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

项目摘要 在所有妇科癌症中，卵巢癌因其临床诊断困难而显示出较高的临床挑战性。 早期发现，死亡率最高。尽管取得了进步和发展 诊断工具，如生物标志物和检测技术，卵巢癌仍然是一种致命的癌症，具有很高的 进步。根据组织学分类，卵巢癌有不同类型；卵巢上皮性癌 癌症(EOC)是最常见的。超过80%的晚期妇女出现EOC，并有并发症 包括肿瘤植入物在整个腹膜腔的扩散。因此，有必要找到新的 具有高特异性和敏感性的生物标记物，用于在疾病的早期阶段检测卵巢癌。最近， 我们发现了一种高度保守的膜相关蛋白多谱勒，它只在肿瘤和 调节血管内皮生长因子在肿瘤中的作用。此外，我们还演示了多佩尔的交互和协作 用VEGFR2刺激肿瘤血管生成。因此，以前的研究证实了我们的猜测，即多普利是一种 TEC特异性标记物和抗肿瘤治疗的最佳靶点。我们假设多普尔驱动卵巢 癌症进展。这项提议的最终目标是评估多普尔的表达是否可以 作为卵巢癌特异性血清标志物及靶向多谱勒治疗新策略的研究 对铂敏感和抗铂的EOC。这项研究的两个具体目的是：(1) 评价多谱勒作为卵巢癌血清生物标志物及多谱勒表达程度的研究 在基于微流体的器质性和原位EOC模型中，多谱勒在恶性腹水形成中的作用。 我们将阐明调节和强化多普勒调节的腹水形成的过程。 卵巢肿瘤。这项拟议的研究将阐明多谱勒表达与恶性之间的关系 卵巢癌的腹水形成和新血管生成。人与人之间的同源相似性 小鼠的多谱勒蛋白也表明，候选的小鼠抗多谱勒单抗可以转化为临床应用。 通过将其人性化。

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.