Defined factors induce reprogramming of gastrointestinal cancer cells
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 report...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2010-01, Vol.107 (1), p.40-45 |
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creator | Miyoshi, Norikatsu Ishii, Hideshi Nagai, Ken-ichi Hoshino, Hiromitsu Mimori, Koshi Tanaka, Fumiaki Nagano, Hiroaki Sekimoto, Mitsugu Doki, Yuichiro Mori, Masaki |
description | 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. |
doi_str_mv | 10.1073/pnas.0912407107 |
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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.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.0912407107</identifier><identifier>PMID: 20018687</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Adipocytes ; Animals ; Antineoplastic Agents - pharmacology ; Biological Sciences ; Biomarkers - metabolism ; Cancer ; Cell Differentiation - drug effects ; Cell Differentiation - physiology ; Cell Line, Tumor ; Cell lines ; Cells ; Cellular differentiation ; Deoxyribonucleic acid ; DNA ; DNA (Cytosine-5-)-Methyltransferases - genetics ; DNA (Cytosine-5-)-Methyltransferases - metabolism ; DNA Methylation ; DNA Methyltransferase 3A ; DNA Methyltransferase 3B ; Embryonic stem cells ; Epigenesis, Genetic ; Epithelial cells ; Eye Proteins - genetics ; Eye Proteins - metabolism ; Gastrointestinal Neoplasms - genetics ; Gastrointestinal Neoplasms - metabolism ; Gastrointestinal Neoplasms - pathology ; Gene expression ; Homeodomain Proteins - genetics ; Homeodomain Proteins - metabolism ; Humans ; Induced pluripotent stem cells ; Lentivirus - genetics ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Nanog Homeobox Protein ; Neoplastic Stem Cells - cytology ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - physiology ; Neurons ; Octamer Transcription Factor-3 - genetics ; Octamer Transcription Factor-3 - metabolism ; Paired Box Transcription Factors - genetics ; Paired Box Transcription Factors - metabolism ; PAX6 Transcription Factor ; Pluripotent stem cells ; Pluripotent Stem Cells - cytology ; Pluripotent Stem Cells - drug effects ; Pluripotent Stem Cells - physiology ; Proteins ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Retroviridae - genetics ; Rodents ; SOXB1 Transcription Factors - genetics ; SOXB1 Transcription Factors - metabolism ; Stem cells</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2010-01, Vol.107 (1), p.40-45</ispartof><rights>Copyright National Academy of Sciences Jan 5, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c552t-b984708aafd26f59a995ed1de94ca12bd5d8a8efab14fb38854dcb74b06f14d13</citedby><cites>FETCH-LOGICAL-c552t-b984708aafd26f59a995ed1de94ca12bd5d8a8efab14fb38854dcb74b06f14d13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/107/1.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/40536224$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/40536224$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20018687$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miyoshi, Norikatsu</creatorcontrib><creatorcontrib>Ishii, Hideshi</creatorcontrib><creatorcontrib>Nagai, Ken-ichi</creatorcontrib><creatorcontrib>Hoshino, Hiromitsu</creatorcontrib><creatorcontrib>Mimori, Koshi</creatorcontrib><creatorcontrib>Tanaka, Fumiaki</creatorcontrib><creatorcontrib>Nagano, Hiroaki</creatorcontrib><creatorcontrib>Sekimoto, Mitsugu</creatorcontrib><creatorcontrib>Doki, Yuichiro</creatorcontrib><creatorcontrib>Mori, Masaki</creatorcontrib><title>Defined factors induce reprogramming of gastrointestinal cancer cells</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>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.</description><subject>Adipocytes</subject><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological Sciences</subject><subject>Biomarkers - metabolism</subject><subject>Cancer</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Differentiation - physiology</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cells</subject><subject>Cellular differentiation</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA (Cytosine-5-)-Methyltransferases - genetics</subject><subject>DNA (Cytosine-5-)-Methyltransferases - metabolism</subject><subject>DNA Methylation</subject><subject>DNA Methyltransferase 3A</subject><subject>DNA Methyltransferase 3B</subject><subject>Embryonic stem cells</subject><subject>Epigenesis, Genetic</subject><subject>Epithelial cells</subject><subject>Eye Proteins - genetics</subject><subject>Eye Proteins - metabolism</subject><subject>Gastrointestinal Neoplasms - genetics</subject><subject>Gastrointestinal Neoplasms - metabolism</subject><subject>Gastrointestinal Neoplasms - pathology</subject><subject>Gene expression</subject><subject>Homeodomain Proteins - genetics</subject><subject>Homeodomain Proteins - metabolism</subject><subject>Humans</subject><subject>Induced pluripotent stem cells</subject><subject>Lentivirus - genetics</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Nanog Homeobox Protein</subject><subject>Neoplastic Stem Cells - cytology</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - physiology</subject><subject>Neurons</subject><subject>Octamer Transcription Factor-3 - genetics</subject><subject>Octamer Transcription Factor-3 - metabolism</subject><subject>Paired Box Transcription Factors - genetics</subject><subject>Paired Box Transcription Factors - metabolism</subject><subject>PAX6 Transcription Factor</subject><subject>Pluripotent stem cells</subject><subject>Pluripotent Stem Cells - cytology</subject><subject>Pluripotent Stem Cells - drug effects</subject><subject>Pluripotent Stem Cells - physiology</subject><subject>Proteins</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Retroviridae - genetics</subject><subject>Rodents</subject><subject>SOXB1 Transcription Factors - genetics</subject><subject>SOXB1 Transcription Factors - metabolism</subject><subject>Stem cells</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUtv1DAUhS0EokNhzYZHxIZV2utX7GwqoVIeUiUW0LXl-BE8mtiDnSDx73E0wxRYWdfnu0f36CD0HMMFBkEv91GXC-gxYSDqxwO0wXVqO9bDQ7QBIKKVjLAz9KSULQD0XMJjdEYAsOyk2KCb986H6GzjtZlTLk2IdjGuyW6f05j1NIU4Nsk3oy5zTiHOrswh6l1jdDQuN8btduUpeuT1rrhnx_cc3X24-Xb9qb398vHz9bvb1nBO5nboJRMgtfaWdJ73uu-5s9i6nhmNyWC5lVo6rwfM_ECl5MyaQbABOo-ZxfQcXR1898swOWtcnLPeqX0Ok86_VNJB_avE8F2N6aciEjqBWTV4ezTI6cdSo6gplDWCji4tRQlKOQfR0Uq--Y_cpiXX4EURwJQB4St0eYBMTqVk50-nYFBrQWotSN0XVDde_Z3gxP9ppAIvjsC6eW8nFFYMqvzyIG9LreukM-C0I2QN-Pqge52UHnMo6u7rejBgQSgGSn8DbS6qMg</recordid><startdate>20100105</startdate><enddate>20100105</enddate><creator>Miyoshi, Norikatsu</creator><creator>Ishii, Hideshi</creator><creator>Nagai, Ken-ichi</creator><creator>Hoshino, Hiromitsu</creator><creator>Mimori, Koshi</creator><creator>Tanaka, Fumiaki</creator><creator>Nagano, Hiroaki</creator><creator>Sekimoto, Mitsugu</creator><creator>Doki, Yuichiro</creator><creator>Mori, Masaki</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100105</creationdate><title>Defined factors induce reprogramming of gastrointestinal cancer cells</title><author>Miyoshi, Norikatsu ; Ishii, Hideshi ; Nagai, Ken-ichi ; Hoshino, Hiromitsu ; Mimori, Koshi ; Tanaka, Fumiaki ; Nagano, Hiroaki ; Sekimoto, Mitsugu ; Doki, Yuichiro ; Mori, Masaki</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c552t-b984708aafd26f59a995ed1de94ca12bd5d8a8efab14fb38854dcb74b06f14d13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adipocytes</topic><topic>Animals</topic><topic>Antineoplastic Agents - 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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.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>20018687</pmid><doi>10.1073/pnas.0912407107</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Adipocytes Animals Antineoplastic Agents - pharmacology Biological Sciences Biomarkers - metabolism Cancer Cell Differentiation - drug effects Cell Differentiation - physiology Cell Line, Tumor Cell lines Cells Cellular differentiation Deoxyribonucleic acid DNA DNA (Cytosine-5-)-Methyltransferases - genetics DNA (Cytosine-5-)-Methyltransferases - metabolism DNA Methylation DNA Methyltransferase 3A DNA Methyltransferase 3B Embryonic stem cells Epigenesis, Genetic Epithelial cells Eye Proteins - genetics Eye Proteins - metabolism Gastrointestinal Neoplasms - genetics Gastrointestinal Neoplasms - metabolism Gastrointestinal Neoplasms - pathology Gene expression Homeodomain Proteins - genetics Homeodomain Proteins - metabolism Humans Induced pluripotent stem cells Lentivirus - genetics Mice Mice, Inbred NOD Mice, SCID Nanog Homeobox Protein Neoplastic Stem Cells - cytology Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - physiology Neurons Octamer Transcription Factor-3 - genetics Octamer Transcription Factor-3 - metabolism Paired Box Transcription Factors - genetics Paired Box Transcription Factors - metabolism PAX6 Transcription Factor Pluripotent stem cells Pluripotent Stem Cells - cytology Pluripotent Stem Cells - drug effects Pluripotent Stem Cells - physiology Proteins Repressor Proteins - genetics Repressor Proteins - metabolism Retroviridae - genetics Rodents SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism Stem cells |
title | Defined factors induce reprogramming of gastrointestinal cancer cells |
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