The role of tumor endothelium-specific prion-gene PRND in epithelial ovarian cancer

项目摘要 在所有的妇科癌症中，卵巢癌显示出很高的临床挑战性，因为它很难被治疗。 早期发现，死亡率最高。尽管取得了进展， 尽管有生物标志物和检测技术等诊断工具，卵巢癌仍然是一种致命的癌症，发病率很高 进展根据组织学分类有不同类型的卵巢癌;上皮性卵巢癌 癌症（EOC）是最常见的。超过80%的女性在晚期并发症中被确定为EOC 包括肿瘤植入物在整个腹膜腔中的扩散。因此，有必要寻找新的 具有高度特异性和敏感性的生物标志物，可在疾病的早期阶段检测卵巢癌。最近， 我们鉴定了一种高度保守的膜相关朊病毒样蛋白Doppel，它只在肿瘤中表达， 调节VEGF在肿瘤中的功能。此外，我们证明了Doppel相互作用和协作 与VEGFR 2一起刺激肿瘤血管生成。因此，以前的研究证实了我们的猜想，即Doppel是一个 TEC特异性标志物和抗肿瘤治疗的最佳靶点。我们假设Doppel驱动卵巢 癌症进展这项建议的最终目标是评估是否可以使用Doppel表达。 作为EOC特异性血清生物标志物，并通过靶向Doppel开发新的治疗策略 针对铂敏感性和铂抗性EOC。本研究的两个具体目的是：（1） 评估Doppel作为血清生物标志物和卵巢癌中Doppel表达的程度;（2）研究 Doppel在基于微流体的类器官和EOC原位模型中恶性腹水形成中的作用。 我们将阐明调节和加强Doppel调节的腹水形成的过程， 卵巢肿瘤这项研究将阐明Doppel表达、恶性肿瘤和恶性肿瘤之间的关系。 腹水形成和卵巢癌中的新血管生成。人类与 鼠Doppel蛋白还提示候选鼠抗Doppel mAb可转化为临床应用 使之人性化。

Project Summary Among all of the gynecological cancers, ovarian cancer shows high clinical challenge because it is difficult to be detected in the early stage and it has the highest mortality rate. Despite advances and the development of diagnostic tools such as biomarkers and detection techniques, ovarian cancer remains a fatal cancer with high progression. There are different types of ovarian cancer based on histological classification; Epithelial Ovarian Cancer (EOC) is the most common. EOC is identified in over 80% of women at late-stage with complications include the spread of tumor implants throughout the peritoneal cavity. Thus, it is necessary to find new biomarkers with high specificity and sensitivity to detect ovarian cancer in the early stages of disease. Recently, we identified a highly conserved membrane-associated prion-like protein Doppel that express only in tumors and regulate the functions of VEGF in tumors. Furthermore, we demonstrated that Doppel interacts and collaborates with VEGFR2 to stimulate tumor angiogenesis. Previous studies thus confirmed our conjecture that Doppel is a TEC-specific marker and an optimal target for anti-tumor therapy. We hypothesize that Doppel drives ovarian cancer progression. The ultimate goals of this proposal are to evaluate whether Doppel expression could be utilized as an EOC-specific serum biomarker and to develop a novel therapeutic strategy by targeting Doppel against both platinum-sensitive and platinum-resistant EOCs. The two specific aims of this study are: (1) To assess Doppel as a serum biomarker and the degree of Doppel expression in ovarian cancers and (2) To study the role of Doppel in malignant ascites formation in a microfluidic-based organoid and orthotopic model of EOC. We will shed lights into the processes that regulate and intensify the Doppel-regulated ascites formation in ovarian tumors. The proposed research will elucidate the relationship between Doppel expression, malignant ascites formation, and neoangiogenesis in ovarian cancers. The homologous similarity between human and murine Doppel protein also suggest that a candidate mouse anti-Doppel mAb can be translated into clinical use by humanizing it.