Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition

Nikolaos A. Dallas, Ling Xia, Fan Fan, Michael J. Gray, Puja Gaur, George Van Buren, Shaija Samuel, Michael P. Kim, Sherry J. Lim, Lee M. Ellis

Research output: Contribution to journalArticlepeer-review

397 Scopus citations

Abstract

5-Fluorouracil (5FU) and oxaliplatin are standard therapy for metastatic colorectal cancer (CRC), but the development of chemoresistance is inevitable. Because cancer stem cells (CSC) are hypothesized to be chemoresistant, we investigated CSC properties in newly developed chemoresistant CRC cell lines and sought to identify targets for therapy. The human CRC cell line HT29 was exposed to increasing doses of 5FU (HT29/5FU-R) or oxaliplatin (HT29/OxR) to achieve resistance at clinically relevant doses. Western blotting and flow cytometry were done to determine molecular alterations. The insulin-like growth factor-I receptor (IGF-IR) monoclonal antibody (mAb) AVE-1642 was used to inhibit signaling in vitro and in vivo using murine xenograft models. HT29/5FU-R and HT29/OxR showed 16-to 30-fold enrichment of CD133+ cells and 2-fold enrichment of CD44+ cells (putative CRC CSC markers). Resistant cells were enriched 5-to 22-fold for double-positive (CD1337CD44+) cells. Consistent with the CSC phenotype, resistant cells exhibited a decrease in cellular proliferation in vitro (47-59%; P < 0.05). Phosphorylated and total IGF-IR levels were increased in resistant cell lines. HT29/5FU-R and HT29/OxR cells were ~ 5-fold more responsive to IGF-IR inhibition relative to parental cells (P < 0.01) in vitro. Tumors derived from HT29/OxR cells showed significantly greater growth inhibition in response to an IGF-IR mAb than did parental cells (P < 0.05). Chemoresistant CRC cells are enriched for CSC markers and the CSC phenotype. Chemo-therapy-induced IGF-IR activation provided for enhanced sensitivity to IGF-IR-targeted therapy. Identification of CSC targets presents a novel therapeutic approach in this disease.

Original languageEnglish (US)
Pages (from-to)1951-1957
Number of pages7
JournalCancer research
Volume69
Issue number5
DOIs
StatePublished - Mar 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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