Increased cycling cell numbers and stem cell associated proteins as potential biomarkers for high grade human papillomavirus+ve pre-neoplastic cervical disease
High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. C...
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| Veröffentlicht in: | PloS one 2014-12, Vol.9 (12), p.e115379-e115379 |
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| creator | Canham, Maurice Charsou, Chara Stewart, June Moncur, Sharon Hoodless, Laura Bhatia, Ramya Cong, Duanduan Cubie, Heather Busby-Earle, Camille Williams, Alistair McLoughlin, Victoria Campbell, John D M Cuschieri, Kate Howie, Sarah |
| description | High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively. |
| doi_str_mv | 10.1371/journal.pone.0115379 |
| format | Article |
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Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0115379</identifier><identifier>PMID: 25531390</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Abnormalities ; Antineoplastic agents ; Archives & records ; Bioindicators ; Biomarkers ; Biomarkers - metabolism ; Blood transfusions ; Breast cancer ; Cancer ; Cell cycle ; Cell growth ; Cell proliferation ; Cell surface ; Cellular biology ; Cervical cancer ; Cervix ; Chorionic gonadotropin ; Chorionic gonadotropins ; Councils ; Cytology ; Cytometry ; DNA microarrays ; DNA, Viral - analysis ; Ethics ; Female ; Flow Cytometry ; Gene expression ; Genotype ; Genotype & phenotype ; Gonadotrophs - metabolism ; Gonadotropins ; Health aspects ; Health risks ; Histology ; Human papillomavirus ; Humans ; Hyperplasia - pathology ; Immunohistochemistry ; Infection ; Infections ; Inflammation ; Invasiveness ; Laboratories ; Medical research ; Medical screening ; Medicine and Health Sciences ; Metastasis ; Neoplastic Stem Cells - cytology ; Neoplastic Stem Cells - metabolism ; Papillomaviridae - genetics ; Papillomavirus ; Papillomavirus infections ; Pituitary (anterior) ; Polymerase Chain Reaction ; Prostate ; Proteins ; Proteomics ; Quality ; Reproductive health ; Risk ; RNA ; RNA, Messenger - metabolism ; Severity of Illness Index ; SOXB1 Transcription Factors - genetics ; SOXB1 Transcription Factors - metabolism ; Statistics ; Stem cells ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Tumors ; Up-Regulation ; Uterine Cervical Diseases - diagnosis ; Uterine Cervical Diseases - pathology ; Uterine Cervical Diseases - virology ; Viruses ; Womens health</subject><ispartof>PloS one, 2014-12, Vol.9 (12), p.e115379-e115379</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 Canham et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 Canham et al 2014 Canham et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6739-d98acf6b4803d90b19f83c72b337e6a0c80fb463c167293ff8f536adfa99a0993</citedby><cites>FETCH-LOGICAL-c6739-d98acf6b4803d90b19f83c72b337e6a0c80fb463c167293ff8f536adfa99a0993</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274002/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274002/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23871,27929,27930,53796,53798</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25531390$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Liu, Xuefeng</contributor><creatorcontrib>Canham, Maurice</creatorcontrib><creatorcontrib>Charsou, Chara</creatorcontrib><creatorcontrib>Stewart, June</creatorcontrib><creatorcontrib>Moncur, Sharon</creatorcontrib><creatorcontrib>Hoodless, Laura</creatorcontrib><creatorcontrib>Bhatia, Ramya</creatorcontrib><creatorcontrib>Cong, Duanduan</creatorcontrib><creatorcontrib>Cubie, Heather</creatorcontrib><creatorcontrib>Busby-Earle, Camille</creatorcontrib><creatorcontrib>Williams, Alistair</creatorcontrib><creatorcontrib>McLoughlin, Victoria</creatorcontrib><creatorcontrib>Campbell, John D M</creatorcontrib><creatorcontrib>Cuschieri, Kate</creatorcontrib><creatorcontrib>Howie, Sarah</creatorcontrib><title>Increased cycling cell numbers and stem cell associated proteins as potential biomarkers for high grade human papillomavirus+ve pre-neoplastic cervical disease</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively.</description><subject>Abnormalities</subject><subject>Antineoplastic agents</subject><subject>Archives & records</subject><subject>Bioindicators</subject><subject>Biomarkers</subject><subject>Biomarkers - metabolism</subject><subject>Blood transfusions</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cell surface</subject><subject>Cellular biology</subject><subject>Cervical cancer</subject><subject>Cervix</subject><subject>Chorionic gonadotropin</subject><subject>Chorionic gonadotropins</subject><subject>Councils</subject><subject>Cytology</subject><subject>Cytometry</subject><subject>DNA microarrays</subject><subject>DNA, Viral - analysis</subject><subject>Ethics</subject><subject>Female</subject><subject>Flow Cytometry</subject><subject>Gene expression</subject><subject>Genotype</subject><subject>Genotype & phenotype</subject><subject>Gonadotrophs - metabolism</subject><subject>Gonadotropins</subject><subject>Health aspects</subject><subject>Health risks</subject><subject>Histology</subject><subject>Human papillomavirus</subject><subject>Humans</subject><subject>Hyperplasia - pathology</subject><subject>Immunohistochemistry</subject><subject>Infection</subject><subject>Infections</subject><subject>Inflammation</subject><subject>Invasiveness</subject><subject>Laboratories</subject><subject>Medical research</subject><subject>Medical screening</subject><subject>Medicine and Health Sciences</subject><subject>Metastasis</subject><subject>Neoplastic Stem Cells - cytology</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Papillomaviridae - genetics</subject><subject>Papillomavirus</subject><subject>Papillomavirus infections</subject><subject>Pituitary (anterior)</subject><subject>Polymerase Chain Reaction</subject><subject>Prostate</subject><subject>Proteins</subject><subject>Proteomics</subject><subject>Quality</subject><subject>Reproductive health</subject><subject>Risk</subject><subject>RNA</subject><subject>RNA, Messenger - 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cytology</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Papillomaviridae - genetics</topic><topic>Papillomavirus</topic><topic>Papillomavirus infections</topic><topic>Pituitary (anterior)</topic><topic>Polymerase Chain Reaction</topic><topic>Prostate</topic><topic>Proteins</topic><topic>Proteomics</topic><topic>Quality</topic><topic>Reproductive health</topic><topic>Risk</topic><topic>RNA</topic><topic>RNA, Messenger - metabolism</topic><topic>Severity of Illness Index</topic><topic>SOXB1 Transcription Factors - genetics</topic><topic>SOXB1 Transcription Factors - metabolism</topic><topic>Statistics</topic><topic>Stem cells</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Tumors</topic><topic>Up-Regulation</topic><topic>Uterine Cervical Diseases - diagnosis</topic><topic>Uterine Cervical Diseases - pathology</topic><topic>Uterine Cervical Diseases - virology</topic><topic>Viruses</topic><topic>Womens health</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Canham, Maurice</creatorcontrib><creatorcontrib>Charsou, Chara</creatorcontrib><creatorcontrib>Stewart, June</creatorcontrib><creatorcontrib>Moncur, Sharon</creatorcontrib><creatorcontrib>Hoodless, Laura</creatorcontrib><creatorcontrib>Bhatia, Ramya</creatorcontrib><creatorcontrib>Cong, Duanduan</creatorcontrib><creatorcontrib>Cubie, Heather</creatorcontrib><creatorcontrib>Busby-Earle, Camille</creatorcontrib><creatorcontrib>Williams, Alistair</creatorcontrib><creatorcontrib>McLoughlin, Victoria</creatorcontrib><creatorcontrib>Campbell, John D M</creatorcontrib><creatorcontrib>Cuschieri, Kate</creatorcontrib><creatorcontrib>Howie, Sarah</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Canham, Maurice</au><au>Charsou, Chara</au><au>Stewart, June</au><au>Moncur, Sharon</au><au>Hoodless, Laura</au><au>Bhatia, Ramya</au><au>Cong, Duanduan</au><au>Cubie, Heather</au><au>Busby-Earle, Camille</au><au>Williams, Alistair</au><au>McLoughlin, Victoria</au><au>Campbell, John D M</au><au>Cuschieri, Kate</au><au>Howie, Sarah</au><au>Liu, Xuefeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increased cycling cell numbers and stem cell associated proteins as potential biomarkers for high grade human papillomavirus+ve pre-neoplastic cervical disease</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-12-22</date><risdate>2014</risdate><volume>9</volume><issue>12</issue><spage>e115379</spage><epage>e115379</epage><pages>e115379-e115379</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>25531390</pmid><doi>10.1371/journal.pone.0115379</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-12, Vol.9 (12), p.e115379-e115379 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1639488370 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Abnormalities Antineoplastic agents Archives & records Bioindicators Biomarkers Biomarkers - metabolism Blood transfusions Breast cancer Cancer Cell cycle Cell growth Cell proliferation Cell surface Cellular biology Cervical cancer Cervix Chorionic gonadotropin Chorionic gonadotropins Councils Cytology Cytometry DNA microarrays DNA, Viral - analysis Ethics Female Flow Cytometry Gene expression Genotype Genotype & phenotype Gonadotrophs - metabolism Gonadotropins Health aspects Health risks Histology Human papillomavirus Humans Hyperplasia - pathology Immunohistochemistry Infection Infections Inflammation Invasiveness Laboratories Medical research Medical screening Medicine and Health Sciences Metastasis Neoplastic Stem Cells - cytology Neoplastic Stem Cells - metabolism Papillomaviridae - genetics Papillomavirus Papillomavirus infections Pituitary (anterior) Polymerase Chain Reaction Prostate Proteins Proteomics Quality Reproductive health Risk RNA RNA, Messenger - metabolism Severity of Illness Index SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism Statistics Stem cells Transcription Factors - genetics Transcription Factors - metabolism Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Tumors Up-Regulation Uterine Cervical Diseases - diagnosis Uterine Cervical Diseases - pathology Uterine Cervical Diseases - virology Viruses Womens health |
| title | Increased cycling cell numbers and stem cell associated proteins as potential biomarkers for high grade human papillomavirus+ve pre-neoplastic cervical disease |
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