title: Chronic chemotherapeutic stress promotes evolution of stemness and WNT/beta-catenin signaling in colorectal cancer cells: implications for clinical use of WNT-signaling inhibitors.
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.
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.|Institut Universitaire de Cancérologie, Pierre et Marie Curie (UPMC) Sorbonne Universités, Paris, France.
authors.forename: Meriam
authors.initials: M
authors.lastname: Ayadi
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.|Institut Universitaire de Cancérologie, Pierre et Marie Curie (UPMC) Sorbonne Universités, Paris, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Bouygues
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.|Institut Universitaire de Cancérologie, Pierre et Marie Curie (UPMC) Sorbonne Universités, Paris, France.
authors.forename: Djamila
authors.initials: D
authors.lastname: Ouaret
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.|Institut Universitaire de Cancérologie, Pierre et Marie Curie (UPMC) Sorbonne Universités, Paris, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Ferrand
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), Gustave-Roussy, Villejuif, France.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore.|Department of Biochemistry, School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute, National University of Singapore, Singapore.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Thiery
authors.affiliation: Laboratory of Epigenetic Regulation, Centre National de la Recherche Scientifique (CNRS), Institut Pasteur, Paris, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Muchardt
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.|Institut Universitaire de Cancérologie, Pierre et Marie Curie (UPMC) Sorbonne Universités, Paris, France.
authors.forename: Michèle
authors.initials: M
authors.lastname: Sabbah
authors.affiliation: Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris, France.|Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.|Institut Universitaire de Cancérologie, Pierre et Marie Curie (UPMC) Sorbonne Universités, Paris, France.
authors.forename: Annette K
authors.initials: AK
authors.lastname: Larsen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005472:Fluorouracil / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D000077146:Irinotecan; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology; D000077150:Oxaliplatin; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011744:Pyrimidinones / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014227:Triazines / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects* / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018960:Hyaluronan Receptors; C492448:ICG 001; D009944:Organoplatinum Compounds; C548732:PKF118-310; D020033:Protein Isoforms; D011744:Pyrimidinones; D014227:Triazines; D000077150:Oxaliplatin; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin
keywords: WNT inhibitors; WNT/beta-catenin signaling; chemotherapeutic stress; colorectal cancer; stemness