Hepatocarcinogenesis in non-cirrhotic liver is associated with a reduced number of clonal hepatocellular patches in non-tumorous liver parenchyma
We investigated circumscribed cell proliferations in healthy livers in comparison to non‐cirrhotic livers bearing hepatocellular carcinoma. Using histochemical staining for cytochrome c oxidase, the fourth complex of the respiratory chain, we visualized patch‐forming descendents of regeneratively ac...
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| Veröffentlicht in: | The Journal of pathology 2012-11, Vol.228 (3), p.333-340 |
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| creator | Adam, Alexander C. Faudou, Viola Paschen, Stefan A Adam, Olaf M Kahl, Philip Drebber, Uta Fischer, Hans-Peter Büttner, Reinhard |
| description | We investigated circumscribed cell proliferations in healthy livers in comparison to non‐cirrhotic livers bearing hepatocellular carcinoma. Using histochemical staining for cytochrome c oxidase, the fourth complex of the respiratory chain, we visualized patch‐forming descendents of regeneratively active liver cells. The clonal nature of these patches was verified by laser‐capture microdissection and Sanger sequencing of the enzyme's core subunits in patches carrying marker mutations on the mtDNA. We demonstrate a highly significant increase of the patch size and also a highly significant increase in the number of patches carrying marker mutations between hepatocellular carcinoma‐free and ‐bearing livers. Thus, the carcinoma‐bearing livers accumulated more genetic damage on mtDNA than the control group. Furthermore, for the first time, we present evidence in hepatocellular carcinoma‐bearing non‐cirrhotic livers of a significantly reduced pool of regeneratively active liver cells that are genetically and functionally altered. The analogy to ageing‐related changes is suggestive of premature ageing of stem cells in non‐cirrhotic hepatocellular carcinoma‐bearing liver as an early step to hepatocarcinogenesis. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
| doi_str_mv | 10.1002/path.4060 |
| format | Article |
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Using histochemical staining for cytochrome c oxidase, the fourth complex of the respiratory chain, we visualized patch‐forming descendents of regeneratively active liver cells. The clonal nature of these patches was verified by laser‐capture microdissection and Sanger sequencing of the enzyme's core subunits in patches carrying marker mutations on the mtDNA. We demonstrate a highly significant increase of the patch size and also a highly significant increase in the number of patches carrying marker mutations between hepatocellular carcinoma‐free and ‐bearing livers. Thus, the carcinoma‐bearing livers accumulated more genetic damage on mtDNA than the control group. Furthermore, for the first time, we present evidence in hepatocellular carcinoma‐bearing non‐cirrhotic livers of a significantly reduced pool of regeneratively active liver cells that are genetically and functionally altered. The analogy to ageing‐related changes is suggestive of premature ageing of stem cells in non‐cirrhotic hepatocellular carcinoma‐bearing liver as an early step to hepatocarcinogenesis. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</description><identifier>ISSN: 0022-3417</identifier><identifier>EISSN: 1096-9896</identifier><identifier>DOI: 10.1002/path.4060</identifier><identifier>PMID: 22685011</identifier><identifier>CODEN: JPTLAS</identifier><language>eng</language><publisher>Chichester, UK: John Wiley & Sons, Ltd</publisher><subject>Aged ; Aging ; Biological and medical sciences ; Biomarkers - metabolism ; carcinogenesis ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Case-Control Studies ; Cell Count ; Cell Transformation, Neoplastic - metabolism ; Cell Transformation, Neoplastic - pathology ; Chromosome aberrations ; Cytochrome-c oxidase ; DNA, Mitochondrial - genetics ; DNA, Mitochondrial - metabolism ; Electron transport ; Electron Transport Complex IV - genetics ; Electron Transport Complex IV - metabolism ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Hepatocellular carcinoma ; Hepatocytes ; Hepatocytes - metabolism ; Hepatocytes - pathology ; Humans ; Investigative techniques, diagnostic techniques (general aspects) ; Liver ; Liver - metabolism ; Liver - pathology ; Liver cancer ; Liver cirrhosis ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; liver patches ; liver stem cell ; Liver. Biliary tract. Portal circulation. Exocrine pancreas ; Male ; Medical sciences ; Middle Aged ; Mitochondrial DNA ; Mutation ; Other diseases. Semiology ; Parenchyma ; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques ; Stem cells ; Succinate Dehydrogenase - genetics ; Succinate Dehydrogenase - metabolism ; Tumors</subject><ispartof>The Journal of pathology, 2012-11, Vol.228 (3), p.333-340</ispartof><rights>Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2012 Pathological Society of Great Britain and Ireland</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4210-94cdf5604b4ee880582f594fbd1cdd331c63f0644eca2e1585a55358ef32eb963</citedby><cites>FETCH-LOGICAL-c4210-94cdf5604b4ee880582f594fbd1cdd331c63f0644eca2e1585a55358ef32eb963</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fpath.4060$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fpath.4060$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,776,780,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26463836$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22685011$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Adam, Alexander C.</creatorcontrib><creatorcontrib>Faudou, Viola</creatorcontrib><creatorcontrib>Paschen, Stefan A</creatorcontrib><creatorcontrib>Adam, Olaf M</creatorcontrib><creatorcontrib>Kahl, Philip</creatorcontrib><creatorcontrib>Drebber, Uta</creatorcontrib><creatorcontrib>Fischer, Hans-Peter</creatorcontrib><creatorcontrib>Büttner, Reinhard</creatorcontrib><title>Hepatocarcinogenesis in non-cirrhotic liver is associated with a reduced number of clonal hepatocellular patches in non-tumorous liver parenchyma</title><title>The Journal of pathology</title><addtitle>J. Pathol</addtitle><description>We investigated circumscribed cell proliferations in healthy livers in comparison to non‐cirrhotic livers bearing hepatocellular carcinoma. Using histochemical staining for cytochrome c oxidase, the fourth complex of the respiratory chain, we visualized patch‐forming descendents of regeneratively active liver cells. The clonal nature of these patches was verified by laser‐capture microdissection and Sanger sequencing of the enzyme's core subunits in patches carrying marker mutations on the mtDNA. We demonstrate a highly significant increase of the patch size and also a highly significant increase in the number of patches carrying marker mutations between hepatocellular carcinoma‐free and ‐bearing livers. Thus, the carcinoma‐bearing livers accumulated more genetic damage on mtDNA than the control group. Furthermore, for the first time, we present evidence in hepatocellular carcinoma‐bearing non‐cirrhotic livers of a significantly reduced pool of regeneratively active liver cells that are genetically and functionally altered. The analogy to ageing‐related changes is suggestive of premature ageing of stem cells in non‐cirrhotic hepatocellular carcinoma‐bearing liver as an early step to hepatocarcinogenesis. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</description><subject>Aged</subject><subject>Aging</subject><subject>Biological and medical sciences</subject><subject>Biomarkers - metabolism</subject><subject>carcinogenesis</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Case-Control Studies</subject><subject>Cell Count</subject><subject>Cell Transformation, Neoplastic - metabolism</subject><subject>Cell Transformation, Neoplastic - pathology</subject><subject>Chromosome aberrations</subject><subject>Cytochrome-c oxidase</subject><subject>DNA, Mitochondrial - genetics</subject><subject>DNA, Mitochondrial - metabolism</subject><subject>Electron transport</subject><subject>Electron Transport Complex IV - genetics</subject><subject>Electron Transport Complex IV - metabolism</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatocytes</subject><subject>Hepatocytes - metabolism</subject><subject>Hepatocytes - pathology</subject><subject>Humans</subject><subject>Investigative techniques, diagnostic techniques (general aspects)</subject><subject>Liver</subject><subject>Liver - metabolism</subject><subject>Liver - pathology</subject><subject>Liver cancer</subject><subject>Liver cirrhosis</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>liver patches</subject><subject>liver stem cell</subject><subject>Liver. Biliary tract. Portal circulation. Exocrine pancreas</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>Mitochondrial DNA</subject><subject>Mutation</subject><subject>Other diseases. Semiology</subject><subject>Parenchyma</subject><subject>Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques</subject><subject>Stem cells</subject><subject>Succinate Dehydrogenase - genetics</subject><subject>Succinate Dehydrogenase - metabolism</subject><subject>Tumors</subject><issn>0022-3417</issn><issn>1096-9896</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kd9q1UAQxhdR7LF64QtIQIR6kXb_n-Sy1NojllqkInizbDYTszXZPd1NrOcxfGM3Jh5B8GoY5vd9M8OH0HOCjwnG9GSrh_aYY4kfoBXBpczLopQP0SrNaM44WR-gJzHeYozLUojH6IBSWQhMyAr93EBSe6ODsc5_BQfRxsy6zHmXGxtC6wdrss5-h5CliY7RG6sHqLN7O7SZzgLUo0mtG_sqMb7JTOed7rJ2doauGzsdstSYFvbew9j74Me4WG91AGfaXa-fokeN7iI8W-oh-vT2_OZsk19-uHh3dnqZG04Jzktu6kZIzCsOUBRYFLQRJW-qmpi6ZowYyRosOQejKRBRCC0EEwU0jEJVSnaIjmbfbfB3I8RB9TZO12oH6S5FCKGMC0aLhL78B731Y0g_RkVxQQSX_Df1eqZM8DEGaNQ22F6HnSJYTTmpKSc15ZTYF4vjWPVQ78k_wSTg1QLoaHTXBO2MjX85ySUr2PTFyczd2w52_9-ork9vNsvqfFbYOMCPvUKHb0qu2Vqoz1cX6j0hV_jj9Rv1hf0CQXG7eQ</recordid><startdate>201211</startdate><enddate>201211</enddate><creator>Adam, Alexander C.</creator><creator>Faudou, Viola</creator><creator>Paschen, Stefan A</creator><creator>Adam, Olaf M</creator><creator>Kahl, Philip</creator><creator>Drebber, Uta</creator><creator>Fischer, Hans-Peter</creator><creator>Büttner, Reinhard</creator><general>John Wiley & Sons, Ltd</general><general>Wiley</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>IQODW</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>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>201211</creationdate><title>Hepatocarcinogenesis in non-cirrhotic liver is associated with a reduced number of clonal hepatocellular patches in non-tumorous liver parenchyma</title><author>Adam, Alexander C. ; Faudou, Viola ; Paschen, Stefan A ; Adam, Olaf M ; Kahl, Philip ; Drebber, Uta ; Fischer, Hans-Peter ; Büttner, Reinhard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4210-94cdf5604b4ee880582f594fbd1cdd331c63f0644eca2e1585a55358ef32eb963</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Aged</topic><topic>Aging</topic><topic>Biological and medical sciences</topic><topic>Biomarkers - metabolism</topic><topic>carcinogenesis</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Case-Control Studies</topic><topic>Cell Count</topic><topic>Cell Transformation, Neoplastic - metabolism</topic><topic>Cell Transformation, Neoplastic - pathology</topic><topic>Chromosome aberrations</topic><topic>Cytochrome-c oxidase</topic><topic>DNA, Mitochondrial - genetics</topic><topic>DNA, Mitochondrial - metabolism</topic><topic>Electron transport</topic><topic>Electron Transport Complex IV - genetics</topic><topic>Electron Transport Complex IV - metabolism</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Hepatocellular carcinoma</topic><topic>Hepatocytes</topic><topic>Hepatocytes - metabolism</topic><topic>Hepatocytes - pathology</topic><topic>Humans</topic><topic>Investigative techniques, diagnostic techniques (general aspects)</topic><topic>Liver</topic><topic>Liver - metabolism</topic><topic>Liver - pathology</topic><topic>Liver cancer</topic><topic>Liver cirrhosis</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>liver patches</topic><topic>liver stem cell</topic><topic>Liver. Biliary tract. Portal circulation. Exocrine pancreas</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>Mitochondrial DNA</topic><topic>Mutation</topic><topic>Other diseases. Semiology</topic><topic>Parenchyma</topic><topic>Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques</topic><topic>Stem cells</topic><topic>Succinate Dehydrogenase - genetics</topic><topic>Succinate Dehydrogenase - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Adam, Alexander C.</creatorcontrib><creatorcontrib>Faudou, Viola</creatorcontrib><creatorcontrib>Paschen, Stefan A</creatorcontrib><creatorcontrib>Adam, Olaf M</creatorcontrib><creatorcontrib>Kahl, Philip</creatorcontrib><creatorcontrib>Drebber, Uta</creatorcontrib><creatorcontrib>Fischer, Hans-Peter</creatorcontrib><creatorcontrib>Büttner, Reinhard</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>The Journal of pathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Adam, Alexander C.</au><au>Faudou, Viola</au><au>Paschen, Stefan A</au><au>Adam, Olaf M</au><au>Kahl, Philip</au><au>Drebber, Uta</au><au>Fischer, Hans-Peter</au><au>Büttner, Reinhard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hepatocarcinogenesis in non-cirrhotic liver is associated with a reduced number of clonal hepatocellular patches in non-tumorous liver parenchyma</atitle><jtitle>The Journal of pathology</jtitle><addtitle>J. Pathol</addtitle><date>2012-11</date><risdate>2012</risdate><volume>228</volume><issue>3</issue><spage>333</spage><epage>340</epage><pages>333-340</pages><issn>0022-3417</issn><eissn>1096-9896</eissn><coden>JPTLAS</coden><abstract>We investigated circumscribed cell proliferations in healthy livers in comparison to non‐cirrhotic livers bearing hepatocellular carcinoma. Using histochemical staining for cytochrome c oxidase, the fourth complex of the respiratory chain, we visualized patch‐forming descendents of regeneratively active liver cells. The clonal nature of these patches was verified by laser‐capture microdissection and Sanger sequencing of the enzyme's core subunits in patches carrying marker mutations on the mtDNA. We demonstrate a highly significant increase of the patch size and also a highly significant increase in the number of patches carrying marker mutations between hepatocellular carcinoma‐free and ‐bearing livers. Thus, the carcinoma‐bearing livers accumulated more genetic damage on mtDNA than the control group. Furthermore, for the first time, we present evidence in hepatocellular carcinoma‐bearing non‐cirrhotic livers of a significantly reduced pool of regeneratively active liver cells that are genetically and functionally altered. The analogy to ageing‐related changes is suggestive of premature ageing of stem cells in non‐cirrhotic hepatocellular carcinoma‐bearing liver as an early step to hepatocarcinogenesis. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</abstract><cop>Chichester, UK</cop><pub>John Wiley & Sons, Ltd</pub><pmid>22685011</pmid><doi>10.1002/path.4060</doi><tpages>8</tpages></addata></record> |
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| subjects | Aged Aging Biological and medical sciences Biomarkers - metabolism carcinogenesis Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Case-Control Studies Cell Count Cell Transformation, Neoplastic - metabolism Cell Transformation, Neoplastic - pathology Chromosome aberrations Cytochrome-c oxidase DNA, Mitochondrial - genetics DNA, Mitochondrial - metabolism Electron transport Electron Transport Complex IV - genetics Electron Transport Complex IV - metabolism Female Gastroenterology. Liver. Pancreas. Abdomen Hepatocellular carcinoma Hepatocytes Hepatocytes - metabolism Hepatocytes - pathology Humans Investigative techniques, diagnostic techniques (general aspects) Liver Liver - metabolism Liver - pathology Liver cancer Liver cirrhosis Liver Neoplasms - metabolism Liver Neoplasms - pathology liver patches liver stem cell Liver. Biliary tract. Portal circulation. Exocrine pancreas Male Medical sciences Middle Aged Mitochondrial DNA Mutation Other diseases. Semiology Parenchyma Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques Stem cells Succinate Dehydrogenase - genetics Succinate Dehydrogenase - metabolism Tumors |
| title | Hepatocarcinogenesis in non-cirrhotic liver is associated with a reduced number of clonal hepatocellular patches in non-tumorous liver parenchyma |
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