Epithelial–mesenchymal transition in ovarian cancer
Introduction
The ability of cancer cells to undergo invasion and metastasis is regulated through the action of a variety of cellular and signalling proteins. This complex environment includes intracellular and membrane proteins that drive mechanically cell migration and protrusion as well as growth factors produced by stroma and tumor cells. To migrate and to spread within the tissues cells modify their shape, they become polarized and extend protrusions allowing for increased migratory capacity.
The metastatic sequence involves numerous steps, including detachment of cells within a primary tumor, penetration of local stroma, entry of local vascular or lymphatic vessels (intravasation), aggregation with platelets, interaction with and adhesion to distant endothelia, extravasation, recolonization, and expansion [1], [2].
It is well established that cancer invasion and metastasis still represent the major causes of the failure of cancer treatment. Furthermore, the identification of molecules and/or signalling pathways involved in these processes is of paramount importance for the development of an appropriate therapy for certain types of cancers like ovarian cancers for which the early-stage detection is still a barrier.
Ovarian cancer is a highly metastatic disease and the leading cause of death from gynecologic malignancy. In 2009 in the United States, it is estimated that ovarian cancer will be diagnosed in 21,550 women with an estimated 14,600 deaths per year (surveillance, epidemiology and end results (SEER) Program of the National Cancer Institute). Despite enormous progress in the understanding of ovarian cancer biology, this disease remains one of the leading cause of cancer death among women in most western countries due to the advanced stage of disease at diagnosis (stages III–IV) when the vast majority of women are diagnosed with disseminated intraperitoneal carcinomatosis.
Ovarian carcinomas include a large group of neoplasms with a wide range of genetic alterations, morphological characteristics and clinical outcome.
Surface epithelial tumors (carcinomas) account for approximately 60% of all ovarian tumors and approximately 90% of malignant ovarian tumors neoplasms and are thought to arise from the normal ovarian surface epithelium (OSE) or inclusion cysts lined with OSE cells that were exposed to inflammatory stimuli, prolonged gonadotropin stimulation or incessant ovulation [3], [4].
OSE covering a nonovulating ovary is a stationary mesothelium that exhibits epithelial and mesenchymal characteristics [5] with the capacity to give rise to inclusion cysts through the lost of mesenchymal characteristics and subsequent acquisition of epithelial characteristics (mesenchymal–epithelial transition, MET) [6].
Additionally, ovarian tumors are also classified in five major subtypes designated as follows: serous, mucinous, endometrioid, clear cell, and transitional cell (or Brenner type). Tumors in each of the categories can be further subdivided into benign, malignant and intermediate (tumor of borderline malignancy, BOT) to reflect or not their capability to invade anatomically distant normal tissues.
Section snippets
Epithelial–mesenchymal transition: the role of E-cadherin
Epithelial tumors commonly use collective migration mechanism to infiltrate neighbouring tissue [7], however, several features set apart ovarian cancer spread from other epithelial tumors.
First, due to the lack of an anatomical barrier, ovarian carcinoma can spread directly throughout the peritoneal cavity, mainly by intra-abdominal dissemination and by lymphatic dissemination, enabling in this way the attachment to peritoneum and omentum. Dissemination through the vasculature is rare [8].
Pathways leading to EMT
Induction of EMT is driven by a complex interplay between cancer cells and their environment including stroma or extracellular components such as cytokines and growth factors acting in an autocrine or paracrine fashion. Here, we performed a PubMed searching to identify factors promoting EMT in ovarian cancer cells. Five molecules have been described to be involved in this process and here described.
Conclusions
The role of EMT in cancer invasion and metastasis is strongly supported by several cellular models. Although the role of EMT in vivo is still debated among pathologists [77], [78], specific inhibition of these signalling pathways proved their clinical efficacy.
Recent studies link EMT with the induction of stem cell markers with new implication in the treatment in ovarian cancer and cancer in general [79], [80], [81]. Experimental findings reported that immortalized human mammary epithelial
Conflicts of interest
None declared.
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