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Review

Chronic Oxaliplatin Resistance Induces Epithelial-to-Mesenchymal Transition in Colorectal Cancer Cell Lines

Anthony D. Yang, Fan Fan, E. Ramsay Camp, George van Buren, Wenbiao Liu, Ray Somcio, Michael J. Gray, Haiyun Cheng, Paulo M. Hoff and Lee M. Ellis
Anthony D. Yang
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Fan Fan
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E. Ramsay Camp
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George van Buren
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Wenbiao Liu
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Ray Somcio
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Michael J. Gray
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Haiyun Cheng
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Paulo M. Hoff
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Lee M. Ellis
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DOI: 10.1158/1078-0432.CCR-06-0038 Published July 2006
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Abstract

Purpose: 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.

Experimental Design: 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.

Results: 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 ∼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 β-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 κB.

Conclusion: 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.

  • oxaliplatin
  • chemoresistance
  • epithelial-to-mesenchymal transition
  • colorectal cancer
  • E-cadherin

Footnotes

  • Grant support: NIH Core Grant CA6672, NIH grant T-32 09599 (A.D. Yang, E.R. Camp, and G. van Buren), and the Lockton Fund for Pancreatic Cancer Research (M.J. Gray and L.M. Ellis).

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • Note: A.D. Yang and F. Fan contributed equally to this work.

    • Accepted May 4, 2006.
    • Received January 9, 2006.
    • Revision received April 20, 2006.
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Clinical Cancer Research: 12 (14)
July 2006
Volume 12, Issue 14
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Chronic Oxaliplatin Resistance Induces Epithelial-to-Mesenchymal Transition in Colorectal Cancer Cell Lines
Anthony D. Yang, Fan Fan, E. Ramsay Camp, George van Buren, Wenbiao Liu, Ray Somcio, Michael J. Gray, Haiyun Cheng, Paulo M. Hoff and Lee M. Ellis
Clin Cancer Res July 15 2006 (12) (14) 4147-4153; DOI: 10.1158/1078-0432.CCR-06-0038

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Chronic Oxaliplatin Resistance Induces Epithelial-to-Mesenchymal Transition in Colorectal Cancer Cell Lines
Anthony D. Yang, Fan Fan, E. Ramsay Camp, George van Buren, Wenbiao Liu, Ray Somcio, Michael J. Gray, Haiyun Cheng, Paulo M. Hoff and Lee M. Ellis
Clin Cancer Res July 15 2006 (12) (14) 4147-4153; DOI: 10.1158/1078-0432.CCR-06-0038
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