E-cadherin: A determinant molecule associated with ovarian cancer progression, dissemination and aggressiveness

PLoS One. 2017 Sep 21;12(9):e0184439. doi: 10.1371/journal.pone.0184439. eCollection 2017.

Abstract

Ovarian cancer (OC) is the fifth cancer death cause in women worldwide. The malignant nature of this disease stems from its unique dissemination pattern. Epithelial-to-mesenchymal transition (EMT) has been reported in OC and downregulation of Epithelial cadherin (E-cadherin) is a hallmark of this process. However, findings on the relationship between E-cadherin levels and OC progression, dissemination and aggressiveness are controversial. In this study, the evaluation of E-cadherin expression in an OC tissue microarray revealed its prognostic value to discriminate between advanced- and early-stage tumors, as well as serous tumors from other histologies. Moreover, E-cadherin, Neural cadherin (N-cadherin), cytokeratins and vimentin expression was assessed in TOV-112, SKOV-3, OAW-42 and OV-90 OC cell lines grown in monolayers and under anchorage-independent conditions to mimic ovarian tumor cell dissemination, and results were associated with cell aggressiveness. According to these EMT-related markers, cell lines were classified as mesenchymal (M; TOV-112), intermediate mesenchymal (IM; SKOV-3), intermediate epithelial (IE; OAW-42) and epithelial (E; OV-90). M- and IM-cells depicted the highest migration capacity when grown in monolayers, and aggregates derived from M- and IM-cell lines showed lower cell death, higher adhesion to extracellular matrices and higher invasion capacity than E- and IE-aggregates. The analysis of E-cadherin, N-cadherin, cytokeratin 19 and vimentin mRNA levels in 20 advanced-stage high-grade serous human OC ascites showed an IM phenotype in all cases, characterized by higher proportions of N- to E-cadherin and vimentin to cytokeratin 19. In particular, higher E-cadherin mRNA levels were associated with cancer antigen 125 levels more than 500 U/mL and platinum-free intervals less than 6 months. Altogether, E-cadherin expression levels were found relevant for the assessment of OC progression and aggressiveness.

MeSH terms

  • Antigens, CD
  • Ascites / metabolism
  • Ascites / pathology
  • Biomarkers, Tumor / metabolism
  • CA-125 Antigen / blood
  • Cadherins / metabolism*
  • Cell Adhesion / physiology
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Cell Survival / physiology
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Membrane Proteins / blood
  • Neoplasm Invasiveness / pathology
  • Neoplasm Invasiveness / physiopathology
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Ovarian Neoplasms / surgery
  • Prognosis
  • RNA, Messenger / metabolism

Substances

  • Antigens, CD
  • Biomarkers, Tumor
  • CA-125 Antigen
  • CDH1 protein, human
  • Cadherins
  • MUC16 protein, human
  • Membrane Proteins
  • RNA, Messenger

Grants and funding

Studies were supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica; http://www.agencia.mincyt.gob.ar/) (Argentina) (Grant PICTSU1072), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); http://www.conicet.gov.ar/) (Argentina) (Grant PIP740) and Instituto Nacional del Cáncer (http://www.msal.gov.ar/inc/) (Argentina) (Grant INC 2014-2015 and INC 2016-2017) to MHVL; Red Temática de Investigación Contra el Cáncer Ministerio de Ciencia e Innovación Español (http://www.rticc.org/) (RTICC; RD12/0036/0035), SGR Departament d’Univeristats, Recerca i Societat de la Informació de la Generalitat de Catalunya: 2014 (http://web.gencat.cat/ca/inici/) (SGR1330) to JR, and IRSES (International Research Staff Exchange Scheme; http://ec.europa.eu/research/mariecurieactions/funded-projects/international-research-staff-exchange-scheme) (Ref. 269285) to JR and MHVL.