Project 2: Heparan Sulfate Proteoglycans in Prostate Cancer Bone Metastasis

项目摘要-项目2 细胞外基质(ECM)是前列腺癌(PC)肿瘤微环境的重要组成部分。工作 在项目2中讨论了关键的硫酸乙酰肝素蛋白多糖Perlecan(PLN)/HSPG2的功能，该蛋白多糖位于 前列腺和骨的基底膜和反应性间质，既具有结构又具有信号 功能。转移性PC细胞必须穿过5个富含PLN的ECM层才能从前列腺迁移并定植 骨头。尽管PLN的规模和复杂性相当大，但其基本架构在进化上是保守的。PLN的 功能结构域同时促进和阻止基本的生物反应，如黏附、迁移、 血管生成和炎症。分子开关取决于上下文，特别是分子开关是否 蛋白多糖是完整的或被基质金属蛋白酶如基质金属蛋白酶-7/基质溶素降解而产生生物活性的 碎片。额外的活性来自于PLN结构域I上HS链的酶修饰剂的作用， 包括乙酰肝素酶(HPSE)和硫酸酯酶(SULF)。这种多样化的活动在正常情况下促进伤口愈合 但被PC细胞所增选，以促进转移和疾病进展。在项目2中工作重点 在结构域I和结构域IV上，结构域I在肝素结合生长因子的传递中起关键作用，结构域IV起作用 一种当降解时参与肿瘤粘连和上皮间质转化的屏障 (EMT)。在这个计划的项目1中，我们展示了一个结构域IV片段积极地参与形成 肿瘤转移启动细胞，或称MICs。每个拟议的实验都利用 PO1，但回答了有关PLN在PC进展、入侵和 转移。我们的莱斯团队为PO1小组做出了独特的贡献，带来了关于 双分子层肿瘤生物工程的两个整合目标蛋白多糖分解代谢和信号转导 设计和制造以促进PO1组更大的目标，包括生长循环中的肿瘤细胞 以及从所有三个项目中以3D方式传播的肿瘤细胞，以及开发侵袭特征的可能性 和转移，有助于更大程度地了解决定 哪些PC患者可能病情进展迅速，因此应更积极地进行治疗 早些时候。在我们对所有四个PI实验室和两个项目的资源的应用中发现了协同效应 核心，特别是PLN或其片段作为诊断工具预测患者的翻译潜力 可能会迅速发展成致命的疾病。

Project Summary - Project 2 The extracellular matrix (ECM) is a key component of the prostate cancer (PC) tumor microenvironment. Work in Project 2 addresses the function of a key heparan sulfate proteoglycan, perlecan (PLN)/HSPG2, found in the basement membrane and reactive stroma of prostate and bone, that possesses both structural and signaling functions. Metastatic PC cells must cross five PLN-rich ECM layers to travel from the prostate to colonize bone. Despite its considerable size and complexity, PLN's basic architecture is evolutionally conserved. PLN's tandem, functional domains both promote and prevent basic biological responses such as adhesion, migration, angiogenesis, and inflammation. The molecular switch depends on context, specifically whether the proteoglycan is intact or degraded by matrix metalloproteinases such as MMP-7/matrilysin to produce bioactive fragments. Additional activity arises from the actions of enzyme modifiers of HS chains on PLN domain I, including heparanase (HPSE) and sulfatases (SULFs). This diverse activity promotes wound healing in normal tissues, but is co-opted by PC cells to facilitate metastasis and disease progression. Work in Project 2 focuses on domain I, which plays a key role in delivery of heparin binding growth factors, and domain IV, which acts as a barrier that when degrades participates in tumor dyscohesion and epithelial mesenchymal transformation (EMT). With Project 1 of this program, we showed that a domain IV fragment actively participates in formation of Metastasis Initiating Cells, or MICs. Each of the proposed experiments leverages existing resources in the PO1, but answers new, broadly-relevant questions regarding the role of PLN in PC progression, invasion, and metastasis. Our Rice team contributes uniquely to this PO1 group by bringing fundamental studies of proteoglycan catabolism and signaling in two integrated Aims, elements of tumor bioengineering in bilayer design and fabrication to facilitate the larger aims of the PO1 group including growing circulating tumor cells and disseminated tumor cells from all three projects in 3D, and the potential to develop a signature for invasion and metastasis that can contribute to a larger understanding of the underlying biological factors that determine which PC patients are likely to suffer rapid disease progression and thus should be treated more aggressively earlier. Synergy is found in our application of resources from all four PIs' laboratories and the two program Cores, particularly in the translational potential for PLN or its fragments as diagnostic tools to predict patients likely to progress rapidly to lethal disease.