Dataset Information

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

ABSTRACT:

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?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.

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.

SUBMITTER: Alonso-Alconada L

PROVIDER: S-EPMC4190574 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Alonso-Alconada Lorena L Muinelo-Romay Laura L Madissoo Kadri K Diaz-Lopez Antonio A Krakstad Camilla C Trovik Jone J Wik Elisabeth E Hapangama Dharani D Coenegrachts Lieve L Cano Amparo A Gil-Moreno Antonio A Chiva Luis L Cueva Juan J Vieito Maria M Ortega Eugenia E Mariscal Javier J Colas Eva E Castellvi Josep J Cusido Maite M Dolcet Xavier X Nijman Hans W HW Bosse Tjalling T Green John A JA Romano Andrea A Reventos Jaume J Lopez-Lopez Rafael R Salvesen Helga B HB Amant Frederic F Matias-Guiu Xavier X Moreno-Bueno Gema G Abal Miguel M

Molecular cancer 20140927

<h4>Background</h4>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.<h4>Methods</h4>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 h ...[more]

PMID: 25261936

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Project description:Metastatic colorectal cancer (mCRC) relies on the detachment of aggressive malignant cells from the primary tumor into the bloodstream, these Circulating Tumor Cells (CTC) being the principal source of the further metastasis. Here, we approached the massive molecular profiling of the CTC population isolated from mCRC patients. Clinically, the presence of CTC is associated with poor prognosis and there exists a clear necessity for more specific and efficient chemotherapies in the treatment of mCRC. Immunoisolation of CTC from these patients combined with a whole transcriptome amplification and hybridization onto gene expression arrays, lead us to specifically describe for the first time a CTC population with adhesive and migratory characteristics, in addition to a modulated expression of genes related to cell death and survival. Furthermore, bioinformatic analysis provided with an armamentarium of highly specific and sensitive valuable markers that should impact on the management and follow-up of mCRC patients. Finally, molecular profiling of CTC resulted in the identification of new therapeutic targets, like TGF-Î²1 impairing, specifically targeting the CTC population which should improve the efficacy in the eradication and prevention of CRC metastasis. In conclusion, molecular profiling of CTC represents an innovative and promising approach in the clinical management of mCRC patients. Circulating Tumor Cells (CTC) were immunoisolated from six metastatic colorectal patients (mCRC). Moreover, blood from three healthy donors were obtained, immunoisolating non-specific cellularity background. RNA was extracted and globally amplified with a Whole Transcriptome Amplification system. Samples were hybridized onto agilent arrays and CTC specific genes were obtained. Gene networks were built with IPA software and a gene ontology analysis was performed. Eleven candidate genes were validated by real time PCR. Finally, TGFB1 was evaluated as a potential drugable target against CTC population.

Dataset Information

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

Background

Methods

Conclusions

Publications

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

Similar Datasets

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