Hyaluronan Receptors in Prostate Cancer Progression

前列腺癌进展中的透明质酸受体

• 批准号: 7802265
• 负责人: James B. McCarthy
• 金额: $ 47.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-02 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802265
• 关键词: Ablation; Adhesives; Aggressive behavior; Anchorage-Independent Growth; Androgens; Animals; Benign; Binding; Blocking Antibodies; Blood Circulation; Bone Marrow; CD44 Antigens; CD44 gene; Cancer Etiology; Cancer Patient; Cell Communication; Cell Line; Cell Survival; Cell surface; Cessation of life; Characteristics; Clinical; Clinical Management; Complex; Data; Diagnosis; Disease; Effectiveness; Endothelial Cells; Environment; Epithelium; Failure; Genes; Gleason Grade for Prostate Cancer; Growth; Growth Factor; HMMR gene; Homing; Human; Hyaluronan; Hyaluronidase; Hyperplasia; In Vitro; Injection of therapeutic agent; Laboratories; Lead; Link; MAPK3 gene; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Weight; Mus; Names; Neoadjuvant Therapy; Neoplasm Metastasis; Organ; Outcome; PC3 cell line; Pathway interactions; Patients; Play; Polysaccharides; Prognostic Factor; Prostate; Prostate carcinoma; Prostatic Neoplasms; Publishing; RHAMM protein; RNA Interference; Reporting; Role; Signal Transduction; Signal Transduction Pathway; Site; Small Interfering RNA; Specimen; Surface; Therapeutic; Tissues; Tumor Cell Line; Tumor Suppressor Genes; United States; Work; Xenograft procedure; angiogenesis; bone; cancer cell; cell growth; cell motility; extracellular; hyaluronan synthase 1; in vivo; men; migration; mouse model; neoplastic cell; prognostic; protein expression; public health relevance; receptor; receptor expression; stoichiometry; synthetic peptide; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Hyaluronan (HA) is a high molecular weight anionic polysaccharide that is elevated in primary prostate tumors. Metastatic prostate cancer cells synthesize and assemble HA into a pericellular matrix that is important for anchorage-independent tumor growth in vitro and tumor growth/angiogenesis in vivo. Prostate tumor cells that express elevated hyaluronan synthases also adhere more readily to microvessel (e.g. bone marrow) endothelial cells in vitro than controls implicating pericellular hyaluronan in the homing of metastatic prostate tumor cells to bone and other organs in vivo. Indeed, we have proposed that an ability to assemble an HA-rich pericellular matrix may offer metastasizing prostate tumor cells a selective advantage by providing them with an adhesive, growth factor-rich protective microenvironment as they adjust and colonize distinct tissues such as bone. Metastatic, androgen independent human prostate carcinoma cell lines express high levels of two HA receptors: CD44 and cell surface RHAMM (gene name is HMMR, also designated CD168), which we have shown to co-associate and which functionally collaborate to promote motility and invasion, particularly through Ras-transformation pathways. Inhibiting endogenous expression of CD44 and/or Rhamm with RNA interference of either receptor significantly reduces anchorage-independent growth in vitro, which is reversed by the addition of exogenous HA. Collectively, these and other studies have led us to propose that prostate cancer progression is hyaluronan-driven. Preliminary data show that RHAMM, HA and Hyaluronidase 1 (HYal1) are elevated in human prostate cancer and in particular RHAMM protein expression increases with increasing Gleason scores. In contrast, CD44 protein expression is significantly decreased in prostate cancer compared to normal or benign hyperplastic tissue. In addition to its role in proliferation and migration/invasion, CD44 is an endocytic receptor that internalizes and targets HA for lysosomal destruction. Therefore the increased HA observed in prostate cancer is at least partly due to decreased CD44 protein expression. Both the decreased CD44 levels and elevated HYal 1 are expected to promote HA/HA fragment accumulation producing a tumor-supporting microenvironment. Conversely, because abundant RHAMM and HA/HA fragments are present in an environment of low CD44, the stoichiometry favors RHAMM-HA-CD44 interactions. Data indicate that cell surface RHAMM maintains CD44 on the cell surface, negating its endocytic function and promoting its signaling function, "hyper-activating" the remaining CD44 resulting in increased aggressiveness of the tumor. The working model for this proposal is that as an HA matrix is synthesized, assembled and then fragmented by the expanding prostate tumor, it creates a microenvironment which facilitates tumor cell survival, growth and invasion by interacting with RHAMM/HA/CD44 complexes on the surface of tumor cells. We propose that selective interference with the HA/tumor cell interaction is a viable neoadjuvant therapeutic approach in patients to enhance the effectiveness of current therapies. PUBLIC HEALTH RELEVANCE: Prostate cancer is the second leading cause of cancer deaths in men in the United States. The projects proposed will study tumor associated changes in the molecular composition of prostate tumor microenvironments which are linked to malignant progression. The focus of this proposal is to determine the mechanisms by which these changes contribute to progression and to use compounds (specific synthetic peptides) that disrupt these mechanisms to inhibit tumor growth, invasion and metastasis.

描述（由申请人提供）：透明质酸（HA）是一种高分子量阴离子多糖，在原发性前列腺肿瘤中含量升高。 转移性前列腺癌细胞合成 HA 并将其组装到细胞周基质中，这对于体外贴壁依赖性肿瘤生长和体内肿瘤生长/血管生成非常重要。 与对照组相比，表达升高的透明质酸合酶的前列腺肿瘤细胞在体外也更容易粘附到微血管（例如骨髓）内皮细胞，这表明细胞周透明质酸在体内转移性前列腺肿瘤细胞归巢到骨骼和其他器官中。 事实上，我们提出，组装富含HA的细胞周基质的能力可以为转移性前列腺肿瘤细胞提供选择性优势，在它们调整和定殖不同的组织（例如骨）时，为它们提供粘附性的、富含生长因子的保护性微环境。 转移性、不依赖雄激素的人前列腺癌细胞系高水平表达两种 HA 受体：CD44 和细胞表面 RHAMM（基因名称为 HMMR，也称为 CD168），我们已证明它们之间存在共同关联，并且在功能上协同促进运动和侵袭。 ，特别是通过 Ras 转化途径。 通过任一受体的 RNA 干扰来抑制 CD44 和/或 Rhamm 的内源性表达，可显着降低体外锚定非依赖性生长，而添加外源性 HA 可逆转这种情况。 总的来说，这些研究和其他研究使我们提出前列腺癌的进展是透明质酸驱动的。 初步数据显示，RHAMM、HA 和透明质酸酶 1 (HYal1) 在人类前列腺癌中升高，特别是 RHAMM 蛋白表达随着格里森评分的增加而增加。 相反，与正常或良性增生组织相比，前列腺癌中的CD44蛋白表达显着降低。 除了在增殖和迁移/侵袭中发挥作用外，CD44 还是一种内吞受体，可内化并靶向 HA 以进行溶酶体破坏。 因此，在前列腺癌中观察到的 HA 增加至少部分是由于 CD44 蛋白表达减少。 降低的 CD44 水平和升高的 HYal 1 预计都会促进 HA/HA 片段的积累，产生支持肿瘤的微环境。 相反，由于在低 CD44 的环境中存在丰富的 RHAMM 和 HA/HA 片段，因此化学计量有利于 RHAMM-HA-CD44 相互作用。 数据表明，细胞表面RHAMM将CD44维持在细胞表面，否定其内吞功能并促进其信号传导功能，“过度激活”剩余的CD44，导致肿瘤的侵袭性增加。 该提案的工作模型是，随着HA基质被不断扩大的前列腺肿瘤合成、组装和破碎，它通过与表面的RHAMM/HA/CD44复合物相互作用，创造了一个促进肿瘤细胞存活、生长和侵袭的微环境。肿瘤细胞。 我们认为，选择性干扰 HA/肿瘤细胞相互作用是一种可行的新辅助治疗方法，可增强现有疗法的有效性。 公共卫生相关性：前列腺癌是美国男性癌症死亡的第二大原因。 拟议的项目将研究与恶性进展相关的前列腺肿瘤微环境分子组成的肿瘤相关变化。 该提案的重点是确定这些变化促进进展的机制，并使用破坏这些机制的化合物（特定合成肽）来抑制肿瘤生长、侵袭和转移。