Novel Biomarkers in Ovarian Cancer

描述（由申请人提供）：在2008年美国约24000例上皮性卵巢癌新发病例中，晚期卵巢癌占大多数（约75%）。每年有超过16,000人死亡，使这种癌症成为最致命的妇科恶性肿瘤。然而，只有少数生物标志物可用于预测卵巢癌患者的总体生存。此外，许多预后生物标志物如果其分子作用被很好地理解，最终可以作为重要的治疗靶点。利用转录谱分析技术结合Cox回归分析，我们之前已经确定了一个假定的基因标记，可以预测晚期高级别浆液性卵巢癌患者的生存。Cox评分最高的基因被称为微原纤维相关糖蛋白（MAGP-2），该基因已被证明与含纤维蛋白的微原纤维相关，并与成纤维细胞中的1V23整合素特异性相互作用。然而，其在癌症发病机制中的作用尚未被探索。我们的初步研究表明，MAGP-2在卵巢肿瘤组织样本中的表达与患者的生存显著相关。此外，MAGP-2在人脐静脉内皮细胞（HUVECs）和卵巢癌细胞中均能诱导细胞生长和运动，表达高水平的1V23整合素。此外，外源性MAGP-2在HUVECs和卵巢癌细胞系OVCA429中显著诱导Ca2+振荡和FAK磷酸化。因此，我们假设表达高水平MAGP-2的卵巢癌细胞通过其与1V23整合素的相互作用调节卵巢癌的生长，从而导致卵巢癌患者的总体生存率降低。在本应用中，我们建议通过大量多中心临床试验标本进一步验证MAGP-2的预后价值，并描述MAGP-2在卵巢发病机制中的功能作用。首先，我们将使用从进入妇科肿瘤组（GOG）方案218的患者中获得的标本将MAGP-2表达与结果联系起来。其次，我们将描述MAGP-2在体外和体内调节卵巢肿瘤生长和进展中的功能作用。最后，我们将描述magp -2诱导卵巢癌细胞和内皮细胞增殖、迁移和侵袭的信号网络。如果这项研究成功，将为我们提供一种新的卵巢癌预后生物标志物。它将引导我们确定新的治疗靶点并开发新的卵巢癌治疗方案。

DESCRIPTION (provided by applicant): Advanced stage ovarian cancer accounts for the majority (>75%) of the approximately 24,000 new cases of epithelial ovarian cancer in year 2008 in the United States. Over 16,000 deaths per year occur, making this cancer the most lethal gynecologic malignancy. However, there are only a few biomarkers that can be used to predict overall ovarian cancer patient survival. In addition, many prognostic biomarkers can ultimately serve as important therapeutic targets if their molecular action is well understood. Using transcriptional profiling technology combined with Cox regression analysis, we have previously identified a putative gene signature, which can predict survival in patients with advanced stage high-grade serous ovarian cancers. The gene with highest Cox score in the signature is called microfibril-associated glycoprotein (MAGP-2), which has been shown to be associated with fibrillin-containing microfibrils and to interact specifically with 1V23 integrin in fibroblasts. However, its role in cancer pathogenesis has not been explored. Our preliminary studies demonstrated that MAGP-2 expression in ovarian tumor tissues samples significantly correlated with patient survival. In addition, MAGP-2 was shown to induce cell growth and motility in both human umbilical vein endothelial cells (HUVECs) and ovarian cancer cells, which expressed high levels of 1V23 integrin. Furthermore, exogenous MAGP-2 was shown to significantly induce Ca2+ oscillation and FAK phosphorylation in HUVECs and an ovarian cancer cell line OVCA429. We therefore hypothesize that ovarian cancer cells expressing high levels of MAGP-2 modulate ovarian cancer growth and through its interaction with 1V23 integrin, which subsequently leads to poorer overall ovarian cancer patient survival. In this application, we proposed to further validate the prognostic value of MAGP-2 using a large collection of multi-center clinical trial specimens, and delineate the functional role of MAGP-2 in ovarian pathogenesis. First, we will correlate MAGP-2 expression with outcomes using specimens obtained from patients entered into the Gynecologic Oncology Group (GOG) protocol 218. Second, we will delineate the functional role of MAGP-2 in modulating ovarian tumor growth and progression, in vitro and in vivo. Finally, we will delineate the signaling network for MAGP-2-induced cell proliferation, migration and invasion in both ovarian cancer cells and endothelial cells. This proposed study if successful will provide us with a new prognostic biomarker for ovarian cancer. It will lead us to the identification of new therapeutic targets and the development of new therapeutic regimens for ovarian cancer treatment. PUBLIC HEALTH RELEVANCE: This grant proposes to validate MAGP-2 as a prognostic biomarker for advanced stage ovarian cancer using prospectively collected specimens from a randomized phase III trial. Mechanistic studies will be performed to understand the mechanisms of action of MAGP2 in ovarian cancer growth.