Extracellular Maspin Acts as a Regulator of the Tumor Microenvironment

描述（由申请人提供）：Maspin是一种上皮特异性丝氨酸蛋白酶抑制剂（serpin），具有肿瘤抑制功能。外源性maspin抑制肿瘤细胞的体外侵袭和运动。相比之下，体内数据显示maspin抑制肿瘤转移。此外，外源性添加maspin，在体内，减少血管生成。Maspin表达与许多癌症（如前列腺癌和乳腺癌）中更好的临床预后相关。不幸的是，maspin的表达往往是下调或丢失的肿瘤进展到转移癌。 Maspin是一种细胞内蛋白以及细胞外蛋白。细胞外maspin调节细胞表面的尿激酶原纤溶酶原激活物（pro-uPA）及其受体uPAR。有趣的是，uPA和uPAR在肿瘤进展中均上调，并且uPA的高表达与不良临床预后相关。细胞外maspin可以发挥其肿瘤抑制作用，至少部分是通过， 阻断uPA激活。然而，细胞外maspin调节pro-uPA的机制尚未确定。maspin调节机制的鉴定可能为新的治疗策略提供见解。 该项目的假设是细胞外maspin作为肿瘤微环境的调节剂。为了解决这一假设，有三个具体目标。具体目标1是研究maspin分泌的机制是否决定其作为肿瘤微环境调节剂的生物学功能。具体目标2是研究uPA/uPAR复合物是否可能是肿瘤微环境中maspin介导的细胞间通讯所必需的。具体目标3是研究细胞外maspin内化后的生物学后果。

DESCRIPTION (provided by applicant): Maspin is an epithelial-specific serine protease inhibitor (serpin) with tumor suppressive function. Exogenously added maspin inhibits tumor cell invasion and motility in vitro. In comparison, in vivo data show that maspin inhibits tumor metastasis. Also, exogenous addition of maspin, in vivo, decreases angiogenesis. Maspin expression is correlated with a better clinical prognosis in many cancers, such as prostate and breast. Unfortunately, maspin expression is often down regulated or lost as the tumor progresses to a metastatic carcinoma. Maspin is an intracellular protein as well as an extracellular protein. Extracelluar maspin regulates pro-urokinase plasminogen activator (pro-uPA), and its receptor, uPAR, at the cell surface. Interestingly, uPA, and uPAR are both up regulated in tumor progression and high expression of uPA has been associated with a poor clinical prognosis. Extracellular maspin may exert its tumor suppressive role, at least in part, by blocking uPA activation. However, the mechanism in which extracellular maspin regulates pro-uPA has yet to be identified. Identification of the mechanism of maspin regulation may provide insight into a novel therapeutic strategy. The hypothesis for the project is that extracellular maspin acts as a regulator of the tumor microenvironment. To address this hypothesis, there are three specific aims. Specific Aim 1 is to investigate whether the mechanism of maspin secretion determines its biological function as a regulator of the tumor microenvironment. Specific Aim 2 is to investigate whether the uPA/uPAR complex may be necessary for maspin-mediated cell-cell communication in the tumor microenvironment. Specific Aim 3 is to investigate the biological consequences of extracellular maspin upon internalization.