Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer

Molecular Cancer

Research

Maite Cusido¹  Antonio Diaz-Lopez²  Amparo Cano²  Gema Moreno-Bueno³  Elisabeth Wik⁴  Camilla Krakstad⁵  Helga B Salvesen⁵  Jone Trovik⁵  Kadri Madissoo⁵  Xavier Dolcet⁶  Eugenia Ortega⁶  Xavier Matias-Guiu⁶  Tjalling Bosse⁷  Dharani Hapangama⁸  John A Green⁸  Frederic Amant⁹  Lieve Coenegrachts⁹  Andrea Romano^1,10  Luis Chiva^1,11  Antonio Gil-Moreno^1,12  Josep Castellvi^1,12  Eva Colas^1,12  Jaume Reventos^1,13  Lorena Alonso-Alconada^1,14  Javier Mariscal^1,14  Laura Muinelo-Romay^1,14  Miguel Abal^1,14  Maria Vieito^1,14  Rafael Lopez-Lopez^1,14  Juan Cueva^1,14  Hans W Nijman^1,15 

[1] Clinical and Surgical Gynaecology R&D + I, Institut Universitari Dexeus, Barcelona, Spain;Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain;Departament of Biochemistry, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain;Hospital MD Anderson Cancer Centre Madrid, Madrid, Spain;Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway;Department of Pathology, Haukeland University Hospital, Bergen, Norway;Department of Obstetrics and Gynecology, Haukeland University Hospital, Bergen, Norway;Department of Clinical Science, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway;Department of Pathology and Molecular Genetics and Research Laboratory, Hospital Universitari Arnau de Vilanova, University of Lleida, IRBLLEIDA, Lleida, Spain;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands;Department of Women’s and Children’s Health, Institute of Translational Medicine, University of Liverpool, Liverpool Women’s Hospital, Crown Street, Liverpool, UK;Division of Gynecologic Oncology, Department of Oncology, KU Leuven, B-3000, Leuven, Belgium;GROW: School for Oncology and Developmental Biology, Department of Obstetrics and Gynaecology, Maastricht University Medical Centre, Maastricht, The Netherlands;Hospital MD Anderson Cancer Centre Madrid, Madrid, Spain;Research Unit in Biomedicine and Translational and Pediatric Oncology, Vall d’Hebron Research Institute and Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain;Research Unit in Biomedicine and Translational and Pediatric Oncology, Vall d’Hebron Research Institute and Hospital and Universitat Autònoma de Barcelona, Barcelona, Spain;Departament de Ciencies Basiques, Universitat Internacional de Catalunya, Barcelona, Spain;Translational Medical Oncology; Health Research Institute of Santiago (IDIS), SERGAS, Trav. Choupana s/n, 15706, Santiago de Compostela, Spain;University Medical Center Groningen, Department of Gynecologic Oncology, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands;

关键词: High-risk endometrial carcinomas;    Circulating tumor cells;    Epithelial to mesenchymal transition;    Stem cell;    ETV5;   

DOI  :  10.1186/1476-4598-13-223

 received in 2014-02-13, accepted in 2014-09-19,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAbout 20% of patients diagnosed with endometrial cancer (EC) are considered high-risk with unfavorable prognosis. In the framework of the European Network for Individualized Treatment in EC (ENITEC), we investigated the presence and phenotypic features of Circulating Tumor Cells (CTC) in high-risk EC patients.MethodsCTC isolation was carried out in peripheral blood samples from 34 patients, ranging from Grade 3 Stage IB to Stage IV carcinomas and recurrences, and 27 healthy controls using two methodologies. Samples were subjected to EpCAM-based immunoisolation using the CELLection™ Epithelial Enrich kit (Invitrogen, Dynal) followed by RTqPCR analysis. The phenotypic determinants of endometrial CTC in terms of pathogenesis, hormone receptor pathways, stem cell markers and epithelial to mesenchymal transition (EMT) drivers were asked. Kruskal-Wallis analysis followed by Dunn’s post-test was used for comparisons between groups. Statistical significance was set at p < 0.05.ResultsEpCAM-based immunoisolation positively detected CTC in high-risk endometrial cancer patients. CTC characterization indicated a remarkable plasticity phenotype defined by the expression of the EMT markers ETV5, NOTCH1, SNAI1, TGFB1, ZEB1 and ZEB2. In addition, the expression of ALDH and CD44 pointed to an association with stemness, while the expression of CTNNB1, STS, GDF15, RELA, RUNX1, BRAF and PIK3CA suggested potential therapeutic targets. We further recapitulated the EMT phenotype found in endometrial CTC through the up-regulation of ETV5 in an EC cell line, and validated in an animal model of systemic dissemination the propensity of these CTC in the accomplishment of metastasis.ConclusionsOur results associate the presence of CTC with high-risk EC. Gene-expression profiling characterized a CTC-plasticity phenotype with stemness and EMT features. We finally recapitulated this CTC-phenotype by over-expressing ETV5 in the EC cell line Hec1A and demonstrated an advantage in the promotion of metastasis in an in vivo mouse model of CTC dissemination and homing.

【 授权许可】

Unknown   
© Alonso-Alconada et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.