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Review
. 2019 Jun 17;11(6):838.
doi: 10.3390/cancers11060838.

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

Nele Loret  1   2   3   4 , Hannelore Denys  5   6 , Philippe Tummers  7   8 , Geert Berx  9   10
Affiliations
Review

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

Nele Loret et al. Cancers (Basel). .

Abstract

Ovarian cancer is the most lethal of all gynecologic malignancies and the eighth leading cause of cancer-related deaths among women worldwide. The main reasons for this poor prognosis are late diagnosis; when the disease is already in an advanced stage, and the frequent development of resistance to current chemotherapeutic regimens. Growing evidence demonstrates that apart from its role in ovarian cancer progression, epithelial-to-mesenchymal transition (EMT) can promote chemotherapy resistance. In this review, we will highlight the contribution of EMT to the distinct steps of ovarian cancer progression. In addition, we will review the different types of ovarian cancer resistance to therapy with particular attention to EMT-mediated mechanisms such as cell fate transitions, enhancement of cancer cell survival, and upregulation of genes related to drug resistance. Preclinical studies of anti-EMT therapies have yielded promising results. However, before anti-EMT therapies can be effectively implemented in clinical trials, more research is needed to elucidate the mechanisms leading to EMT-induced therapy resistance.

Keywords: cancer stem cell (CSC); epithelial-to-mesenchymal transition (EMT); mesenchymal-to-epithelial transition (MET); ovarian cancer; peritoneal metastasis; therapy resistance.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in study design, data collection, analyses, interpretation, manuscript writing, or the decision to publish the results.

Figures

Figure 1
Figure 1
The potential role of epithelial-to-mesenchymal (EMT) plasticity during high-grade serous (HGS) ovarian cancer progression. (A) The color of the cells represents their EMT-state (blue = epithelial, purple = spectrum of epithelial/mesenchymal differentiation and red = mesenchymal). TGFβ present in follicular fluid, which is released during ovulation, can induce EMT in the normal fallopian tube epithelium (FTE). This can lead to the development of STIC (serous tubal intraepithelial carcinoma) lesions. Acitivin A, another component of the follicular fluid, stimulates migration of the STIC cells to the ovary, where they undergo mesenchymal-to-epithelial transition (MET) and form a primary tumor. In a later stage, cells exfoliate from the primary tumor and survive as single cells or spheroids in the ascites. Finally, they invade the mesothelium and again undergo MET to form macroscopic peritoneal or omental metastases. (B) EMT plasticity with EMT and MET alternately taking place during HGS ovarian cancer progression.
Figure 2
Figure 2
Different EMT-driven mechanisms leading to carboplatin and/or paclitaxel resistance in ovarian cancer cells: the presence of β-tubulin variants; lower drug uptake; higher drug efflux; increased DNA repair capacity; decreased apoptosis; changes in the cell cycle; changes in miRNA; and changes in different pathways (MAPK/ERK, TGFβ-SMAD, JAK/STAT, PI3K-AKT-NFκB). In addition, factors secreted by the microenvironment can induce EMT-related therapy resistance.
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