Stem Cell Biology Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
Department of Pharmacology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Oncogene. 2018 Apr;37(16):2089-2103. doi: 10.1038/s41388-017-0106-y. Epub 2018 Jan 30.
Epithelial ovarian carcinoma (EOC) patients often acquire resistance against common chemotherapeutic drugs like paclitaxel and cisplatin. The mechanism responsible for the same is ambiguous. We have identified a putative drug-resistant tumour cell phenotype (EpCAMCD45) in the ascitic fluid of EOC patients, which appears to originate from the primary tumour. These cells represent the major tumour burden and are more drug resistant compared to EpCAM tumour cells due to the over-expression of SIRT1, ABCA1 and BCL2 genes. We have found that the entire EpCAMCD45 population is highly invasive with signature mesenchymal gene expression and also consists of subpopulations of ovarian cancer stem cells (CD133 and CD117CD44). Additionally, we demonstrate that the EpCAMCD45 tumour cells over-express major histocompatibility complex class I antigen, which enable them to evade the natural killer cell-mediated immune surveillance. Preliminary evidence obtained in OVCAR-5 cells suggests that exosomes, secreted by non-tumour cells of the ascitic fluid, play an important role in rendering drug resistance and invasive properties to the cancer cells. Identification of such aggressive tumour cells and deciphering their origin is important for designing better drug targets for EOC.
上皮性卵巢癌 (EOC) 患者通常会对紫杉醇和顺铂等常用化疗药物产生耐药性。导致这种情况的机制尚不清楚。我们在 EOC 患者的腹水中发现了一种假定的耐药肿瘤细胞表型（EpCAMCD45），它似乎源自原发性肿瘤。这些细胞代表了主要的肿瘤负担，并且由于 SIRT1、ABCA1 和 BCL2 基因的过度表达，比 EpCAM 肿瘤细胞具有更高的耐药性。我们发现整个 EpCAMCD45 群体具有高度侵袭性，具有特征性的间充质基因表达，并且还包含卵巢癌干细胞 (CD133 和 CD117CD44) 的亚群。此外，我们证明 EpCAMCD45 肿瘤细胞过度表达主要组织相容性复合体 I 类抗原，这使它们能够逃避自然杀伤细胞介导的免疫监视。在 OVCAR-5 细胞中获得的初步证据表明，腹水中非肿瘤细胞分泌的外泌体在赋予癌细胞耐药性和侵袭性方面发挥着重要作用。鉴定这种侵袭性肿瘤细胞并阐明其起源对于设计更好的 EOC 药物靶点很重要。
