Cited by 47Colorectal Cancer Treatments and StudiesCancer Cells and MetastasisHER2/EGFR in Cancer Research

Stem cell property epithelial‐to‐mesenchymal transition is a core transcriptional network for predicting cetuximab (Erbitux™) efficacy in KRAS wild‐type tumor cells

Oliveras‐Ferraros, Cristina, Vazquez‐Martin, Alejandro, Cufí, Sílvia, Queralt, Bernardo, Báez, Luciana, Guardeño, Raquel, Hernández‐Yagüe, Xavier, Martin‐Castillo, Begoña +2 more·2011·Journal of Cellular Biochemistry

Abstract

Beyond a well‐recognized effect of KRAS mutations in determining de novo inefficacy of cetuximab (CTX) in metastatic colorectal cancer, we urgently need a biomarker signature for predicting CTX efficacy in KRAS wild‐type (WT) tumors. CTX‐adapted EGFR gene‐amplified KRAS WT tumor cell populations were induced by stepwise‐chronic exposure of A431 epidermoid cancer cells to CTX. Genome‐wide analyses of 44K Agilent's whole human arrays were bioinformatically evaluated by Gene Set Enrichment Analysis (GSEA)‐based screening of the KEGG pathway database. Molecular functioning of CTX was found to depend on: (i) The occurrence of a positive feedback loop on Epidermal Growth Factor Receptor (EGFR) activation driven by genes coding for EGFR ligands (e.g., amphiregulin); (ii) the lack of a negative feedback on mitogen‐activated protein kinase (MAPK) activation regulated by dual‐specificity phosphatases (e.g., DUSP6) and; (iii) the transcriptional status of gene pathways controlling the epithelial‐to‐mesenchymal transition (EMT) and its reversal (MET) program (actin cytoskeleton and cell–cell communication—e.g., keratins—focal adhesion signaling—e.g., integrins—and EMT‐inducing cytokines – e.g., transforming growth factor‐β). Quantitative real‐time PCR, high‐content immunostaining, and flow‐cytometry analyses confirmed that CTX efficacy depends on its ability to promote: (i) Stronger cell–cell contacts by up‐regulating the expression of the epithelial markers E‐cadherin and occludin; (ii) down‐regulation of the epithelial transcriptional repressors Zeb, Snail, and Slug accompanied by restoration of cortical F‐actin; and (iii) complete prevention of the CD44 pos/CD24 neg/low mesenchymal immunophenotype. The impact of EGFR ligands/MAPK phosphatases gene transcripts in predicting CTX efficacy in KRAS WT tumors may be tightly linked with the ability of CTX to concurrently reverse the EMT status, a pivotal property of migrating cancer stem cells. J. Cell. Biochem. 112: 10–29, 2011. © 2010 Wiley‐Liss, Inc.

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Crossref · 10.1002/jcb.22952

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Authors
Oliveras‐Ferraros, C., Vazquez‐Martin, A., Cufí, S., Queralt, B., Báez, L., Guardeño, R., Hernández‐Yagüe, X., Martin‐Castillo, B., Brunet, J., & Menendez, J. A.
Affiliations
Institut Català d'Oncologia (ES)
Venue
Journal of Cellular Biochemistry
Publisher
Wiley
Published
2011-01
Volume
112
Issue
1
Pages
10-29
ISSN
  • 0730-2312 (ISSN-L)
  • 1097-4644
OpenAlex
W2041777830
Cited by
47
References
77
Citations by year
2025: 1 · 2024: 2 · 2022: 3 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 1 · 2017: 3 · 2016: 4 · 2015: 2 · 2014: 3 · 2013: 5 · 2012: 9
FWCI
2.84
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Cellular Biochemistry (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Keywords
cetuximab, KRAS wild-type tumors, metastatic colorectal cancer, epithelial-mesenchymal transition, cancer stem cells, EGFR, EGFR ligands, amphiregulin, MAPK signaling, DUSP6, E-cadherin, occludin, ZEB, snails, Slug, F-actin, predictive biomarkers, drug resistance
MeSH terms
Cetuximab, Antibodies, Monoclonal, Antineoplastic Agents, Carcinoma, Squamous Cell, Female, Humans, Proto-Oncogene Proteins, Vulvar Neoplasms, Down-Regulation, Proto-Oncogene Proteins p21(ras), Neoplasms, Squamous Cell, ras Proteins, Hyaluronan Receptors, Cell Line, Tumor, CD24 Antigen, Gene Regulatory Networks, Epithelial-Mesenchymal Transition, Antibodies, Monoclonal, Humanized, ErbB Receptors

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