Abstract
Although cancer is a disease with genetic and epigenetic origins, the possible effects of reprogramming by defined factors remain to be fully understood. We studied the effects of the induction or inhibition of cancer-related genes and immature status-related genes whose alterations have been reported in gastrointestinal cancer cells. Retroviral-mediated introduction of induced pluripotent stem (iPS) cell genes was necessary for inducing the expression of immature status-related proteins, including Nanog, Ssea4, Tra-1-60, and Tra-1-80 in esophageal, stomach, colorectal, liver, pancreatic, and cholangiocellular cancer cells. Induced cells, but not parental cells, possessed the potential to express morphological patterns of ectoderm, mesoderm, and endoderm, which was supported by epigenetic studies, indicating methylation of DNA strands and the histone H3 protein at lysine 4 in promoter regions of pluripotency-associated genes such as NANOG. In in vitro analysis induced cells showed slow proliferation and were sensitized to differentiation-inducing treatment, and in vivo tumorigenesis was reduced in NOD/SCID mice. This study demonstrated that pluripotency was manifested in induced cells, and that the induced pluripotent cancer (iPC) cells were distinct from natural cancer cells with regard to their sensitivity to differentiation-inducing treatment. Retroviral-mediated introduction of iPC cells confers higher sensitivity to chemotherapeutic agents and differentiation-inducing treatment.
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Biomarkers / metabolism
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Cell Differentiation / drug effects
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Cell Differentiation / physiology
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Cell Line, Tumor
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DNA (Cytosine-5-)-Methyltransferases / genetics
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DNA (Cytosine-5-)-Methyltransferases / metabolism
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DNA Methylation
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DNA Methyltransferase 3A
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DNA Methyltransferase 3B
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Epigenesis, Genetic
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Eye Proteins / genetics
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Eye Proteins / metabolism
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Gastrointestinal Neoplasms / genetics*
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Gastrointestinal Neoplasms / metabolism
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Gastrointestinal Neoplasms / pathology*
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Lentivirus / genetics
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Nanog Homeobox Protein
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Neoplastic Stem Cells / cytology
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Neoplastic Stem Cells / drug effects
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Neoplastic Stem Cells / physiology*
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Octamer Transcription Factor-3 / genetics
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Octamer Transcription Factor-3 / metabolism
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PAX6 Transcription Factor
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Paired Box Transcription Factors / genetics
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Paired Box Transcription Factors / metabolism
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Pluripotent Stem Cells / cytology
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Pluripotent Stem Cells / drug effects
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Pluripotent Stem Cells / physiology*
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Retroviridae / genetics
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SOXB1 Transcription Factors / genetics
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SOXB1 Transcription Factors / metabolism
Substances
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Antineoplastic Agents
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Biomarkers
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DNMT3A protein, human
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Eye Proteins
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Homeodomain Proteins
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MSX2 protein
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Nanog Homeobox Protein
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Nanog protein, mouse
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Octamer Transcription Factor-3
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PAX6 Transcription Factor
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PAX6 protein, human
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Paired Box Transcription Factors
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Pax6 protein, mouse
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Repressor Proteins
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SOXB1 Transcription Factors
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Sox2 protein, mouse
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DNA (Cytosine-5-)-Methyltransferases
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DNA Methyltransferase 3A