化结果 导致前列腺癌进展的细胞外基质的结构和功能紊乱。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对 临床标本解决这一假说的具体目的如下：1)评估DG的原因 低糖基化及其对前列腺癌进展的影响；2)确定DG缺失的影响 在前列腺癌小鼠模型中对肿瘤进展和转移的作用；3)确定 前列腺癌中DG糖基化状态和高表达对预后的意义这个 这些研究的成功完成将确定一种新的致病机制和疾病生物标志物 前列腺癌的潜在进展。了解推动前列腺癌进展的生物学机制对于开发新的 治疗和诊断这种疾病的方法。在这项提案中，我们关注的是营养不良多糖，一种受体，如何 细胞外基质蛋白参与了这一过程。

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 hypoglycosylation 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. 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.