Extracellular Maspin Acts as a Regulator of the Tumor Microenvironment

描述(申请人提供)：Maspin是一种具有肿瘤抑制功能的上皮特异性丝氨酸蛋白酶抑制剂(Serpin)。外源性添加的maspin在体外抑制肿瘤细胞的侵袭和运动。相比之下，体内数据显示，maspin抑制肿瘤转移。此外，在体内外源性添加maspin会减少血管生成。在许多癌症中，Maspin的表达与较好的临床预后相关，例如前列腺癌和乳腺癌。不幸的是，当肿瘤进展为转移性癌时，maspin的表达通常下调或丢失。Maspin是一种胞内蛋白，也是一种胞外蛋白。细胞外Maspin调节细胞表面的尿激酶型纤溶酶原激活物(Pro-uPA)及其受体uPAR。有趣的是，uPA和uPAR在肿瘤进展过程中均上调，uPA的高表达与临床预后不良有关。细胞外Maspin可能发挥其肿瘤抑制作用，至少部分是通过 阻断uPA的激活。然而，细胞外maspin调节uPA原的机制尚不清楚。Maspin调节机制的识别可能为新的治疗策略提供洞察力。该项目的假设是，细胞外maspin充当肿瘤微环境的调节器。要解决这一假设，有三个具体目标。具体目的1是研究maspin的分泌机制是否决定了其作为肿瘤微环境调节因子的生物学功能。具体目的2是研究在肿瘤微环境中，uPA/uPAR复合体是否对maspin介导的细胞间通讯可能是必需的。具体目标3是研究细胞外maspin对内化的生物学影响。 与公共卫生相关：肿瘤的进展最终会导致转移，而转移是无法治愈的。本项目研究肿瘤抑制因子Maspin，它可能在抑制肿瘤转移中发挥重要作用。

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. PUBLIC HEALTH RELEVANCE: Tumor progression eventually leads to metastasis, in which there is not a cure. This project investigates the tumor suppressor, maspin, which may play an important role in inhibiting tumor metastasis.