Yang AD, Fan F, Camp ER, Van BG, Liu W, Somcio R et al.. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res 12: 4147-4153

Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1402, USA.
Clinical Cancer Research (Impact Factor: 8.72). 07/2006; 12(14 Pt 1):4147-53. DOI: 10.1158/1078-0432.CCR-06-0038
Source: PubMed


Epithelial-to-mesenchymal transition (EMT) is a process whereby cells acquire molecular alterations that facilitate cell motility and invasion. In preliminary studies, we observed that oxaliplatin-resistant (OxR) colorectal cancer (CRC) cells underwent morphologic changes suggestive of a migratory phenotype, leading us to hypothesize that OxR CRC cells undergo EMT.
The human CRC cell lines KM12L4 and HT29 were exposed to increasing doses of oxaliplatin to establish stable cell lines resistant to oxaliplatin. Migration and invasion were assessed by modified Boyden chamber assays. Morphologic and molecular changes characteristic of EMT were determined by immunofluorescence staining and Western blot analyses.
The OxR cells showed phenotypic changes consistent with EMT: spindle-cell shape, loss of polarity, intercellular separation, and pseudopodia formation. KM12L4 and HT29 OxR cells exhibited an approximately 8- to 15-fold increase in migrating and invading cells, respectively (P < 0.005 for both). Immunofluorescence staining of OxR cells revealed translocation of E-cadherin and beta-catenin from their usual membrane-bound complex to the cytoplasm and nucleus, respectively. The OxR cells also had decreased expression of the epithelial adhesion molecules E-cadherin and plakoglobin and an increase in the mesenchymal marker vimentin. The KM12L4 OxR cells exhibited increased nuclear expression of Snail, an EMT-regulatory transcription factor, whereas the HT29 OxR cells exhibited an increase in nuclear expression of the EMT-associated transcription factor nuclear factor kappaB.
We hypothesize that induction of EMT may contribute to the decreased efficacy of therapy in chemoresistant CRC, as the tumor cells switch from a proliferative to invasive phenotype. Further understanding of the mechanisms of chemoresistance in CRC will enable improvements in chemotherapy for metastatic disease.

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    • "ABC-transporters, cell cycle), and a heatmap showing the expression of the significantly deregulated transcripts belonging to each cluster was made (Figure 3). In addition , significantly deregulated transcripts belonging to a published signature of genes known to be either up-or downregulated during EMT (Huang et al., 2012), a process previously reported to be associated with chemoresistance (Fan et al., 2012; Hoshino et al., 2009; Hwang et al., 2011; Yang et al., 2006), was seen. "
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    ABSTRACT: Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
    Full-text · Article · Feb 2015 · Molecular oncology
    • "Depletion of synergistic effects in cetuximab is observed in head and neck tumors with c-myc up-regulation and EMT progression (Skvortsova et al. 2010). Similarly, colorectal cancer cells resistant to oxaliplatin-induced EMT through Vimentin induction (Yang et al. 2006b). Overexpression of Twist, Snail and FOXC2 in breast cancer cells not only provide tumor cells EMT activation but also ABC transporter upregulation and subsequent MDR (Saxena et al. 2011). "
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    ABSTRACT: Purpose: In multiple cell metazoans, the ability of polarized epithelial cells to convert to motile mesenchymal cells in order to relocate to another location is governed by a unique process termed epithelial-mesenchymal transition (EMT). While being an essential process of cellular plasticity for normal tissue and organ developments, EMT is found to be involved in an array of malignant phenotypes of tumor cells including proliferation and invasion, angiogenesis, stemness of cancer cells and resistance to chemo-radiotherapy. Although EMT is being extensively studied and demonstrated to play a key role in tumor metastasis and in sustaining tumor hallmarks, there is a lack of clear picture of the overall EMT signaling network, wavering the potential clinical trials targeting EMT. Methods: In this review, we highlight the potential key therapeutic targets of EMT linked with tumor aggressiveness, hypoxia, angiogenesis and cancer stem cells, emphasizing on an emerging EMT-associated NF-κB/HER2/STAT3 pathway in radioresistance of breast cancer stem cells. Results: Further definition of cancer stem cell repopulation due to EMT-controlled tumor microenvironment will help to understand how tumors exploit the EMT mechanisms for their survival and expansion advantages. Conclusions: The knowledge of EMT will offer more effective targets in clinical trials to treat therapy-resistant metastatic lesions.
    No preview · Article · Oct 2014 · Journal of Cancer Research and Clinical Oncology
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    • "However, the EMT status, as well as the rates of a reduced E-cadherin expression and the presence of a nuclear expression of Snail in the primary and metastatic tumors, were similar. In the current study, the data for the EMT status, which was represented by both a reduced E-cadherin expression and the presence of a nuclear Snail expression in the ovarian cancer specimens, indicated that the EMT appears to promote the dissemination of cells from the tumor mass [37] and that cells undergoing the EMT become invasive and develop resistance to anticancer agents [38,39]. The EMT can induce resistance to multiple drugs, permitting rapid tumor progression. "
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    ABSTRACT: Objectives The epithelial-mesenchymal-transition (EMT) is an important step in the invasion and metastasis of cancer. A critical molecular feature of this process is the downregulation of the E-cadherin expression, which is primarily controlled by Snail-related zinc-finger transcription factors. The aim of this study was to evaluate the prognostic impact of the expression of EMT-related proteins (E-cadherin and Snail) in patients with ovarian cancer. Methods An immunohistochemical analysis was conducted using tissue microarray samples of 174 primary tumors and 34 metastases of ovarian carcinoma, and the relationships between the protein expression, clinicopathological features and outcomes were investigated. Results A reduced E-cadherin expression was observed in 36.8% of the primary tumors and 30.4%, 35.7%, 37.7% and 52.7% of the stage I, II, III and IV tumors, respectively. The nuclear expression of Snail was positive in 33.9% of the primary tumors. The rate of an EMT-positive status, as represented by both a reduced E-cadherin expression and a nuclear expression of Snail, was significantly higher in the patients with peritoneal dissemination than in those without (p < 0.05). The EMT status was significantly associated with both the progression-free survival and overall survival (p <0.01). A multivariate analysis showed an EMT-positive status to be a significant predictor of both the progression-free survival (p < 0.05) and overall survival (P < 0.01). Conclusions These data indicate that the EMT status is significantly associated with peritoneal metastasis and both the progression-free survival and overall survival in patients with ovarian cancer. Therefore, clarifying and controlling EMT signaling is a promising approach to molecular targeted therapy for ovarian cancer.
    Full-text · Article · Jul 2014 · Journal of Ovarian Research
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