Chronic chemotherapeutic stress promotes evolution of stemness and WNT/beta-catenin signaling in colorectal cancer cells: implications for clinical use of WNT-signaling inhibitors

Oncotarget. 2015 Jul 30;6(21):18518-33. doi: 10.18632/oncotarget.3934.

Abstract

Most solid tumors contain a subfraction of cells with stem/progenitor cell features. Stem cells are naturally chemoresistant suggesting that chronic chemotherapeutic stress may select for cells with increased "stemness". We carried out a comprehensive molecular and functional analysis of six independently selected colorectal cancer (CRC) cell lines with acquired resistance to three different chemotherapeutic agents derived from two distinct parental cell lines. Chronic drug exposure resulted in complex alterations of stem cell markers that could be classified into three categories: 1) one cell line, HT-29/5-FU, showed increased "stemness" and WNT-signaling, 2) three cell lines showed decreased expression of stem cell markers, decreased aldehyde dehydrogenase activity, attenuated WNT-signaling and lost the capacity to form colonospheres and 3) two cell lines displayed prominent expression of ABC transporters with a heterogeneous response for stem cell markers. While WNT-signaling could be attenuated in the HT-29/5-FU cells by the WNT-signaling inhibitors ICG-001 and PKF-118, this was not accompanied by any selective growth inhibitory effect suggesting that the cytotoxic activity of these compounds is not directly linked to WNT-signaling inhibition. We conclude that classical WNT-signaling inhibitors have toxic off-target activities that need to be addressed for clinical development.

Keywords: WNT inhibitors; WNT/beta-catenin signaling; chemotherapeutic stress; colorectal cancer; stemness.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Blotting, Western
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Camptothecin / analogs & derivatives
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Irinotecan
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Organoplatinum Compounds / pharmacology
  • Oxaliplatin
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Pyrimidinones / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Triazines / pharmacology
  • Wnt Signaling Pathway / drug effects*
  • Wnt Signaling Pathway / genetics

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Hyaluronan Receptors
  • ICG 001
  • Organoplatinum Compounds
  • PKF118-310
  • Protein Isoforms
  • Pyrimidinones
  • Triazines
  • Oxaliplatin
  • Irinotecan
  • Fluorouracil
  • Camptothecin