title: Human colonic fibroblasts regulate stemness and chemotherapy resistance of colon cancer stem cells.
abstract: There is increasing evidence that cancers are heterogeneous and contain a hierarchical organization consisting of cancer stem cells and their differentiated cell progeny. These cancer stem cells are at the core of the tumor as they represent the clonogenic cells within a tumor. Moreover, these cells are considered to contain selective therapy resistance, which suggests a pivotal role in therapy resistance and tumor relapse. Here we show that differentiated cells can re-acquire stemness through factors secreted from fibroblasts. This induced CSC state also coincides with re-acquisition of resistance to chemotherapy. Resistance induced in newly formed CSCs is mediated by the anti-apoptotic molecule BCLXL and inhibition of BCLXL with the BH3 mimetic ABT-737 sensitizes these cancer cells toward chemotherapy. These data point to an important interplay between tumor cells and their microenvironment in the regulation of stemness and therapy resistance.
authors.affiliation: a LEXOR (Laboratory of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine Academic Medical Center , University of Amsterdam , Amsterdam , The Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: Colak
authors.affiliation: a LEXOR (Laboratory of Experimental Oncology and Radiobiology), Center for Experimental Molecular Medicine Academic Medical Center , University of Amsterdam , Amsterdam , The Netherlands.|b Cancer Genomics Center , The Netherlands.
authors.forename: J P
authors.initials: JP
authors.lastname: Medema
mesh_terms: D000071916:AC133 Antigen / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001685:Biological Factors / Q000378:metabolism* / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002450:Cell Communication; D016923:Cell Death; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053554:Keratin-20 / Q000235:genetics / Q000378:metabolism; D055262:Mucin-2 / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D061251:Primary Cell Culture; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology*; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: C501332:ABT-737; D000071916:AC133 Antigen; D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D001685:Biological Factors; D015415:Biomarkers; D001713:Biphenyl Compounds; D017077:Culture Media, Conditioned; C507499:KRT20 protein, human; D053554:Keratin-20; C116884:LGR5 protein, human; C524625:MUC2 protein, human; D055262:Mucin-2; D009596:Nitrophenols; C000606023:PROM1 protein, human; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D013449:Sulfonamides; D051020:bcl-X Protein; D049452:Green Fluorescent Proteins
keywords: ABT-737; BCLXL; apoptosis; cancer stem cell; chemotherapy; colorectal cancer; fibroblast; microenvironment; resistance