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Título:
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Molecular profiling of circulating tumor cells links plasticity to the metastatic process in endometrial cancer
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Autor/a:
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Alonso-Alconada, Lorena; Muinelo-Romay, Laura; Madissoo, Kadri; Díaz-López, Antonio; Krakstad, Camilla; Trovik, Jone; Wik, Elisabeth; Hapangama, Dharani; Coenegrachts, Lieve; Cano, Amparo; Gil-Moreno, Antonio; Chiva, Luís; Cueva, Juan; Vieito, María; Ortega Izquierdo, Maria Eugenia; Mariscal, Javier; Colás, Eva; Castellví, Josep; Cusido, Maite; Dolcet Roca, Xavier; Nijman, Hans W.; Bosse, Tjalling; Green, John A.; Romano, Andrea; Reventós, Jaume; López-López, Rafael; Salvesen, Helga B.; Amant, Frederic; Matias-Guiu, Xavier; Moreno-Bueno, Gema; Abal, Miguel
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Notas:
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Background: About 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.
Methods: CTC 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.
Results: EpCAM-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.
Conclusions: Our 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.
ISCIII PI11/00873; Fundación Asociación Española Contra el Cancer (AECC), Grupos Estables 2011; InveNNta (Innovation in Nanomedicine), co-financed by the European Union (EU) through the Operational Programme for Cross-border Cooperation, Spain-Portugal (POCTEP 2007-2013), European Regional Development Fund (ERDF); Helse Vest, Research Council of Norway, Norwegian Cancer Society and Harald Andersens legat (H.B.S.);
L. Alonso-Alconada is recipient of fellowship from the Basque Government (Spain). |
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Materia(s):
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-High-risk endometrial carcinomas
-Circulating tumor cells
-Epithelial to mesenchymal transition
-Endometri -- Càncer |
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Derechos:
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cc-by (c) Alonso-Alconada, Lorena et al., 2014
http://creativecommons.org/licenses/by/3.0/es/
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Tipo de documento:
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article
publishedVersion |
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Editor:
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Biomed Central
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Compartir:
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