Hyaluronan Receptors in Prostate Cancer Progression

描述（由申请人提供）：Hybryonan（HA）是一种高分子量阴离子多糖，在原发性前列腺肿瘤中升高。 转移性前列腺癌细胞合成HA并将其组装成细胞周基质，其对于体外非贴壁依赖性肿瘤生长和体内肿瘤生长/血管生成是重要的。 表达升高的透明质酸转移酶的前列腺肿瘤细胞在体外也比对照组更容易粘附于微血管（例如骨髓）内皮细胞，这暗示细胞周透明质酸参与了体内转移性前列腺肿瘤细胞向骨和其他器官的归巢。 事实上，我们已经提出，组装富含HA的细胞周基质的能力可以通过为转移的前列腺肿瘤细胞提供粘附性、富含生长因子的保护性微环境来为它们提供选择性优势，因为它们调节并定殖于不同的组织如骨。 转移性、雄激素非依赖性人前列腺癌细胞系表达高水平的两种HA受体：CD 44和细胞表面RHAMM（基因名称为HMMR，也称为CD 168），我们已经证明它们相互关联，并在功能上协同促进运动和侵袭，特别是通过Ras转化途径。 用任一受体的RNA干扰抑制CD 44和/或Rhamm的内源性表达显著降低了体外锚定非依赖性生长，这通过添加外源性HA而逆转。 总的来说，这些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（HYal 1）在人前列腺癌中升高，特别是RHAMM蛋白表达随着Gleason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CD 44蛋白表达显著降低。 除了其在增殖和迁移/侵袭中的作用之外，CD 44是内化和靶向HA以进行溶酶体破坏的内吞受体。 因此，在前列腺癌中观察到的HA增加至少部分是由于CD 44蛋白表达降低。 预期降低的⑶ 44水平和升高的HYal 1均促进HA/HA片段积累，产生肿瘤支持微环境。 相反，由于大量的RHAMM和HA/HA片段存在于低CD 44的环境中，化学计量有利于RHAMM-HA-CD 44相互作用。 数据表明，细胞表面RHAMM将CD 44维持在细胞表面上，否定其内吞功能并促进其信号传导功能，“过度活化”剩余的CD 44，导致肿瘤的侵袭性增加。 该提议的工作模型是，由于HA基质被合成、组装并随后被扩张的前列腺肿瘤片段化，其通过与肿瘤细胞表面上的RHAMM/HA/CD 44复合物相互作用而产生促进肿瘤细胞存活、生长和侵袭的微环境。 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，可提高目前治疗的有效性。 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有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有助于进展的机制，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。

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.