IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer
Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Proinflammatory cytokines have been suggested to regulate preneoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB-regulated cytokine that acts on epithelial and immu...
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| Veröffentlicht in: | Cancer cell 2009-02, Vol.15 (2), p.103-113 |
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| creator | Grivennikov, Sergei Karin, Eliad Terzic, Janos Mucida, Daniel Yu, Guann-Yi Vallabhapurapu, Sivakumar Scheller, Jürgen Rose-John, Stefan Cheroutre, Hilde Eckmann, Lars Karin, Michael |
| description | Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Proinflammatory cytokines have been suggested to regulate preneoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB-regulated cytokine that acts on epithelial and immune cells. Using genetic tools, we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor-initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and premalignant intestinal epithelial cells (IECs) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by the transcription factor Stat3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-κB-IL-6-Stat3 cascade is an important regulator of the proliferation and survival of tumor-initiating IECs. |
| doi_str_mv | 10.1016/j.ccr.2009.01.001 |
| format | Article |
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Proinflammatory cytokines have been suggested to regulate preneoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB-regulated cytokine that acts on epithelial and immune cells. Using genetic tools, we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor-initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and premalignant intestinal epithelial cells (IECs) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by the transcription factor Stat3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-κB-IL-6-Stat3 cascade is an important regulator of the proliferation and survival of tumor-initiating IECs.</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2009.01.001</identifier><identifier>PMID: 19185845</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Bone Marrow Cells - cytology ; Bone Marrow Cells - physiology ; Cell Proliferation ; Cell Survival - physiology ; CELLCYCLE ; Colitis, Ulcerative - complications ; Colitis, Ulcerative - immunology ; Colitis, Ulcerative - pathology ; Epithelial Cells - cytology ; Epithelial Cells - physiology ; Gene Expression Regulation ; Humans ; Interleukin-6 - genetics ; Interleukin-6 - metabolism ; Intestinal Mucosa - cytology ; Intestinal Mucosa - pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neoplasms - etiology ; Neoplasms - immunology ; Neoplasms - pathology ; NF-kappa B - metabolism ; Signal Transduction - physiology ; STAT3 Transcription Factor - genetics ; STAT3 Transcription Factor - metabolism ; Tumor Necrosis Factor-alpha - immunology</subject><ispartof>Cancer cell, 2009-02, Vol.15 (2), p.103-113</ispartof><rights>2009 Elsevier Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c546t-4bd31e0ba3eccea67c10629ba3b995c1856424fb2072d13cc73468c4b77a43ec3</citedby><cites>FETCH-LOGICAL-c546t-4bd31e0ba3eccea67c10629ba3b995c1856424fb2072d13cc73468c4b77a43ec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610809000026$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19185845$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Grivennikov, Sergei</creatorcontrib><creatorcontrib>Karin, Eliad</creatorcontrib><creatorcontrib>Terzic, Janos</creatorcontrib><creatorcontrib>Mucida, Daniel</creatorcontrib><creatorcontrib>Yu, Guann-Yi</creatorcontrib><creatorcontrib>Vallabhapurapu, Sivakumar</creatorcontrib><creatorcontrib>Scheller, Jürgen</creatorcontrib><creatorcontrib>Rose-John, Stefan</creatorcontrib><creatorcontrib>Cheroutre, Hilde</creatorcontrib><creatorcontrib>Eckmann, Lars</creatorcontrib><creatorcontrib>Karin, Michael</creatorcontrib><title>IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Proinflammatory cytokines have been suggested to regulate preneoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB-regulated cytokine that acts on epithelial and immune cells. Using genetic tools, we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor-initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and premalignant intestinal epithelial cells (IECs) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by the transcription factor Stat3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-κB-IL-6-Stat3 cascade is an important regulator of the proliferation and survival of tumor-initiating IECs.</description><subject>Animals</subject><subject>Bone Marrow Cells - cytology</subject><subject>Bone Marrow Cells - physiology</subject><subject>Cell Proliferation</subject><subject>Cell Survival - physiology</subject><subject>CELLCYCLE</subject><subject>Colitis, Ulcerative - complications</subject><subject>Colitis, Ulcerative - immunology</subject><subject>Colitis, Ulcerative - pathology</subject><subject>Epithelial Cells - cytology</subject><subject>Epithelial Cells - physiology</subject><subject>Gene Expression Regulation</subject><subject>Humans</subject><subject>Interleukin-6 - genetics</subject><subject>Interleukin-6 - metabolism</subject><subject>Intestinal Mucosa - cytology</subject><subject>Intestinal Mucosa - pathology</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Neoplasms - etiology</subject><subject>Neoplasms - immunology</subject><subject>Neoplasms - pathology</subject><subject>NF-kappa B - metabolism</subject><subject>Signal Transduction - physiology</subject><subject>STAT3 Transcription Factor - genetics</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Tumor Necrosis Factor-alpha - immunology</subject><issn>1535-6108</issn><issn>1878-3686</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkd-K1DAUxoMo7rr6AN5Ir7xrTdI0aRGEoe7qwIDg6nVI01M3Q6eZTdKCb-Oz-GR7ygz-udGrnEN-5-N85yPkJaMFo0y-2RfWhoJT2hSUFZSyR-SS1arOS1nLx1hXZZVLRusL8izGPQKSqeYpuWANq6taVJdk3u5ymZmpz26TSWW2CZB9hvvZBeizwYfsdg6LW8yY-SHbTglichN210eX7mB0WLYwjnGV-PnjPSww-uMBprTyrR9dcjHfxOitMwklWzNZCM_Jk8GMEV6c3yvy9eb6S_sx3336sG03u9xWQqZcdH3JgHamBGvBSGUZlbzBvmuayqIHKbgYOk4V71lprSqFrK3olDICZ8or8u6ke5y7A_QW9wpm1MfgDiZ81944_ffP5O70N79oLqViVKHA67NA8PczmtcHFy0aNhP4OWqJh5aNqP4LcsobxfgKshNog48xwPBrG0b1mqrea0xVr6lqyjSGhjOv_rTxe-IcIwJvTwDgMRcHQUfrAC_dY4426d67f8g_AMP5tME</recordid><startdate>20090203</startdate><enddate>20090203</enddate><creator>Grivennikov, Sergei</creator><creator>Karin, Eliad</creator><creator>Terzic, Janos</creator><creator>Mucida, Daniel</creator><creator>Yu, Guann-Yi</creator><creator>Vallabhapurapu, Sivakumar</creator><creator>Scheller, Jürgen</creator><creator>Rose-John, Stefan</creator><creator>Cheroutre, Hilde</creator><creator>Eckmann, Lars</creator><creator>Karin, Michael</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</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>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20090203</creationdate><title>IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer</title><author>Grivennikov, Sergei ; Karin, Eliad ; Terzic, Janos ; Mucida, Daniel ; Yu, Guann-Yi ; Vallabhapurapu, Sivakumar ; Scheller, Jürgen ; Rose-John, Stefan ; Cheroutre, Hilde ; Eckmann, Lars ; Karin, Michael</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c546t-4bd31e0ba3eccea67c10629ba3b995c1856424fb2072d13cc73468c4b77a43ec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Animals</topic><topic>Bone Marrow Cells - cytology</topic><topic>Bone Marrow Cells - physiology</topic><topic>Cell Proliferation</topic><topic>Cell Survival - physiology</topic><topic>CELLCYCLE</topic><topic>Colitis, Ulcerative - complications</topic><topic>Colitis, Ulcerative - immunology</topic><topic>Colitis, Ulcerative - pathology</topic><topic>Epithelial Cells - cytology</topic><topic>Epithelial Cells - physiology</topic><topic>Gene Expression Regulation</topic><topic>Humans</topic><topic>Interleukin-6 - genetics</topic><topic>Interleukin-6 - metabolism</topic><topic>Intestinal Mucosa - cytology</topic><topic>Intestinal Mucosa - pathology</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Neoplasms - etiology</topic><topic>Neoplasms - immunology</topic><topic>Neoplasms - pathology</topic><topic>NF-kappa B - metabolism</topic><topic>Signal Transduction - physiology</topic><topic>STAT3 Transcription Factor - genetics</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Tumor Necrosis Factor-alpha - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Grivennikov, Sergei</creatorcontrib><creatorcontrib>Karin, Eliad</creatorcontrib><creatorcontrib>Terzic, Janos</creatorcontrib><creatorcontrib>Mucida, Daniel</creatorcontrib><creatorcontrib>Yu, Guann-Yi</creatorcontrib><creatorcontrib>Vallabhapurapu, Sivakumar</creatorcontrib><creatorcontrib>Scheller, Jürgen</creatorcontrib><creatorcontrib>Rose-John, Stefan</creatorcontrib><creatorcontrib>Cheroutre, Hilde</creatorcontrib><creatorcontrib>Eckmann, Lars</creatorcontrib><creatorcontrib>Karin, Michael</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Grivennikov, Sergei</au><au>Karin, Eliad</au><au>Terzic, Janos</au><au>Mucida, Daniel</au><au>Yu, Guann-Yi</au><au>Vallabhapurapu, Sivakumar</au><au>Scheller, Jürgen</au><au>Rose-John, Stefan</au><au>Cheroutre, Hilde</au><au>Eckmann, Lars</au><au>Karin, Michael</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2009-02-03</date><risdate>2009</risdate><volume>15</volume><issue>2</issue><spage>103</spage><epage>113</epage><pages>103-113</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Colitis-associated cancer (CAC) is the most serious complication of inflammatory bowel disease. Proinflammatory cytokines have been suggested to regulate preneoplastic growth during CAC tumorigenesis. Interleukin 6 (IL-6) is a multifunctional NF-κB-regulated cytokine that acts on epithelial and immune cells. Using genetic tools, we now demonstrate that IL-6 is a critical tumor promoter during early CAC tumorigenesis. In addition to enhancing proliferation of tumor-initiating cells, IL-6 produced by lamina propria myeloid cells protects normal and premalignant intestinal epithelial cells (IECs) from apoptosis. The proliferative and survival effects of IL-6 are largely mediated by the transcription factor Stat3, whose IEC-specific ablation has profound impact on CAC tumorigenesis. Thus, the NF-κB-IL-6-Stat3 cascade is an important regulator of the proliferation and survival of tumor-initiating IECs.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>19185845</pmid><doi>10.1016/j.ccr.2009.01.001</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Cell Press Free Archives; Elsevier ScienceDirect Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Bone Marrow Cells - cytology Bone Marrow Cells - physiology Cell Proliferation Cell Survival - physiology CELLCYCLE Colitis, Ulcerative - complications Colitis, Ulcerative - immunology Colitis, Ulcerative - pathology Epithelial Cells - cytology Epithelial Cells - physiology Gene Expression Regulation Humans Interleukin-6 - genetics Interleukin-6 - metabolism Intestinal Mucosa - cytology Intestinal Mucosa - pathology Mice Mice, Inbred C57BL Mice, Knockout Neoplasms - etiology Neoplasms - immunology Neoplasms - pathology NF-kappa B - metabolism Signal Transduction - physiology STAT3 Transcription Factor - genetics STAT3 Transcription Factor - metabolism Tumor Necrosis Factor-alpha - immunology |
| title | IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer |
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