Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor
Interleukin (IL)‐18 is a proinflammatory and immune‐enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL‐18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (...
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| Veröffentlicht in: | International journal of cancer 2011-09, Vol.129 (5), p.1116-1125 |
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| creator | Orengo, Anna Maria Fabbi, Marina Miglietta, Loredana Andreani, Cristian Bruzzone, Milena Puppo, Andrea Cristoforoni, Paolo Centurioni, Maria Grazia Gualco, Marina Salvi, Sandra Boccardo, Simona Truini, Mauro Piazza, Tiziana Canevari, Silvana Mezzanzanica, Delia Ferrini, Silvano |
| description | Interleukin (IL)‐18 is a proinflammatory and immune‐enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL‐18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro‐IL‐18) in vitro. In addition, IL‐18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL‐18 is increased in EOC patients' sera at diagnosis as compared with age‐matched healthy women. IL‐18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL‐18 expression in cytokeratine‐positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL‐18. The detection of human IL‐18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL‐18 is tumor‐derived. However, IL‐18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL‐18 present in the ascitic fluid as pro‐IL‐18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL‐18 levels. Altogether these data indicate that IL‐18 in EOC fluids is predominantly tumor‐derived and that its lack of biological activity may represent a mechanism of tumor‐escape. |
| doi_str_mv | 10.1002/ijc.25757 |
| format | Article |
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We previously reported that IL‐18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro‐IL‐18) in vitro. In addition, IL‐18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL‐18 is increased in EOC patients' sera at diagnosis as compared with age‐matched healthy women. IL‐18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL‐18 expression in cytokeratine‐positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL‐18. The detection of human IL‐18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL‐18 is tumor‐derived. However, IL‐18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL‐18 present in the ascitic fluid as pro‐IL‐18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL‐18 levels. Altogether these data indicate that IL‐18 in EOC fluids is predominantly tumor‐derived and that its lack of biological activity may represent a mechanism of tumor‐escape.</description><identifier>ISSN: 0020-7136</identifier><identifier>ISSN: 1097-0215</identifier><identifier>EISSN: 1097-0215</identifier><identifier>DOI: 10.1002/ijc.25757</identifier><identifier>PMID: 21710494</identifier><identifier>CODEN: IJCNAW</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Adenocarcinoma, Mucinous - blood ; Adenocarcinoma, Mucinous - immunology ; Adult ; Aged ; Aged, 80 and over ; Animals ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - metabolism ; Antitumor activity ; Ascitic fluid ; Ascitic Fluid - metabolism ; Biological and medical sciences ; biomarker ; biomarkers ; Blotting, Western ; Cystadenocarcinoma, Serous - blood ; Cystadenocarcinoma, Serous - immunology ; Data processing ; Endometrial Neoplasms - blood ; Endometrial Neoplasms - immunology ; Endometrium ; Enzyme-Linked Immunosorbent Assay ; Female ; Female genital diseases ; Gynecology. Andrology. Obstetrics ; Humans ; IL‐18 ; immature precursor ; Immunodeficiency ; Immunoenzyme Techniques ; Immunoprecipitation ; Inflammation ; Interferon ; Interferon-gamma - metabolism ; Interleukin 18 ; Interleukin-18 - blood ; Interleukin-18 - immunology ; Lymphoid cells ; Medical sciences ; Mice ; Mice, Inbred BALB C ; Mice, Inbred NOD ; Mice, SCID ; Middle Aged ; Monoclonal antibodies ; ovarian cancer ; Ovarian carcinoma ; Ovarian Neoplasms - blood ; Ovarian Neoplasms - immunology ; Peritoneum ; Serum levels ; Tumor Cells, Cultured ; Tumors</subject><ispartof>International journal of cancer, 2011-09, Vol.129 (5), p.1116-1125</ispartof><rights>Copyright © 2011 UICC</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2010 UICC.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4887-ea1064caf6c065bf7d9baf6438eab0d5a431f875ee566a9645737ec2039387ef3</citedby><cites>FETCH-LOGICAL-c4887-ea1064caf6c065bf7d9baf6438eab0d5a431f875ee566a9645737ec2039387ef3</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%2Fijc.25757$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fijc.25757$$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=24369777$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21710494$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Orengo, Anna Maria</creatorcontrib><creatorcontrib>Fabbi, Marina</creatorcontrib><creatorcontrib>Miglietta, Loredana</creatorcontrib><creatorcontrib>Andreani, Cristian</creatorcontrib><creatorcontrib>Bruzzone, Milena</creatorcontrib><creatorcontrib>Puppo, Andrea</creatorcontrib><creatorcontrib>Cristoforoni, Paolo</creatorcontrib><creatorcontrib>Centurioni, Maria Grazia</creatorcontrib><creatorcontrib>Gualco, Marina</creatorcontrib><creatorcontrib>Salvi, Sandra</creatorcontrib><creatorcontrib>Boccardo, Simona</creatorcontrib><creatorcontrib>Truini, Mauro</creatorcontrib><creatorcontrib>Piazza, Tiziana</creatorcontrib><creatorcontrib>Canevari, Silvana</creatorcontrib><creatorcontrib>Mezzanzanica, Delia</creatorcontrib><creatorcontrib>Ferrini, Silvano</creatorcontrib><title>Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor</title><title>International journal of cancer</title><addtitle>Int J Cancer</addtitle><description>Interleukin (IL)‐18 is a proinflammatory and immune‐enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL‐18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro‐IL‐18) in vitro. In addition, IL‐18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL‐18 is increased in EOC patients' sera at diagnosis as compared with age‐matched healthy women. IL‐18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL‐18 expression in cytokeratine‐positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL‐18. The detection of human IL‐18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL‐18 is tumor‐derived. However, IL‐18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL‐18 present in the ascitic fluid as pro‐IL‐18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL‐18 levels. Altogether these data indicate that IL‐18 in EOC fluids is predominantly tumor‐derived and that its lack of biological activity may represent a mechanism of tumor‐escape.</description><subject>Adenocarcinoma, Mucinous - blood</subject><subject>Adenocarcinoma, Mucinous - immunology</subject><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Animals</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - metabolism</subject><subject>Antitumor activity</subject><subject>Ascitic fluid</subject><subject>Ascitic Fluid - metabolism</subject><subject>Biological and medical sciences</subject><subject>biomarker</subject><subject>biomarkers</subject><subject>Blotting, Western</subject><subject>Cystadenocarcinoma, Serous - blood</subject><subject>Cystadenocarcinoma, Serous - immunology</subject><subject>Data processing</subject><subject>Endometrial Neoplasms - blood</subject><subject>Endometrial Neoplasms - immunology</subject><subject>Endometrium</subject><subject>Enzyme-Linked Immunosorbent Assay</subject><subject>Female</subject><subject>Female genital diseases</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>IL‐18</subject><subject>immature precursor</subject><subject>Immunodeficiency</subject><subject>Immunoenzyme Techniques</subject><subject>Immunoprecipitation</subject><subject>Inflammation</subject><subject>Interferon</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukin 18</subject><subject>Interleukin-18 - blood</subject><subject>Interleukin-18 - immunology</subject><subject>Lymphoid cells</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Middle Aged</subject><subject>Monoclonal antibodies</subject><subject>ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>Ovarian Neoplasms - blood</subject><subject>Ovarian Neoplasms - immunology</subject><subject>Peritoneum</subject><subject>Serum levels</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>0020-7136</issn><issn>1097-0215</issn><issn>1097-0215</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp90c9u1DAQBnALgehSOPACyBdEKzWtnfhfjtUKylYrcYFzNHEm4NaJF3tTtOLCI_CMPAlOd6EnOI2s-emzNB8hLzk754yVF-7GnpdSS_2ILDirdcFKLh-TRd6xQvNKHZFnKd0wxrlk4ik5KrnmTNRiQb6vxi1Gj9OtG-nJan3668dPbs4o0NaFAeItRhp6-mUaYKThDqLL00K0bszrM-oS3UTswuBGGLd-RyN6hIQdhTRH-PDZWfB5kYHdujucvZ1iCvE5edKDT_jiMI_Jp3dvPy7fF-sPV6vl5bqwwhhdIHCmhIVeWaZk2-uubvNDVAahZZ0EUfHeaIkolYJaCakrjbZkVV0ZjX11TN7sczcxfJ0wbZvBJYvew4hhSo3Rghsljcry5L-S54MaURs109M9tTGkFLFvNtHlg-0yauZWmtxKc99Ktq8OsVM7YPdX_qkhg9cHAClfq48wWpcenKhUrfUcdLF335zH3b9_bFbXy_3XvwG-VqS7</recordid><startdate>20110901</startdate><enddate>20110901</enddate><creator>Orengo, Anna Maria</creator><creator>Fabbi, Marina</creator><creator>Miglietta, Loredana</creator><creator>Andreani, Cristian</creator><creator>Bruzzone, Milena</creator><creator>Puppo, Andrea</creator><creator>Cristoforoni, Paolo</creator><creator>Centurioni, Maria Grazia</creator><creator>Gualco, Marina</creator><creator>Salvi, Sandra</creator><creator>Boccardo, Simona</creator><creator>Truini, Mauro</creator><creator>Piazza, Tiziana</creator><creator>Canevari, Silvana</creator><creator>Mezzanzanica, Delia</creator><creator>Ferrini, Silvano</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley-Blackwell</general><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>7T5</scope><scope>H94</scope><scope>7X8</scope></search><sort><creationdate>20110901</creationdate><title>Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor</title><author>Orengo, Anna Maria ; Fabbi, Marina ; Miglietta, Loredana ; Andreani, Cristian ; Bruzzone, Milena ; Puppo, Andrea ; Cristoforoni, Paolo ; Centurioni, Maria Grazia ; Gualco, Marina ; Salvi, Sandra ; Boccardo, Simona ; Truini, Mauro ; Piazza, Tiziana ; Canevari, Silvana ; Mezzanzanica, Delia ; Ferrini, Silvano</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4887-ea1064caf6c065bf7d9baf6438eab0d5a431f875ee566a9645737ec2039387ef3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Adenocarcinoma, Mucinous - blood</topic><topic>Adenocarcinoma, Mucinous - immunology</topic><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Animals</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - metabolism</topic><topic>Antitumor activity</topic><topic>Ascitic fluid</topic><topic>Ascitic Fluid - metabolism</topic><topic>Biological and medical sciences</topic><topic>biomarker</topic><topic>biomarkers</topic><topic>Blotting, Western</topic><topic>Cystadenocarcinoma, Serous - blood</topic><topic>Cystadenocarcinoma, Serous - immunology</topic><topic>Data processing</topic><topic>Endometrial Neoplasms - blood</topic><topic>Endometrial Neoplasms - immunology</topic><topic>Endometrium</topic><topic>Enzyme-Linked Immunosorbent Assay</topic><topic>Female</topic><topic>Female genital diseases</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>IL‐18</topic><topic>immature precursor</topic><topic>Immunodeficiency</topic><topic>Immunoenzyme Techniques</topic><topic>Immunoprecipitation</topic><topic>Inflammation</topic><topic>Interferon</topic><topic>Interferon-gamma - metabolism</topic><topic>Interleukin 18</topic><topic>Interleukin-18 - blood</topic><topic>Interleukin-18 - immunology</topic><topic>Lymphoid cells</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Middle Aged</topic><topic>Monoclonal antibodies</topic><topic>ovarian cancer</topic><topic>Ovarian carcinoma</topic><topic>Ovarian Neoplasms - blood</topic><topic>Ovarian Neoplasms - immunology</topic><topic>Peritoneum</topic><topic>Serum levels</topic><topic>Tumor Cells, Cultured</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Orengo, Anna Maria</creatorcontrib><creatorcontrib>Fabbi, Marina</creatorcontrib><creatorcontrib>Miglietta, Loredana</creatorcontrib><creatorcontrib>Andreani, Cristian</creatorcontrib><creatorcontrib>Bruzzone, Milena</creatorcontrib><creatorcontrib>Puppo, Andrea</creatorcontrib><creatorcontrib>Cristoforoni, Paolo</creatorcontrib><creatorcontrib>Centurioni, Maria Grazia</creatorcontrib><creatorcontrib>Gualco, Marina</creatorcontrib><creatorcontrib>Salvi, Sandra</creatorcontrib><creatorcontrib>Boccardo, Simona</creatorcontrib><creatorcontrib>Truini, Mauro</creatorcontrib><creatorcontrib>Piazza, Tiziana</creatorcontrib><creatorcontrib>Canevari, Silvana</creatorcontrib><creatorcontrib>Mezzanzanica, Delia</creatorcontrib><creatorcontrib>Ferrini, Silvano</creatorcontrib><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>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>International journal of cancer</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Orengo, Anna Maria</au><au>Fabbi, Marina</au><au>Miglietta, Loredana</au><au>Andreani, Cristian</au><au>Bruzzone, Milena</au><au>Puppo, Andrea</au><au>Cristoforoni, Paolo</au><au>Centurioni, Maria Grazia</au><au>Gualco, Marina</au><au>Salvi, Sandra</au><au>Boccardo, Simona</au><au>Truini, Mauro</au><au>Piazza, Tiziana</au><au>Canevari, Silvana</au><au>Mezzanzanica, Delia</au><au>Ferrini, Silvano</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor</atitle><jtitle>International journal of cancer</jtitle><addtitle>Int J Cancer</addtitle><date>2011-09-01</date><risdate>2011</risdate><volume>129</volume><issue>5</issue><spage>1116</spage><epage>1125</epage><pages>1116-1125</pages><issn>0020-7136</issn><issn>1097-0215</issn><eissn>1097-0215</eissn><coden>IJCNAW</coden><abstract>Interleukin (IL)‐18 is a proinflammatory and immune‐enhancing cytokine, which exerts antitumor effects in vivo, mediated by the induction of interferon (IFN)γ. We previously reported that IL‐18 processing is defective in epithelial ovarian carcinoma (EOC) cells, which secrete an inactive precursor (pro‐IL‐18) in vitro. In addition, IL‐18 was reported as a potential biomarker of EOC. Here, we further investigated its role as a serological marker in human EOC and addressed its possible biological activity in vivo. Our data indicate that immunoreactive IL‐18 is increased in EOC patients' sera at diagnosis as compared with age‐matched healthy women. IL‐18 levels were higher in the ascitic fluids than in sera, suggesting a local production in the peritoneal cavity. Indeed, immunohistochemical analysis of tumors showed IL‐18 expression in cytokeratine‐positive neoplastic cells, although also scattered histiocytes and some lymphoid cells stained for IL‐18. The detection of human IL‐18 in sera and ascitic fluids of immunodeficient mice, orthotopically implanted with human EOC cells, further suggested that circulating IL‐18 is tumor‐derived. However, IL‐18 is not an EOC specific biomarker, as increased serum levels were found also in some endometrial cancer patients. By means of a new monoclonal antibody, we characterized IL‐18 present in the ascitic fluid as pro‐IL‐18, which is biologically inactive. Accordingly, IFNγ was not increased in EOC patients' sera and ascitic fluids and showed no correlation with IL‐18 levels. Altogether these data indicate that IL‐18 in EOC fluids is predominantly tumor‐derived and that its lack of biological activity may represent a mechanism of tumor‐escape.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>21710494</pmid><doi>10.1002/ijc.25757</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | International journal of cancer, 2011-09, Vol.129 (5), p.1116-1125 |
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| subjects | Adenocarcinoma, Mucinous - blood Adenocarcinoma, Mucinous - immunology Adult Aged Aged, 80 and over Animals Antibodies, Monoclonal - immunology Antibodies, Monoclonal - metabolism Antitumor activity Ascitic fluid Ascitic Fluid - metabolism Biological and medical sciences biomarker biomarkers Blotting, Western Cystadenocarcinoma, Serous - blood Cystadenocarcinoma, Serous - immunology Data processing Endometrial Neoplasms - blood Endometrial Neoplasms - immunology Endometrium Enzyme-Linked Immunosorbent Assay Female Female genital diseases Gynecology. Andrology. Obstetrics Humans IL‐18 immature precursor Immunodeficiency Immunoenzyme Techniques Immunoprecipitation Inflammation Interferon Interferon-gamma - metabolism Interleukin 18 Interleukin-18 - blood Interleukin-18 - immunology Lymphoid cells Medical sciences Mice Mice, Inbred BALB C Mice, Inbred NOD Mice, SCID Middle Aged Monoclonal antibodies ovarian cancer Ovarian carcinoma Ovarian Neoplasms - blood Ovarian Neoplasms - immunology Peritoneum Serum levels Tumor Cells, Cultured Tumors |
| title | Interleukin (IL)‐18, a biomarker of human ovarian carcinoma, is predominantly released as biologically inactive precursor |
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