Novel Biomarkers in Ovarian Cancer

描述（由申请人提供）：晚期卵巢癌占2008年美国约24，000例上皮性卵巢癌新发病例的大多数（>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率。此外，许多预后生物标志物可以最终作为重要的治疗目标，如果他们的分子作用是很好地理解。利用转录谱分析技术结合考克斯回归分析，我们以前已经确定了一个假定的基因签名，它可以预测晚期高级别浆液性卵巢癌患者的生存。标记中具有最高考克斯分数的基因被称为微原纤维相关糖蛋白（MAGP-2），其已显示与含原纤维蛋白的微原纤维相关，并与成纤维细胞中的1V 23整联蛋白特异性相互作用。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，卵巢肿瘤组织样本中MAGP-2的表达与患者的生存率显著相关。此外，MAGP-2显示在表达高水平的1V 23整联蛋白的人脐静脉内皮细胞（HUVEC）和卵巢癌细胞中诱导细胞生长和运动。此外，外源性MAGP-2显示出显著诱导HUVEC和卵巢癌细胞系OVCA 429中的Ca 2+振荡和FAK磷酸化。因此，我们假设卵巢癌细胞表达高水平的MAGP-2调节卵巢癌的生长，并通过其与1V 23整合素的相互作用，从而导致卵巢癌患者的总体生存率较差。在本申请中，我们提出使用大量多中心临床试验样本进一步验证MAGP-2的预后价值，并描绘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的患者获得的标本将MAGP-2表达与结果相关联。其次，我们将描述MAGP-2在调节卵巢肿瘤生长和进展中的功能作用，在体外和体内。最后，我们将描绘MAGP-2诱导的细胞增殖，迁移和侵袭卵巢癌细胞和内皮细胞的信号网络。这项研究如果成功，将为我们提供一种新的卵巢癌预后生物标志物。它将引导我们识别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.