Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.
Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.
Cell Prolif. 2021 May;54(5):e13029. doi: 10.1111/cpr.13029. Epub 2021 Mar 25.
High-grade serous carcinoma (HGSC) is the most common and malignant histological type of epithelial ovarian cancer, the origin of which remains controversial. Currently, the secretory epithelial cells of the fallopian tube are regarded as the main origin and the ovarian surface epithelial cells as a minor origin. In tubal epithelium, these cells acquire TP53 mutations and expand to a morphologically normal 'p53 signature' lesion, transform to serous tubal intraepithelial carcinoma and metastasize to the ovaries and peritoneum where they develop into HGSC. This shifting paradigm of the main cell of origin has revolutionarily changed the focus of HGSC research. Various cell lines have been derived from the two cellular origins by acquiring immortalization via overexpression of hTERT plus disruption of TP53 and the CDK4/RB pathway. Malignant transformation was achieved by adding canonical driver mutations (such as gain of CCNE1) revealed by The Cancer Genome Atlas or by noncanonical gain of YAP and miR181a. Alternatively, because of the extreme chromosomal instability, spontaneous transformation can be achieved by long passage of murine immortalized cells, whereas in humans, it requires ovulatory follicular fluid, containing regenerating growth factors to facilitate spontaneous transformation. These artificially and spontaneously transformed cell systems in both humans and mice have been widely used to discover carcinogens, oncogenic pathways and malignant behaviours in the development of HGSC. Here, we review the origin, aetiology and carcinogenic mechanism of HGSC and comprehensively summarize the cell models used to study this fatal cancer having multiple cells of origin and overt genomic instability.
高级别浆液性癌（HGSC）是最常见和恶性的上皮性卵巢癌组织学类型，其起源仍存在争议。目前，输卵管的分泌上皮细胞被认为是主要起源，而卵巢表面上皮细胞则是次要起源。在输卵管上皮中，这些细胞获得 TP53 突变并扩展为形态正常的“p53 特征性病变”，转化为浆液性输卵管上皮内癌并转移到卵巢和腹膜，在那里发展为 HGSC。这种主要起源细胞的转变范式彻底改变了 HGSC 研究的重点。通过过度表达 hTERT 并破坏 TP53 和 CDK4/RB 通路实现永生化，从这两种细胞起源中衍生出了各种细胞系。通过添加癌症基因组图谱揭示的典型驱动突变（如 CCNE1 的获得）或非典型的 YAP 和 miR181a 的获得，实现了恶性转化。或者，由于极端的染色体不稳定性，通过对小鼠永生化细胞的长时间传代，可以自发转化，而在人类中，需要含有再生生长因子的排卵卵泡液来促进自发转化。这些在人和小鼠中人工和自发转化的细胞系统已被广泛用于发现 HGSC 发展中的致癌物、致癌途径和恶性行为。在这里，我们综述了 HGSC 的起源、病因和致癌机制，并全面总结了用于研究这种具有多种起源细胞和明显基因组不稳定性的致命癌症的细胞模型。
