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）肿瘤微环境的关键组成部分。工作 在项目2中，研究了硫酸乙酰肝素蛋白聚糖的关键功能，串珠素（PLN）/HSPG2，发现于 前列腺和骨的基底膜和反应性基质，具有结构和信号传导 功能协调发展的转移性PC细胞必须穿过五个富含PLN的ECM层才能从前列腺移行到定植 骨头尽管其规模和复杂性相当大，但PLN的基本架构在进化上是保守的。pln的 串联功能结构域既促进又防止基本生物反应，如粘附，迁移， 血管生成和炎症。分子开关取决于环境，特别是 蛋白聚糖是完整的或被基质金属蛋白酶如MMP-7/基质溶解素降解， 片段额外的活性来自HS链的酶修饰剂对PLN结构域I的作用， 包括乙酰肝素酶（HPSE）和硫酸酯酶（SULF）。这种不同的活动促进伤口愈合正常 组织，但被PC细胞增选以促进转移和疾病进展。项目2的工作重点 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递送中起关键作用，结构域IV充当 一种降解时参与肿瘤粘连不良和上皮间质转化的屏障 （EMT）。在该项目的项目1中，我们发现结构域IV片段积极参与形成， 的转移启动细胞，或MIC。每个拟议的实验利用现有的资源， PO1，但回答了新的，广泛相关的问题，PLN在PC进展，侵袭， 转移我们的Rice团队为这个PO1小组做出了独特的贡献， 蛋白聚糖催化剂和信号转导两个整合的目的，双层中的肿瘤生物工程元素 设计和制造以促进PO 1组的更大目标，包括生长循环肿瘤细胞 和扩散的肿瘤细胞从所有三个项目的3D，并有可能开发一个入侵的签名， 和转移，这有助于更深入地了解决定癌症的潜在生物学因素， 哪些PC患者可能会遭受快速疾病进展，因此应该更积极地治疗 之前协同作用是发现在我们的应用程序的资源从所有四个PI的实验室和两个计划 核心，特别是在翻译潜力的PLN或其片段作为诊断工具，以预测患者 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.