Cancer Letters

Cancer Letters

Volume 291, Issue 1, 1 May 2010, Pages 59-66
Cancer Letters

Epithelial–mesenchymal transition in ovarian cancer

https://doi.org/10.1016/j.canlet.2009.09.017Get rights and content

Abstract

Ovarian cancer is a highly metastatic disease and the leading cause of death from gynecologic malignancy. Hence, and understanding of the molecular changes associated with ovarian cancer metastasis could lead to the identification of targets for novel therapeutic interventions.

The conversion of an epithelial cell to a mesenchymal cell plays a key role both in the embryonic development and cancer invasion and metastasis. Cells undergoing epithelial–mesenchymal transition (EMT) lose their epithelial morphology, reorganize their cytoskeleton and acquire a motile phenotype through the up- and down-regulation of several molecules including tight and adherent junctions proteins and mesenchymal markers.

EMT is believed to be governed by signals from the neoplastic microenvironment including a variety of cytokines and growth factors. In ovarian cancer EMT is induced by transforming growth factor-β (TGF-β), epidermal growth factor (EGF), hepatocyte growth factor (HGF) and endothelin-1 (ET-1). Alterations in these cellular pathways candidate them as useful target for ovarian cancer treatment.

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.

References (83)

  • S.D. Yamada et al.

    Ovarian carcinoma cell cultures are resistant to TGF-β1-mediated growth inhibition despite expression of functional receptors

    Gynecol. Oncol.

    (1999)
  • W. Cui et al.

    TGF-β1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice

    Cell

    (1996)
  • M. Colomiere et al.

    Epidermal growth factor-induced ovarian carcinoma cell migration is associated with JAK2/STAT3 signals and changes in the abundance and localization of α6 and β1 integrin

    Int. J. Biochem. Cell. Biol.

    (2009)
  • A.S. Wong et al.

    Progressive changes in Met-dependent signaling in a human ovarian surface epithelial model of malignant transformation

    Exp. Cell. Res.

    (2004)
  • D. Salani et al.

    Role of endothelin-1 in neovascularization of ovarian carcinoma

    Am. J. Pathos.

    (2000)
  • S.A. Mani et al.

    The epithelial–mesenchymal transition generates cells with properties of stem cells

    Cell

    (2008)
  • Ie.M. Shih et al.

    Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis

    Am. J. Pathol.

    (2004)
  • E.W. Thompson et al.

    Carcinoma invasion and metastasis: a role for epithelial–mesenchymal transition?

    Cancer Res.

    (2005)
  • D.H. Geho et al.

    Physiological mechanisms of tumor-cell invasion and migration

    Physiology

    (2005)
  • V.W. Chen et al.

    Pathology and classification of ovarian tumors

    Cancer

    (2003)
  • N. Auersperg et al.

    Ovarian surface epithelium: biology, endocrinology and pathology

    Endocr. Rev.

    (2001)
  • S. Okamoto et al.

    Mesenchymal to epithelial transition in the human ovarian surface epithelium focusing on inclusion cysts

    Oncol. Rep.

    (2009)
  • P. Friedl et al.

    Tumour-cell invasion and migration: diversity and escape mechanisms

    Nat. Rev. Cancer

    (2003)
  • H. Naora et al.

    Ovarian cancer metastasis: integrating insights from disparate model organisms

    Nat. Rev. Cancer

    (2005)
  • D.C. Radisky

    Epithelial–mesenchymal transition

    J. Cell. Sci.

    (2005)
  • J.P. Thiery et al.

    Complex networks orchestrate epithelial–mesenchymal transitions

    Nat. Rev. Mol. Cell. Biol.

    (2006)
  • U. Cavallaro et al.

    Cell adhesion and signalling by cadherins and Ig-CAMs in cancer

    Nat. Rev. Cancer

    (2004)
  • C. Gamallo et al.

    Correlation of E-cadherin expression with differentiation grade and histological type in breast carcinoma

    Am. J. Pathol.

    (1993)
  • J. von Burstin et al.

    E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex

    Gastroenterology

    (2009)
  • Y. Kuwabara et al.

    Establishment of an ovarian metastasis model and possible involvement of E-cadherin down-regulation in the metastasis

    Cancer Sci.

    (2008)
  • K. Sawada et al.

    Loss of E-cadherin promotes ovarian cancer metastasis via α5-integrin, which is a therapeutic target

    Cancer Res.

    (2008)
  • K. Sundfeldt et al.

    E-cadherin expression in human epithelial ovarian cancer and normal ovary

    Int. J. Cancer

    (1997)
  • N. Auersperg et al.

    E-cadherin induces mesenchymal-to-epithelial transition in human ovarian surface epithelium

    Proc. Natl. Acad. Sci. USA

    (1999)
  • E.Y. Cho et al.

    Immunohistochemical study of the expression of adhesion molecules in ovarian serous neoplasms

    Pathol. Int.

    (2006)
  • A.L. Veatch et al.

    Differential expression of the cell–cell adhesion molecule E-cadherin in ascites and solid human ovarian tumor cells

    Int. J. Cancer

    (1994)
  • E. Batlle et al.

    The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells

    Nat. Cell. Biol.

    (2000)
  • V. Bolós et al.

    The transcription factor Slug represses E-cadherin expression and induces epithelial to mesenchymal transitions: a comparison with Snail and E47 repressors

    J. Cell. Sci.

    (2003)
  • J. Yoshida et al.

    Changes in the expression of E-cadherin repressors, Snail, Slug, SIP1 and Twist, in the development and progression of ovarian carcinoma: the important role of Snail in ovarian tumorigenesis and progression

    Med. Mol. Morphol.

    (2009)
  • A.B. Roberts et al.

    New class of transforming growth factors potentiated by epidermal growth factor: Isolation from non-neoplastic tissues

    Proc. Natl. Acad. Sci. USA

    (1981)
  • R. Derynck et al.

    TGF-β signaling in tumor suppression and cancer progression

    Nat. Genet.

    (2001)
  • J. Massagué

    TGF-β signal transduction

    Annu. Rev. Biochem.

    (1998)
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