Abstract
BackgroundHigh grade epithelial ovarian cancer (EOC) is commonly characterised by widespread peritoneal dissemination and ascites. Metastatic EOC tumour cells can attach directly to neighbouring organs or alternatively, maintain long term tumourigenicity and chemoresistance by forming cellular aggregates (spheroids). Cancer stem-like cells are proposed to facilitate this mechanism. This study aimed to investigate the role of Oct4A, an embryonic stem cell factor and known master regulator of pluripotency in EOC progression, metastasis and chemoresistance.MethodsTo investigate the expression of Oct4A in primary EOC tumours, IHC and qRT-PCR analyses were used. The expression of Oct4A in chemonaive and recurrent EOC patient ascites-derived tumour cells samples was investigated by qRT-PCR. The functional role of Oct4A in EOC was evaluated by generating stable knockdown Oct4A clones in the established EOC cell line HEY using shRNA-mediated silencing technology. Cellular proliferation, spheroid forming ability, migration and chemosensitivty following loss of Oct4A in HEY cells was measured by in vitro functional assays. These observations were further validated in an in vivo mouse model using intraperitoneal (IP) injection of established Oct4A KD clones into Balb/c nu/nu mice.ResultsWe demonstrate that, compared to normal ovaries Oct4A expression significantly increases with tumour dedifferentiation. Oct4A expression was also significantly high in the ascites-derived tumour cells of recurrent EOC patients compared to chemonaive patients. Silencing of Oct4A in HEY cells resulted in decreased cellular proliferation, migration, spheroid formation and increased chemosensitivity to cisplatin in vitro. IP injection of Oct4A knockdown cells in vivo produced significantly reduced tumour burden, tumour size and invasiveness in mice, which overall resulted in significantly increased mouse survival rates compared to mice injected with control cells.ConclusionsThis data highlights a crucial role for Oct4A in the progression and metastasis of EOC. Targeting Oct4A may prove to be an effective strategy in the treatment and management of epithelial ovarian tumours.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0417-y) contains supplementary material, which is available to authorized users.
Highlights
Epithelial ovarian cancer (EOC) remains the most prevalent of all the gynaecological malignancies with approximately 250,000 women diagnosed worldwide with the disease each year [1]
Oct4A is over expressed in primary serous ovarian carcinomas and in the ascites-derived isolated tumour cells of recurrent patients To first establish whether Oct4A is expressed in primary serous ovarian tumours, a total of 26 paraffin embedded cases (Table 1), consisting of 6 normal ovarian epithelia, 5 well differentiated borderline serous tumours, 7 moderately differentiated grade 2 serous tumours, and 8 poorly differentiated grade 3 serous tumours were analysed by immunohistochemistry using a human Oct4Aspecific antibody targeting the N-terminal of the Oct4 protein
To determine whether Oct4A may play a role in the chemoresistant nature exhibited by recurrent epithelial ovarian cancer (EOC) tumour cells, we examined the expression Oct4A in isolated tumour cells derived from the ascites of chemonaïve and recurrent patients (Table 3.3)
Summary
Epithelial ovarian cancer (EOC) remains the most prevalent of all the gynaecological malignancies with approximately 250,000 women diagnosed worldwide with the disease each year [1]. Exfoliated tumour cells can maintain long term tumourigenicity within the peritoneal cavity by forming non-adherent multicellular tumour aggregates (spheroids) in the ascites microenvironment [5] This combined with the emergence of drug resistant tumour cells following extensive chemotherapy regimens presents a major challenge in the management of the disease [6, 7]. Recent evidence suggests solid tumours including those of ovarian origin contain a sub-population of tumour cells exhibiting unlimited self-renewal and pluripotent abilities [8] These cells, termed cancer stem cells (CSCs) have gained considerable momentum in cancer biology over the past decade and are hypothesized to mediate tumour cell survival [9], sustain cytotoxic pressure [10, 11] and initiate metastatic recurrence [12]. This study aimed to investigate the role of Oct4A, an embryonic stem cell factor and known master regulator of pluripotency in EOC progression, metastasis and chemoresistance
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