Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells

Abstract

BackgroundAccumulating evidence suggests that somatic stem cells undergo mutagenic transformation into cancer initiating cells. The serous subtype of ovarian adenocarcinoma in humans has been hypothesized to arise from at least two possible classes of progenitor cells: the ovarian surface epithelia (OSE) and/or an as yet undefined class of progenitor cells residing in the distal end of the fallopian tube.MethodsComparative gene expression profiling analyses were carried out on OSE removed from the surface of normal human ovaries and ovarian cancer epithelial cells (CEPI) isolated by laser capture micro-dissection (LCM) from human serous papillary ovarian adenocarcinomas. The results of the gene expression analyses were randomly confirmed in paraffin embedded tissues from ovarian adenocarcinoma of serous subtype and non-neoplastic ovarian tissues using immunohistochemistry. Differentially expressed genes were analyzed using gene ontology, molecular pathway, and gene set enrichment analysis algorithms.ResultsConsistent with multipotent capacity, genes in pathways previously associated with adult stem cell maintenance are highly expressed in ovarian surface epithelia and are not expressed or expressed at very low levels in serous ovarian adenocarcinoma. Among the over 2000 genes that are significantly differentially expressed, a number of pathways and novel pathway interactions are identified that may contribute to ovarian adenocarcinoma development.ConclusionsOur results are consistent with the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as the origin of ovarian adenocarcinoma. While our findings do not rule out the possibility that ovarian cancers may also arise from other sources, they are inconsistent with claims that ovarian surface epithelia cannot serve as the origin of ovarian cancer initiating cells.

Epithelial ovarian cancer stem cells: underlying complexity of a simple paradigm

“…While the OSE has been suggested to be largely composed of somatic stem cells (Bowen et al 2009), a number of recent studies have sought to attribute stem cell properties only to the subsets of cells on the ovary. The somatic stem cells in the OSE have been investigated in three distinct contexts: potential stem cells able to regenerate germ cells (Parte et al 2011, Patel et al 2013, Virant-Klun et al 2013a, potential stem cells that give rise to granulosa cells (Hummitzsch et al 2013), and more traditional somatic stem cells whose role is to replenish the OSE following ovulatory wounding (Szotek et al 2008, Motohara et al 2011, Usongo & Farookhi 2012, Auersperg 2013, Flesken-Nikitin et al 2013, Ng et al 2014.…”

Epiregulin as a marker for the initial steps of ovarian cancer development

“…Ovarian cancer is the most lethal gynecological cancer in women because early detection is extremely difficult (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) and because it is resistant to most chemotherapic drugs (15)(16)(17). The average lifespan after detection is 40.8 months for serous cancer, 21.3 months for clear cell carcinomas, 17.6 months for mucinous carcinomas and 50.9 months for endometrioid ovarian carcinomas (11).…”

Nuclear localization of phosphorylated ERK1 and ERK2 as markers for the progression of ovarian cancer

“…It is subdivided according to the pathological appearance and molecular markers to four groups: serous-adenocarcinomas comprises 80% of the cancer and the rest are mucinous carcinomas, endometrioid carcinomas and clear cell carcinomas (reviewed in refs. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. Earlier it was reported that about 12-13% of total ovarian carcinomas are mucinous carcinomas, but recently, using new molecular markers, it was considered as only 2-3% of total ovarian carcinomas (16).…”

“…[1][2][3][4][5][6][7][8][9][10][11][12][13][14]. It is subdivided according to the pathological appearance and molecular markers to four groups: serous-adenocarcinomas comprises 80% of the cancer and the rest are mucinous carcinomas, endometrioid carcinomas and clear cell carcinomas (reviewed in refs.…”