CD90参与浆液性卵巢癌干细胞筛选及干细胞相关耐药的机制研究

Resistance to chemotherapy is the main causal factor for cancer-related mortality, especially in ovarian cancer patients. Since several lines of evidences suggested that cancer stem cell plays an important role in drug resistance, it is of great importance to identify these cancer stem cells and their corresponding specific marker so that strategies targeting these cancer stem cells could be developed to treat the drug resistance of ovarian cancer. In previous research, we confirmed that cells with high expression of CD90 showed the property of stem cells and were resistant to cisplatin-based chemotherapy. CD90-blocking antibody could be used to treat drug resistance of ovarian cancer cells. Based on our previous data, this project is designed to investigate whether CD90 could be a specific marker and also a target for serous epithelial oviran cancer stem cells. We will perform experiments to explore the underlying mechanisms for CD90’s potentials to maintain the state of ovarian cancer stem cells, and to investigate the singaling pathways responsible for CD90-related drug resistance in ovarian cancers. Our project will provide new insight for the molecular-classification of ovarian cancers as well as cancer stem cell based therapy.

化疗耐药是肿瘤复发致死的关键因素，在卵巢癌中尤为明显。研究表明，肿瘤干细胞在肿瘤耐药中扮演了重要角色，因此鉴定卵巢癌干细胞，探索新的干预靶点，对于解决卵巢癌耐药具有较大的临床价值。我们的前期研究发现CD90高表达的浆液性卵巢癌细胞具有干细胞属性且明显耐药，通过制备CD90封闭抗体能够缓解体外培养浆液性卵巢癌细胞的耐药。在前期研究的基础上，我们拟在细胞和整体水平验证CD90是否可作为浆液性卵巢癌干细胞鉴定的分子靶标，及其在卵巢癌干细胞属性维持及化疗耐药中发挥的作用和具体机制，为进一步研究卵巢癌分子分型及临床靶向治疗提供理论依据。

上皮性卵巢癌是最致命的妇科恶性肿瘤之一，在过去的五十年中，其总生存率几乎没有改善。上皮性卵巢癌治疗最棘手的问题是治疗抵抗力和术后肿瘤复发。研究表明，肿瘤干细胞在肿瘤耐药中扮演了重要角色。尽管CD90被公认为是各种癌症的干细胞标志物，但CD90作为上皮性卵巢癌中肿瘤干细胞的标志物的机制尚未阐明。本研究中，我们发现CD90是肿瘤干细胞的表面标记，代表上皮性卵巢癌中具有高转移潜力的亚群。临床数据表明，卵巢癌中CD90高表达与不良预后有关。上皮性卵巢癌细胞中高表达的CD90群体具有干性和致瘤性。卵巢癌细胞中CD90转染的细胞显示出显着较高的侵袭转移能力。进一步的实验表明，ITGA5/SRC/FAK途径是CD90高表达卵巢癌细胞具有转移表型的一种机制。我们对原位卵巢癌模型的研究还证实CD90促进癌细胞在腹膜腔中的播散，而达沙替尼治疗可部分阻断这一过程。因此，我们的研究表明CD90是上皮性卵巢癌中的肿瘤干细胞标记，靶向ITGA5/SRC/FAK途径可能是CD90高表达的上皮性卵巢癌的一种新型治疗策略。总之，我们的研究验证了CD90可作为浆液性卵巢癌干细胞鉴定的分子靶标，为进一步研究卵巢癌分子分型及临床靶向治疗提供理论依据。