Project 2: Heparan Sulfate Proteoglycans in Prostate Cancer Bone Metastasis

项目2：硫酸乙酰肝素蛋白多糖在前列腺癌骨转移中的作用

• 批准号: 8794375
• 负责人: MARY C FARACH-CARSON
• 金额: $ 30.98万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-17 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794375
• 关键词: Address; Adhesions; Architecture; Basement membrane; Binding; Bioinformatics; Biological; Biological Factors; Biology; Biomedical Engineering; Blood Vessels; Blood capillaries; Bone Marrow; Bone Tissue; Cancer Biology; Cancer Cell Growth; Cancer Patient; Catabolism; Cells; Cholesterol; Collaborations; Data; Diagnostic; Disease; Disease Progression; Elements; Enzymes; Epithelial; Epithelial Cells; Epithelium; Extracellular Matrix; Extravasation; Failure; Figs - dietary; Growth Factor; Heparan Sulfate Proteoglycan; Heparin Binding Growth Factor; Heparitin Sulfate; Host Defense; Hydrogels; Immune; Inflammation; Laboratories; Malignant neoplasm of prostate; Matrilysin; Matrix Metalloproteinases; Mesenchymal; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Molecular; Neoplasm Circulating Cells; Neoplasm Metastasis; Normal tissue morphology; Pathologic; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Play; Primary Neoplasm; Process; Prostate; Prostatic; Protein Fragment; Proteoglycan; Recruitment Activity; Resistance; Resources; Rice; Role; Signal Transduction; Site; Staining method; Stains; Stromal Cells; Structure; Sulfatases; System; TNFSF11 gene; Tissues; Travel; Tumor Angiogenesis; Tumor Tissue; University of Texas M D Anderson Cancer Center; Work; Wound Healing; angiogenesis; bone; cancer cell; cell motility; design; disorder control; heparanase; member; migration; mimicry; neoplastic cell; next generation; perlecan; prevent; programs; prostate cancer cell; receptor; research study; response; soft tissue; therapeutic target; tool; tumor; tumor growth; tumor microenvironment; tumor progression; wound

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.

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 项目 2 解决了一种关键的硫酸乙酰肝素蛋白多糖 Perlecan (PLN)/HSPG2 的功能，该蛋白存在于 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。转移性 PC 细胞必须穿过五个富含 PLN 的 ECM 层才能从前列腺转移到定植 骨。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 串联的功能域既促进又防止基本的生物反应，例如粘附、迁移、 血管生成和炎症。分子开关取决于上下文，特别是是否 蛋白多糖是完整的或被基质金属蛋白酶（例如 MMP-7/基质溶素）降解以产生生物活性 碎片。额外的活性源自 PLN 结构域 I 上 HS 链酶修饰剂的作用， 包括乙酰肝素酶 (HPSE) 和硫酸酯酶 (SULF)。这种多样化的活动可以促进正常情况下的伤口愈合 组织，但被 PC 细胞选择以促进转移和疾病进展。项目 2 的工作重点 结构域 I（在肝素结合生长因子的递送中起关键作用）和结构域 IV（充当 当降解时参与肿瘤粘连不良和上皮间质转化的屏障 （急救医疗队）。通过该项目的项目 1，我们展示了 IV 域片段积极参与形成 转移起始细胞 (MIC)。每个提议的实验都利用了现有资源 PO1，但回答了有关 PLN 在 PC 进展、侵袭和侵袭中的作用的新的、广泛相关的问题 转移。我们的 Rice 团队通过对 PO1 组的基础研究做出了独特的贡献 两个综合目标中的蛋白聚糖分解代谢和信号传导，双层肿瘤生物工程的要素 设计和制造以促进 PO1 小组的更大目标，包括生长循环肿瘤细胞 并从所有三个项目中以 3D 方式传播肿瘤细胞，以及开发入侵特征的潜力 和转移，有助于更好地了解决定的潜在生物学因素 哪些 PC 患者可能会出现疾病快速进展，因此应该更积极地治疗 早些时候。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作用 核心，特别是 PLN 或其片段作为预测患者的诊断工具的转化潜力 可能迅速发展为致命疾病。