A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer
Most high-grade serous ovarian cancer (HGSOC) patients develop recurrent disease after first-line treatment, frequently with fatal outcome. This work aims at studying the molecular biology of both primary and recurrent HGSOC. Gene expression profiles of matched primary and recurrent fresh-frozen tum...
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Veröffentlicht in: | Clinical cancer research 2017-12, Vol.23 (24), p.7621-7632 |
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creator | Kreuzinger, Caroline Geroldinger, Angelika Smeets, Dominiek Braicu, Elena Ioana Sehouli, Jalid Koller, Julia Wolf, Andrea Darb-Esfahani, Silvia Joehrens, Korinna Vergote, Ignace Vanderstichele, Adriaan Boeckx, Bram Lambrechts, Diether Gabra, Hani Wisman, G Bea A Trillsch, Fabian Heinze, Georg Horvat, Reinhard Polterauer, Stephan Berns, Els Theillet, Charles Cacsire Castillo-Tong, Dan |
description | Most high-grade serous ovarian cancer (HGSOC) patients develop recurrent disease after first-line treatment, frequently with fatal outcome. This work aims at studying the molecular biology of both primary and recurrent HGSOC.
Gene expression profiles of matched primary and recurrent fresh-frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. Clustering analyses and pairwise comparison of the profiles between matched samples and subsequent functional alignment were used for the identification of molecular characteristics of HGSOC.
Both primary and recurrent HGSOC samples presented predominant gene expression differences in their microenvironment, determined by a panel of genes covering all major pathways of immune activation together with a number of genes involved in the remodeling of extracellular matrix and adipose tissues. Stratifying tumor tissues into immune active and silent groups, we further discovered that although some recurrent tumors shared the same immune status as their primary counterparts, others switched the immune status, either from silent to active or active to silent. Interestingly, genes belonging to the B7-CD28 immune checkpoint family, known for their major role as negative regulators of the immune response, were overexpressed in the immune active tumors. Searching for potential tumor antigens,
, a member of the carcinoembryonic antigen family, was found to be significantly overexpressed in immune active tissues in comparison with the silent ones.
The results illustrate the complexity of the tumor microenvironment in HGSOC and reveal the molecular relationship between primary and recurrent tumors, which have multiple therapeutic implications.
. |
doi_str_mv | 10.1158/1078-0432.CCR-17-1159 |
format | Article |
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Gene expression profiles of matched primary and recurrent fresh-frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. Clustering analyses and pairwise comparison of the profiles between matched samples and subsequent functional alignment were used for the identification of molecular characteristics of HGSOC.
Both primary and recurrent HGSOC samples presented predominant gene expression differences in their microenvironment, determined by a panel of genes covering all major pathways of immune activation together with a number of genes involved in the remodeling of extracellular matrix and adipose tissues. Stratifying tumor tissues into immune active and silent groups, we further discovered that although some recurrent tumors shared the same immune status as their primary counterparts, others switched the immune status, either from silent to active or active to silent. Interestingly, genes belonging to the B7-CD28 immune checkpoint family, known for their major role as negative regulators of the immune response, were overexpressed in the immune active tumors. Searching for potential tumor antigens,
, a member of the carcinoembryonic antigen family, was found to be significantly overexpressed in immune active tissues in comparison with the silent ones.
The results illustrate the complexity of the tumor microenvironment in HGSOC and reveal the molecular relationship between primary and recurrent tumors, which have multiple therapeutic implications.
.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-17-1159</identifier><identifier>PMID: 28972047</identifier><language>eng</language><publisher>United States: American Association for Cancer Research Inc</publisher><subject>Adipose tissue ; Adult ; Aged ; Antigen (tumor-associated) ; Antigens ; Antigens, Neoplasm - genetics ; Antigens, Neoplasm - immunology ; B7 antigen ; Cancer ; Carcinoembryonic antigen ; CD28 antigen ; Cell Line, Tumor ; Clustering ; Complexity ; Cystadenocarcinoma, Serous - genetics ; Cystadenocarcinoma, Serous - immunology ; Cystadenocarcinoma, Serous - pathology ; Experimental design ; Extracellular matrix ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Gene sequencing ; Genes ; Humans ; Immune checkpoint ; Immune response ; Immune status ; Immune system ; Life Sciences ; Medical treatment ; Middle Aged ; Molecular biology ; Neoplasm Grading ; Neoplasm Recurrence, Local - genetics ; Neoplasm Recurrence, Local - pathology ; Ovarian cancer ; Ovarian Neoplasms - genetics ; Ovarian Neoplasms - immunology ; Ovarian Neoplasms - pathology ; Patients ; Regulators ; Ribonucleic acid ; RNA ; Sequence Analysis, RNA ; Tissues ; Tumor Microenvironment - genetics ; Tumor Microenvironment - immunology ; Tumors</subject><ispartof>Clinical cancer research, 2017-12, Vol.23 (24), p.7621-7632</ispartof><rights>2017 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research Inc Dec 15, 2017</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c470t-3100a8a47a9c69ba3f13089f4fcba8ae0c9a6ba235f6162393d7f71a2570ff3b3</citedby><cites>FETCH-LOGICAL-c470t-3100a8a47a9c69ba3f13089f4fcba8ae0c9a6ba235f6162393d7f71a2570ff3b3</cites><orcidid>0000-0002-3429-302X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28972047$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.umontpellier.fr/hal-02279442$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Kreuzinger, Caroline</creatorcontrib><creatorcontrib>Geroldinger, Angelika</creatorcontrib><creatorcontrib>Smeets, Dominiek</creatorcontrib><creatorcontrib>Braicu, Elena Ioana</creatorcontrib><creatorcontrib>Sehouli, Jalid</creatorcontrib><creatorcontrib>Koller, Julia</creatorcontrib><creatorcontrib>Wolf, Andrea</creatorcontrib><creatorcontrib>Darb-Esfahani, Silvia</creatorcontrib><creatorcontrib>Joehrens, Korinna</creatorcontrib><creatorcontrib>Vergote, Ignace</creatorcontrib><creatorcontrib>Vanderstichele, Adriaan</creatorcontrib><creatorcontrib>Boeckx, Bram</creatorcontrib><creatorcontrib>Lambrechts, Diether</creatorcontrib><creatorcontrib>Gabra, Hani</creatorcontrib><creatorcontrib>Wisman, G Bea A</creatorcontrib><creatorcontrib>Trillsch, Fabian</creatorcontrib><creatorcontrib>Heinze, Georg</creatorcontrib><creatorcontrib>Horvat, Reinhard</creatorcontrib><creatorcontrib>Polterauer, Stephan</creatorcontrib><creatorcontrib>Berns, Els</creatorcontrib><creatorcontrib>Theillet, Charles</creatorcontrib><creatorcontrib>Cacsire Castillo-Tong, Dan</creatorcontrib><title>A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Most high-grade serous ovarian cancer (HGSOC) patients develop recurrent disease after first-line treatment, frequently with fatal outcome. This work aims at studying the molecular biology of both primary and recurrent HGSOC.
Gene expression profiles of matched primary and recurrent fresh-frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. Clustering analyses and pairwise comparison of the profiles between matched samples and subsequent functional alignment were used for the identification of molecular characteristics of HGSOC.
Both primary and recurrent HGSOC samples presented predominant gene expression differences in their microenvironment, determined by a panel of genes covering all major pathways of immune activation together with a number of genes involved in the remodeling of extracellular matrix and adipose tissues. Stratifying tumor tissues into immune active and silent groups, we further discovered that although some recurrent tumors shared the same immune status as their primary counterparts, others switched the immune status, either from silent to active or active to silent. Interestingly, genes belonging to the B7-CD28 immune checkpoint family, known for their major role as negative regulators of the immune response, were overexpressed in the immune active tumors. Searching for potential tumor antigens,
, a member of the carcinoembryonic antigen family, was found to be significantly overexpressed in immune active tissues in comparison with the silent ones.
The results illustrate the complexity of the tumor microenvironment in HGSOC and reveal the molecular relationship between primary and recurrent tumors, which have multiple therapeutic implications.
.</description><subject>Adipose tissue</subject><subject>Adult</subject><subject>Aged</subject><subject>Antigen (tumor-associated)</subject><subject>Antigens</subject><subject>Antigens, Neoplasm - genetics</subject><subject>Antigens, Neoplasm - immunology</subject><subject>B7 antigen</subject><subject>Cancer</subject><subject>Carcinoembryonic antigen</subject><subject>CD28 antigen</subject><subject>Cell Line, Tumor</subject><subject>Clustering</subject><subject>Complexity</subject><subject>Cystadenocarcinoma, Serous - genetics</subject><subject>Cystadenocarcinoma, Serous - immunology</subject><subject>Cystadenocarcinoma, Serous - pathology</subject><subject>Experimental design</subject><subject>Extracellular matrix</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene sequencing</subject><subject>Genes</subject><subject>Humans</subject><subject>Immune checkpoint</subject><subject>Immune response</subject><subject>Immune status</subject><subject>Immune system</subject><subject>Life Sciences</subject><subject>Medical treatment</subject><subject>Middle Aged</subject><subject>Molecular biology</subject><subject>Neoplasm Grading</subject><subject>Neoplasm Recurrence, Local - genetics</subject><subject>Neoplasm Recurrence, Local - pathology</subject><subject>Ovarian cancer</subject><subject>Ovarian Neoplasms - genetics</subject><subject>Ovarian Neoplasms - immunology</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Patients</subject><subject>Regulators</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Sequence Analysis, RNA</subject><subject>Tissues</subject><subject>Tumor Microenvironment - genetics</subject><subject>Tumor Microenvironment - immunology</subject><subject>Tumors</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkctOwzAQRS0E4v0JIEtsYBHw-BHHyyoCilSoBGVtOakNgSQuTlPg73FUyoKNbV2fGc3ci9AJkEsAkV0BkVlCOKOXef6YgEyiqrbQPgghE0ZTsR3fG2YPHXTdGyHAgfBdtEczJSnhch89j3Dum0Vtv_CDXX768I69w7O-8QHfV2Xwtl1VwbeNbZe4avG4b0w8q5fX5DaYucVPNvi-w9OVCVX8yU1b2nCEdpypO3v8ex-i55vrWT5OJtPbu3w0SUouyTJhQIjJDJdGlakqDHPASKYcd2URdUtKZdLCUCZcCillis2lk2CokMQ5VrBDdLHu-2pqvQhVY8K39qbS49FEDxqhVCrO6Qoie75mF8F_9LZb6qbqSlvXprVxAw2Kp5yJTAzo2T_0zfehjZtEKmMcor0yUmJNRZe6Llj3NwEQPWSkB__14L-OGWmQg6pi3elv975o7PyvahMK-wGi6YqA</recordid><startdate>20171215</startdate><enddate>20171215</enddate><creator>Kreuzinger, Caroline</creator><creator>Geroldinger, Angelika</creator><creator>Smeets, Dominiek</creator><creator>Braicu, Elena Ioana</creator><creator>Sehouli, Jalid</creator><creator>Koller, Julia</creator><creator>Wolf, Andrea</creator><creator>Darb-Esfahani, Silvia</creator><creator>Joehrens, Korinna</creator><creator>Vergote, Ignace</creator><creator>Vanderstichele, Adriaan</creator><creator>Boeckx, Bram</creator><creator>Lambrechts, Diether</creator><creator>Gabra, Hani</creator><creator>Wisman, G Bea A</creator><creator>Trillsch, Fabian</creator><creator>Heinze, Georg</creator><creator>Horvat, Reinhard</creator><creator>Polterauer, Stephan</creator><creator>Berns, Els</creator><creator>Theillet, Charles</creator><creator>Cacsire Castillo-Tong, Dan</creator><general>American Association for Cancer Research Inc</general><general>American Association for Cancer Research</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>7QO</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-3429-302X</orcidid></search><sort><creationdate>20171215</creationdate><title>A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer</title><author>Kreuzinger, Caroline ; Geroldinger, Angelika ; Smeets, Dominiek ; Braicu, Elena Ioana ; Sehouli, Jalid ; Koller, Julia ; Wolf, Andrea ; Darb-Esfahani, Silvia ; Joehrens, Korinna ; Vergote, Ignace ; Vanderstichele, Adriaan ; Boeckx, Bram ; Lambrechts, Diether ; Gabra, Hani ; Wisman, G Bea A ; Trillsch, Fabian ; Heinze, Georg ; Horvat, Reinhard ; Polterauer, Stephan ; Berns, Els ; Theillet, Charles ; Cacsire Castillo-Tong, Dan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c470t-3100a8a47a9c69ba3f13089f4fcba8ae0c9a6ba235f6162393d7f71a2570ff3b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adipose tissue</topic><topic>Adult</topic><topic>Aged</topic><topic>Antigen (tumor-associated)</topic><topic>Antigens</topic><topic>Antigens, Neoplasm - genetics</topic><topic>Antigens, Neoplasm - immunology</topic><topic>B7 antigen</topic><topic>Cancer</topic><topic>Carcinoembryonic antigen</topic><topic>CD28 antigen</topic><topic>Cell Line, Tumor</topic><topic>Clustering</topic><topic>Complexity</topic><topic>Cystadenocarcinoma, Serous - genetics</topic><topic>Cystadenocarcinoma, Serous - immunology</topic><topic>Cystadenocarcinoma, Serous - pathology</topic><topic>Experimental design</topic><topic>Extracellular matrix</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene sequencing</topic><topic>Genes</topic><topic>Humans</topic><topic>Immune checkpoint</topic><topic>Immune response</topic><topic>Immune status</topic><topic>Immune system</topic><topic>Life Sciences</topic><topic>Medical treatment</topic><topic>Middle Aged</topic><topic>Molecular biology</topic><topic>Neoplasm Grading</topic><topic>Neoplasm Recurrence, Local - genetics</topic><topic>Neoplasm Recurrence, Local - pathology</topic><topic>Ovarian cancer</topic><topic>Ovarian Neoplasms - genetics</topic><topic>Ovarian Neoplasms - immunology</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Patients</topic><topic>Regulators</topic><topic>Ribonucleic acid</topic><topic>RNA</topic><topic>Sequence Analysis, RNA</topic><topic>Tissues</topic><topic>Tumor Microenvironment - genetics</topic><topic>Tumor Microenvironment - immunology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kreuzinger, Caroline</creatorcontrib><creatorcontrib>Geroldinger, Angelika</creatorcontrib><creatorcontrib>Smeets, Dominiek</creatorcontrib><creatorcontrib>Braicu, Elena Ioana</creatorcontrib><creatorcontrib>Sehouli, Jalid</creatorcontrib><creatorcontrib>Koller, Julia</creatorcontrib><creatorcontrib>Wolf, Andrea</creatorcontrib><creatorcontrib>Darb-Esfahani, Silvia</creatorcontrib><creatorcontrib>Joehrens, Korinna</creatorcontrib><creatorcontrib>Vergote, Ignace</creatorcontrib><creatorcontrib>Vanderstichele, Adriaan</creatorcontrib><creatorcontrib>Boeckx, Bram</creatorcontrib><creatorcontrib>Lambrechts, Diether</creatorcontrib><creatorcontrib>Gabra, Hani</creatorcontrib><creatorcontrib>Wisman, G Bea A</creatorcontrib><creatorcontrib>Trillsch, Fabian</creatorcontrib><creatorcontrib>Heinze, Georg</creatorcontrib><creatorcontrib>Horvat, Reinhard</creatorcontrib><creatorcontrib>Polterauer, Stephan</creatorcontrib><creatorcontrib>Berns, Els</creatorcontrib><creatorcontrib>Theillet, Charles</creatorcontrib><creatorcontrib>Cacsire Castillo-Tong, Dan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS 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>MEDLINE - Academic</collection><collection>Hyper Article en Ligne (HAL)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kreuzinger, Caroline</au><au>Geroldinger, Angelika</au><au>Smeets, Dominiek</au><au>Braicu, Elena Ioana</au><au>Sehouli, Jalid</au><au>Koller, Julia</au><au>Wolf, Andrea</au><au>Darb-Esfahani, Silvia</au><au>Joehrens, Korinna</au><au>Vergote, Ignace</au><au>Vanderstichele, Adriaan</au><au>Boeckx, Bram</au><au>Lambrechts, Diether</au><au>Gabra, Hani</au><au>Wisman, G Bea A</au><au>Trillsch, Fabian</au><au>Heinze, Georg</au><au>Horvat, Reinhard</au><au>Polterauer, Stephan</au><au>Berns, Els</au><au>Theillet, Charles</au><au>Cacsire Castillo-Tong, Dan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2017-12-15</date><risdate>2017</risdate><volume>23</volume><issue>24</issue><spage>7621</spage><epage>7632</epage><pages>7621-7632</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Most high-grade serous ovarian cancer (HGSOC) patients develop recurrent disease after first-line treatment, frequently with fatal outcome. This work aims at studying the molecular biology of both primary and recurrent HGSOC.
Gene expression profiles of matched primary and recurrent fresh-frozen tumor tissues from 66 HGSOC patients were obtained by RNA sequencing. Clustering analyses and pairwise comparison of the profiles between matched samples and subsequent functional alignment were used for the identification of molecular characteristics of HGSOC.
Both primary and recurrent HGSOC samples presented predominant gene expression differences in their microenvironment, determined by a panel of genes covering all major pathways of immune activation together with a number of genes involved in the remodeling of extracellular matrix and adipose tissues. Stratifying tumor tissues into immune active and silent groups, we further discovered that although some recurrent tumors shared the same immune status as their primary counterparts, others switched the immune status, either from silent to active or active to silent. Interestingly, genes belonging to the B7-CD28 immune checkpoint family, known for their major role as negative regulators of the immune response, were overexpressed in the immune active tumors. Searching for potential tumor antigens,
, a member of the carcinoembryonic antigen family, was found to be significantly overexpressed in immune active tissues in comparison with the silent ones.
The results illustrate the complexity of the tumor microenvironment in HGSOC and reveal the molecular relationship between primary and recurrent tumors, which have multiple therapeutic implications.
.</abstract><cop>United States</cop><pub>American Association for Cancer Research Inc</pub><pmid>28972047</pmid><doi>10.1158/1078-0432.CCR-17-1159</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-3429-302X</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Adipose tissue Adult Aged Antigen (tumor-associated) Antigens Antigens, Neoplasm - genetics Antigens, Neoplasm - immunology B7 antigen Cancer Carcinoembryonic antigen CD28 antigen Cell Line, Tumor Clustering Complexity Cystadenocarcinoma, Serous - genetics Cystadenocarcinoma, Serous - immunology Cystadenocarcinoma, Serous - pathology Experimental design Extracellular matrix Female Gene expression Gene Expression Regulation, Neoplastic Gene sequencing Genes Humans Immune checkpoint Immune response Immune status Immune system Life Sciences Medical treatment Middle Aged Molecular biology Neoplasm Grading Neoplasm Recurrence, Local - genetics Neoplasm Recurrence, Local - pathology Ovarian cancer Ovarian Neoplasms - genetics Ovarian Neoplasms - immunology Ovarian Neoplasms - pathology Patients Regulators Ribonucleic acid RNA Sequence Analysis, RNA Tissues Tumor Microenvironment - genetics Tumor Microenvironment - immunology Tumors |
title | A Complex Network of Tumor Microenvironment in Human High-Grade Serous Ovarian Cancer |
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