Protease activated receptor-2 (PAR-2) signaling and metastatic ovarian cancer

总结 卵巢癌是最致命的妇科恶性肿瘤。每69名女性中就有一人会患上卵巢癌， 只有不到一半的人能存活五年尽管最近我们在理解上取得了一些进展， 卵巢癌的病因和病理生物学，诊断卵巢癌的患者生存率低 与乳腺癌或前列腺癌相比。导致这种低生存率的因素是肿瘤 持久性、肿瘤复发和化学抗性。迫切需要开发二线疗法 以提高常规治疗的疗效并提供替代治疗方法 复发性卵巢癌患者的选择。靶向VEGF和VEGF受体的抗血管生成疗法 血管生成素/Tie 2通路已显示出临床疗效，目前正积极寻求作为辅助治疗 复发性卵巢癌的治疗方法不幸的是，最近的临床试验结果喜忧参半， 对抗血管生成治疗无反应或耐药、毒性和随后的肿瘤复发 和转移具有有限的治疗成功。这在很大程度上是由于对 涉及的基本机制。这项研究的科学前提是， G蛋白偶联的蛋白酶激活受体-2（PAR-2）通过不同的蛋白酶调节肿瘤 血管生成对于卵巢肿瘤转移是重要的。我们发现了膜锚定丝氨酸 蛋白酶睾丸素（也称为PRSS 21）在广泛的卵巢癌中异常表达， 是PAR-2的有效细胞表面蛋白水解激活剂。强有力的初步数据显示， 睾丸素在卵巢肿瘤中的组成型表达促进抗血管生成信号传导并抑制 卵巢癌临床前异种移植模型中的卵巢肿瘤转移和腹水形成。这 独特的活性是出乎意料的，揭示了我们对PAR-2如何血管生成的理解的一个主要空白。 信号由不同的蛋白酶调节，特别是那些在空间上接近PAR-2的蛋白酶。这样的“偏见” 激动作用“可能开始解释患者对抗血管生成治疗反应的显著变化， 卵巢癌患者拟议的研究计划将利用原代人类卵巢肿瘤细胞和细胞 线与体内小鼠模型相一致，以解决以下具体目标：1）确定 睾丸素抑制实验性卵巢肿瘤转移的机制，以及2）确定 睾丸素介导PAR-2脱敏及其调控的分子和细胞机制 血管生成的过程。睾丸素-PAR-2途径引起的天然拮抗作用的增强可能 发现与其它抗血管生成疗法联合使用以减少所需的治疗剂量，从而 最大限度地减少副作用，并为管理这种毁灭性疾病提供独特的治疗方法。的事实 女性没有正常的大量睾丸，这使得睾丸成为一种独特的，特别有吸引力的 卵巢肿瘤的治疗靶点，也是潜在有用的生物标志物。

SUMMARY Ovarian cancer is the most lethal gynecological malignancy. One in 69 women will develop ovarian cancer, and less than half will survive for five years. Despite a number of recent advances in our understanding of ovarian cancer etiology and pathobiology, the survival rate of patients diagnosed with ovarian cancer is low when compared to that of breast or prostate cancer. Factors contributing to this poor survival rate are tumor persistence, tumor recurrence and chemoresistance. There is an urgent need to develop second line therapies to both improve the therapeutic efficacy of conventional treatments and to provide alternative therapeutic options for patients with recurrent ovarian cancer. Anti-angiogenesis therapies targeting the VEGF and the angiopoietins/Tie2 pathways have shown clinical efficacy and are currently being actively pursued as adjunct therapies for recurrent ovarian cancers. Unfortunately, outcomes of recent clinical trials have been mixed and non-responsiveness or resistance to anti-angiogenic treatment, toxicities and subsequent tumor recurrence and metastasis have limited therapeutic success. This is largely due to an incomplete of understanding of the basic mechanisms involved. The scientific premise underlying this research is that differential triggering of the G-protein coupled Protease Activated Receptor-2 (PAR-2) by different proteases modulates tumor angiogenesis important for ovarian tumor metastasis. We discovered the membrane-anchored serine protease, testisin (also known as PRSS21), to be aberrantly expressed in a broad range of ovarian cancers and to be a potent cell surface proteolytic activator of PAR-2. Strong preliminary data show that the aberrent constitutive expression of testisin in ovarian tumors promotes anti-angiogenic signaling and suppresses ovarian tumor metastasis and ascites formation in a preclinical xenograft model of ovarian cancer. This unique activity is unexpected, and reveals a major gap in our understanding of how PAR-2 angiogenic signals are modulated by different proteases, specifically those in spatial proximity to PAR-2. Such `biased agonism' may start to explain significant variations in patient responses to anti-angiogenic therapies in ovarian cancer patients. The proposed research plan will utilize primary human ovarian tumor cells and cell lines in concert with in vivo mouse models to address the following specific aims: 1) to determine mechanisms by which testisin suppresses experimental ovarian tumor metastasis, and 2) to determine molecular and cellular mechanisms associated with testisin-mediated desensitization PAR-2 and modulation of angiogenesis. Augmentation of the natural antagonism resulting from the testisin-PAR-2 pathway could find utility in combination with other anti-angiogenic therapies, to reduce therapeutic doses required, thereby minimizing side effects and provide a unique therapy for managing this devastating disease. The fact that females do not have a normal abundance of testisin makes testisin a unique and particularly attractive therapeutic target for ovarian tumors and also a potentially useful biomarker.