Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice
Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the grow...
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| Veröffentlicht in: | The American journal of pathology 2017-05, Vol.187 (5), p.1093-1105 |
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| creator | Martínez, Allyson K Jensen, Kendal Hall, Chad O'Brien, April Ehrlich, Laurent White, Tori Meng, Fanyin Zhou, Tianhao Greene, John Bernuzzi, Francesca Invernizzi, Pietro Dostal, David E Lairmore, Terry Alpini, Gianfranco Glaser, Shannon |
| description | Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR–dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation. |
| doi_str_mv | 10.1016/j.ajpath.2017.01.011 |
| format | Article |
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However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR–dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation.</description><identifier>ISSN: 0002-9440</identifier><identifier>EISSN: 1525-2191</identifier><identifier>DOI: 10.1016/j.ajpath.2017.01.011</identifier><identifier>PMID: 28315314</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aged ; alpha7 Nicotinic Acetylcholine Receptor - physiology ; Animals ; Bile Duct Neoplasms - metabolism ; Bile Duct Neoplasms - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cholangiocarcinoma - metabolism ; Cholangiocarcinoma - pathology ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Female ; Fibrosis - metabolism ; Heterografts ; Humans ; Keratin-19 - metabolism ; Male ; MAP Kinase Signaling System - physiology ; Mice ; Middle Aged ; Neoplasm Transplantation ; Nicotine - pharmacology ; Nicotinic Agonists - pharmacology ; Pathology ; S100 Calcium-Binding Protein A4 - metabolism</subject><ispartof>The American journal of pathology, 2017-05, Vol.187 (5), p.1093-1105</ispartof><rights>2017 American Society for Investigative Pathology</rights><rights>Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-d25f36b998d8746b23c9f0eda9dd3f7e6a058a7b5414c36f26d1591321d428033</citedby><cites>FETCH-LOGICAL-c529t-d25f36b998d8746b23c9f0eda9dd3f7e6a058a7b5414c36f26d1591321d428033</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0002944017302262$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28315314$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Martínez, Allyson K</creatorcontrib><creatorcontrib>Jensen, Kendal</creatorcontrib><creatorcontrib>Hall, Chad</creatorcontrib><creatorcontrib>O'Brien, April</creatorcontrib><creatorcontrib>Ehrlich, Laurent</creatorcontrib><creatorcontrib>White, Tori</creatorcontrib><creatorcontrib>Meng, Fanyin</creatorcontrib><creatorcontrib>Zhou, Tianhao</creatorcontrib><creatorcontrib>Greene, John</creatorcontrib><creatorcontrib>Bernuzzi, Francesca</creatorcontrib><creatorcontrib>Invernizzi, Pietro</creatorcontrib><creatorcontrib>Dostal, David E</creatorcontrib><creatorcontrib>Lairmore, Terry</creatorcontrib><creatorcontrib>Alpini, Gianfranco</creatorcontrib><creatorcontrib>Glaser, Shannon</creatorcontrib><title>Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice</title><title>The American journal of pathology</title><addtitle>Am J Pathol</addtitle><description>Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR–dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation.</description><subject>Aged</subject><subject>alpha7 Nicotinic Acetylcholine Receptor - physiology</subject><subject>Animals</subject><subject>Bile Duct Neoplasms - metabolism</subject><subject>Bile Duct Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cholangiocarcinoma - metabolism</subject><subject>Cholangiocarcinoma - pathology</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Female</subject><subject>Fibrosis - metabolism</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Keratin-19 - metabolism</subject><subject>Male</subject><subject>MAP Kinase Signaling System - physiology</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Neoplasm Transplantation</subject><subject>Nicotine - pharmacology</subject><subject>Nicotinic Agonists - pharmacology</subject><subject>Pathology</subject><subject>S100 Calcium-Binding Protein A4 - metabolism</subject><issn>0002-9440</issn><issn>1525-2191</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1r3DAQhkVoaLZp_0EoPubirUaSbemQQFjaJJAvSAu9Ca00zsq1rY3kTcm_j5ZNc8ilMDAMvPP1vIQcAZ0DhfpbNzfd2kyrOaPQzCnkgD0yg4pVJQMFH8iMUspKJQQ9IJ9S6nJZc0k_kgMmOVQcxIyc3HgbJj9icRfDECZMxWIVejM--GBNtH4MgynOY_g7rQo_Fr9xDA_RtFNx7S1-Jvut6RN-ec2H5NeP7z8XF-XV7fnl4uyqtBVTU-lY1fJ6qZR0shH1knGrWorOKOd422BtaCVNs6wECMvrltUOKgWcgRNMUs4PyfFu7jqGxw2mSQ8-WezznRg2SYNspGRCKJGlYie1MaQUsdXr6AcTnzVQvQWnO70Dp7fgNIUckNu-vm7YLAd0b03_SGXB6U6A-c8nj1En63G06HxEO2kX_P82vB9gez96a_o_-IypC5s4ZoYadGKa6vuteVvvoOGUsZrxF4yflBc</recordid><startdate>20170501</startdate><enddate>20170501</enddate><creator>Martínez, Allyson K</creator><creator>Jensen, Kendal</creator><creator>Hall, Chad</creator><creator>O'Brien, April</creator><creator>Ehrlich, Laurent</creator><creator>White, Tori</creator><creator>Meng, Fanyin</creator><creator>Zhou, Tianhao</creator><creator>Greene, John</creator><creator>Bernuzzi, Francesca</creator><creator>Invernizzi, Pietro</creator><creator>Dostal, David E</creator><creator>Lairmore, Terry</creator><creator>Alpini, Gianfranco</creator><creator>Glaser, Shannon</creator><general>Elsevier Inc</general><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>7X8</scope></search><sort><creationdate>20170501</creationdate><title>Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice</title><author>Martínez, Allyson K ; Jensen, Kendal ; Hall, Chad ; O'Brien, April ; Ehrlich, Laurent ; White, Tori ; Meng, Fanyin ; Zhou, Tianhao ; Greene, John ; Bernuzzi, Francesca ; Invernizzi, Pietro ; Dostal, David E ; Lairmore, Terry ; Alpini, Gianfranco ; Glaser, Shannon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-d25f36b998d8746b23c9f0eda9dd3f7e6a058a7b5414c36f26d1591321d428033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Aged</topic><topic>alpha7 Nicotinic Acetylcholine Receptor - physiology</topic><topic>Animals</topic><topic>Bile Duct Neoplasms - metabolism</topic><topic>Bile Duct Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cholangiocarcinoma - metabolism</topic><topic>Cholangiocarcinoma - pathology</topic><topic>Extracellular Signal-Regulated MAP Kinases - metabolism</topic><topic>Female</topic><topic>Fibrosis - metabolism</topic><topic>Heterografts</topic><topic>Humans</topic><topic>Keratin-19 - metabolism</topic><topic>Male</topic><topic>MAP Kinase Signaling System - physiology</topic><topic>Mice</topic><topic>Middle Aged</topic><topic>Neoplasm Transplantation</topic><topic>Nicotine - pharmacology</topic><topic>Nicotinic Agonists - pharmacology</topic><topic>Pathology</topic><topic>S100 Calcium-Binding Protein A4 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martínez, Allyson K</creatorcontrib><creatorcontrib>Jensen, Kendal</creatorcontrib><creatorcontrib>Hall, Chad</creatorcontrib><creatorcontrib>O'Brien, April</creatorcontrib><creatorcontrib>Ehrlich, Laurent</creatorcontrib><creatorcontrib>White, Tori</creatorcontrib><creatorcontrib>Meng, Fanyin</creatorcontrib><creatorcontrib>Zhou, Tianhao</creatorcontrib><creatorcontrib>Greene, John</creatorcontrib><creatorcontrib>Bernuzzi, Francesca</creatorcontrib><creatorcontrib>Invernizzi, Pietro</creatorcontrib><creatorcontrib>Dostal, David E</creatorcontrib><creatorcontrib>Lairmore, Terry</creatorcontrib><creatorcontrib>Alpini, Gianfranco</creatorcontrib><creatorcontrib>Glaser, Shannon</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>The American journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martínez, Allyson K</au><au>Jensen, Kendal</au><au>Hall, Chad</au><au>O'Brien, April</au><au>Ehrlich, Laurent</au><au>White, Tori</au><au>Meng, Fanyin</au><au>Zhou, Tianhao</au><au>Greene, John</au><au>Bernuzzi, Francesca</au><au>Invernizzi, Pietro</au><au>Dostal, David E</au><au>Lairmore, Terry</au><au>Alpini, Gianfranco</au><au>Glaser, Shannon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice</atitle><jtitle>The American journal of pathology</jtitle><addtitle>Am J Pathol</addtitle><date>2017-05-01</date><risdate>2017</risdate><volume>187</volume><issue>5</issue><spage>1093</spage><epage>1105</epage><pages>1093-1105</pages><issn>0002-9440</issn><eissn>1525-2191</eissn><abstract>Nicotine, the main addictive substance in tobacco, is known to play a role in the development and/or progression of a number of malignant tumors. However, nicotine's involvement in the pathogenesis of cholangiocarcinoma is controversial. Therefore, we studied the effects of nicotine on the growth of cholangiocarcinoma cells in vitro and the progression of cholangiocarcinoma in a mouse xenograft model. The predominant subunit responsible for nicotine-mediated proliferation in normal and cancer cells, the α7 nicotinic acetylcholine receptor (α7-nAChR), was more highly expressed in human cholangiocarcinoma cell lines compared with normal human cholangiocytes. Nicotine also stimulated the proliferation of cholangiocarcinoma cell lines and promoted α7-nAChR–dependent activation of proliferation and phosphorylation of extracellular-regulated kinase in Mz-ChA-1 cells. In addition, nicotine and PNU282987 (α7-nAChR agonist) accelerated the growth of the cholangiocarcinoma tumors in our xenograft mouse model and increased fibrosis, proliferation of the tumor cells, and phosphorylation of extracellular-regulated kinase activation. Finally, α7-nAChR was expressed at significantly higher levels in human cholangiocarcinoma compared with normal human control liver samples. Taken together, results of this study suggest that nicotine acts through α7-nAChR and plays a novel role in the pathogenesis of cholangiocarcinoma. Furthermore, nicotine may act as a mitogen in cholestatic liver disease processes, thereby facilitating malignant transformation.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28315314</pmid><doi>10.1016/j.ajpath.2017.01.011</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged alpha7 Nicotinic Acetylcholine Receptor - physiology Animals Bile Duct Neoplasms - metabolism Bile Duct Neoplasms - pathology Cell Line, Tumor Cell Proliferation - drug effects Cholangiocarcinoma - metabolism Cholangiocarcinoma - pathology Extracellular Signal-Regulated MAP Kinases - metabolism Female Fibrosis - metabolism Heterografts Humans Keratin-19 - metabolism Male MAP Kinase Signaling System - physiology Mice Middle Aged Neoplasm Transplantation Nicotine - pharmacology Nicotinic Agonists - pharmacology Pathology S100 Calcium-Binding Protein A4 - metabolism |
| title | Nicotine Promotes Cholangiocarcinoma Growth in Xenograft Mice |
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