The origin of ovarian cancer

Abstract

A prerequisite for the success of early detection of a disease is the clear understanding of its natural history. The cellular origin of ovarian cancer has remained elusive, and this has delayed our understanding of the biology of initiation and progression of the disease, and has hampered the development of effective early detection methods. As a consequence, ovarian cancer remains one of the most fatal malignancies in women worldwide. In this issue of BJOG Sharma et al. present important evidence from a prospective study of more than 48 000 postmenopausal women indicating that small ovarian inclusion cysts, of <10 mm in diameter, are not associated with an increased risk of invasive epithelial ovarian cancer. This finding has an important implication for the management of this common condition, as it confirms the safety of the current practice of conservative management of such lesions. In addition, Sharma et al. discuss the implication of their finding for identifying the cellular origin of epithelial ovarian cancers. As 'ovarian cancers' in all probability arise from several different sites, some additional discussion may help to place their paper in perspective.According to Hamilton, 1 the concept that epithelial ovarian cancers arise from ovarian surface epithelial (OSE) cells was proposed by Sir Spencer Wells in 1872. More than a century later, this hypothesis remains controversial. The OSE cells are mesothelial-like cells that share embryological origin with the Müllerian tract epithelium, which eventually gives rise to tubal, endometrial and endocervical epithelium. It has long been thought that epithelial ovarian tumours arise from the less differentiated OSE cells, and subsequently differentiate into histological subtypes according to specific molecular perturbations. This hypothesis is supported by the finding that mouse ovarian surface epithelial cells (MOSEC) grown in culture can undergo spontaneous malignant transformation.2 Importantly, ectopic expression of HOXA9, HOXA10 and HOXA11 genes in MOSEC followed by intraperitoneal injection into mice resulted in the establishment of cancers of serous, endometrioid and mucinous subtypes, respectively.2 These findings give direct evidence that OSE cells can indeed be transformed into cancer cells and forced to differentiate into the three most common types of epithelial ovarian cancers. Therefore, the formation of inclusion cysts (ICs) lined by OSE cells has been suggested as the lesion of origin of epithelial ovarian cancers. The current findings from Sharma et al. argue against this hypothesis, at least in a subset of epithelial cancers. In their study, out of the 48 230 postmenopausal women with no family history of ovarian cancer who had a pelvic ultrasound in the first year of the study, 1234 women had inclusion cysts (2.6%). For the 22 914 women who had a normal scan in the first year, ICs developed at a rate of 2-3% per year on subsequent annual scans. After a median follow-up period of 6 years, the authors could not find an increase in the risk o...

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“…33 Because our study was designed to be exploratory, we deliberately included different histologic subtypes of ovarian cancer, because we were acutely aware of the recent controversy regarding their differing origin and pathogenesis. 34,35 Nevertheless, the vast majority of our patients, particularly in the validation cohort, were diagnosed with advanced stage, high-grade, serous ovarian cancer. Hence, we propose the further evaluation of TUSC3 as a prognostic factor primarily in this subset of patients with ovarian cancer.…”

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