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.
Keywords:
ABT-737; BCLXL; apoptosis; cancer stem cell; chemotherapy; colorectal cancer; fibroblast; microenvironment; resistance.
MeSH terms
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AC133 Antigen / genetics
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AC133 Antigen / metabolism
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Antineoplastic Agents / pharmacology*
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Biological Factors / metabolism*
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Biological Factors / pharmacology
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Biomarkers / metabolism
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Biphenyl Compounds / pharmacology*
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Cell Communication
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Cell Death
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Cell Differentiation
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Colonic Neoplasms / genetics
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Colonic Neoplasms / metabolism
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Colonic Neoplasms / pathology
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Culture Media, Conditioned / chemistry
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Culture Media, Conditioned / pharmacology
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Drug Resistance, Neoplasm
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Fibroblasts / drug effects
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Fibroblasts / metabolism*
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Fibroblasts / pathology
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Gene Expression Regulation, Neoplastic*
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Genes, Reporter
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Green Fluorescent Proteins / genetics
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Green Fluorescent Proteins / metabolism
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Humans
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Keratin-20 / genetics
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Keratin-20 / metabolism
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Mucin-2 / genetics
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Mucin-2 / metabolism
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Nitrophenols / pharmacology*
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Piperazines / pharmacology
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Primary Cell Culture
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction
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Spheroids, Cellular / drug effects
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Spheroids, Cellular / metabolism
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Spheroids, Cellular / pathology
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Sulfonamides / pharmacology*
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bcl-X Protein / genetics*
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bcl-X Protein / metabolism
Substances
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ABT-737
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AC133 Antigen
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Antineoplastic Agents
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BCL2L1 protein, human
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Biological Factors
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Biomarkers
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Biphenyl Compounds
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Culture Media, Conditioned
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KRT20 protein, human
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Keratin-20
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LGR5 protein, human
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MUC2 protein, human
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Mucin-2
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Nitrophenols
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PROM1 protein, human
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Piperazines
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Receptors, G-Protein-Coupled
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Sulfonamides
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bcl-X Protein
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Green Fluorescent Proteins