PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma
Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum...
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| creator | Thomsen, Jacob Hjortebjerg, Rikke Espelund, Ulrick Ørtoft, Gitte Vestergaard, Poul Magnusson, Nils E Conover, Cheryl A Tramm, Trine Hager, Henrik Høgdall, Claus Høgdall, Estrid Oxvig, Claus Frystyk, Jan |
| description | Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P < 0.001). The majority (80%) of PAPP-A was enzymatically active. This is supported by the finding that ascites contained more cleaved than intact IGFBP-4 (P < 0.03). Ascites was more potent than serum in activating the IGF-I receptor (IGF-IR) in vitro (+31%, P < 0.05); in 8 of 22 patients by more than two-fold. In contrast, ascites contained similar levels of immunoreactive IGF-I, and lower levels of IGF-II (P < 0.001). Immunohistochemistry demonstrated the presence of IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P < 0.05). In conclusion, human ovarian tumors express PAPP-A, IGFBP-4 and IGFs and these proteins are also present in ascites. We suggest that both soluble PAPP-A in ascites and tissue-associated PAPP-A serve to increase IGF bioactivity and, thereby, to stimulate IGF-IR-mediated tumor growth. |
| doi_str_mv | 10.18632/oncotarget.5010 |
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In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P < 0.001). The majority (80%) of PAPP-A was enzymatically active. This is supported by the finding that ascites contained more cleaved than intact IGFBP-4 (P < 0.03). Ascites was more potent than serum in activating the IGF-I receptor (IGF-IR) in vitro (+31%, P < 0.05); in 8 of 22 patients by more than two-fold. In contrast, ascites contained similar levels of immunoreactive IGF-I, and lower levels of IGF-II (P < 0.001). Immunohistochemistry demonstrated the presence of IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P < 0.05). In conclusion, human ovarian tumors express PAPP-A, IGFBP-4 and IGFs and these proteins are also present in ascites. We suggest that both soluble PAPP-A in ascites and tissue-associated PAPP-A serve to increase IGF bioactivity and, thereby, to stimulate IGF-IR-mediated tumor growth.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.5010</identifier><identifier>PMID: 26336825</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Aged ; Ascitic Fluid - enzymology ; Carcinoma - enzymology ; Case-Control Studies ; Clinical Research Paper ; Denmark ; Female ; HEK293 Cells ; Humans ; Insulin-Like Growth Factor Binding Protein 4 - metabolism ; Insulin-Like Growth Factor I - metabolism ; Insulin-Like Growth Factor II - metabolism ; Middle Aged ; Ovarian Neoplasms - enzymology ; Pregnancy-Associated Plasma Protein-A - metabolism ; Receptor, IGF Type 1 ; Receptors, Somatomedin - genetics ; Receptors, Somatomedin - metabolism ; Signal Transduction ; Transfection ; Up-Regulation</subject><ispartof>Oncotarget, 2015-10, Vol.6 (31), p.32266-32278</ispartof><rights>Copyright: © 2015 Thomsen et al. 2015</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c396t-496fe90eeda1350ecdb3cefa72c5afb1c95ce516a76e38db4e3f755ee24208dc3</citedby><cites>FETCH-LOGICAL-c396t-496fe90eeda1350ecdb3cefa72c5afb1c95ce516a76e38db4e3f755ee24208dc3</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/PMC4741676/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741676/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27923,27924,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26336825$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Thomsen, Jacob</creatorcontrib><creatorcontrib>Hjortebjerg, Rikke</creatorcontrib><creatorcontrib>Espelund, Ulrick</creatorcontrib><creatorcontrib>Ørtoft, Gitte</creatorcontrib><creatorcontrib>Vestergaard, Poul</creatorcontrib><creatorcontrib>Magnusson, Nils E</creatorcontrib><creatorcontrib>Conover, Cheryl A</creatorcontrib><creatorcontrib>Tramm, Trine</creatorcontrib><creatorcontrib>Hager, Henrik</creatorcontrib><creatorcontrib>Høgdall, Claus</creatorcontrib><creatorcontrib>Høgdall, Estrid</creatorcontrib><creatorcontrib>Oxvig, Claus</creatorcontrib><creatorcontrib>Frystyk, Jan</creatorcontrib><title>PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P < 0.001). The majority (80%) of PAPP-A was enzymatically active. This is supported by the finding that ascites contained more cleaved than intact IGFBP-4 (P < 0.03). Ascites was more potent than serum in activating the IGF-I receptor (IGF-IR) in vitro (+31%, P < 0.05); in 8 of 22 patients by more than two-fold. In contrast, ascites contained similar levels of immunoreactive IGF-I, and lower levels of IGF-II (P < 0.001). Immunohistochemistry demonstrated the presence of IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P < 0.05). In conclusion, human ovarian tumors express PAPP-A, IGFBP-4 and IGFs and these proteins are also present in ascites. We suggest that both soluble PAPP-A in ascites and tissue-associated PAPP-A serve to increase IGF bioactivity and, thereby, to stimulate IGF-IR-mediated tumor growth.</description><subject>Aged</subject><subject>Ascitic Fluid - enzymology</subject><subject>Carcinoma - enzymology</subject><subject>Case-Control Studies</subject><subject>Clinical Research Paper</subject><subject>Denmark</subject><subject>Female</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Insulin-Like Growth Factor Binding Protein 4 - metabolism</subject><subject>Insulin-Like Growth Factor I - metabolism</subject><subject>Insulin-Like Growth Factor II - metabolism</subject><subject>Middle Aged</subject><subject>Ovarian Neoplasms - enzymology</subject><subject>Pregnancy-Associated Plasma Protein-A - metabolism</subject><subject>Receptor, IGF Type 1</subject><subject>Receptors, Somatomedin - genetics</subject><subject>Receptors, Somatomedin - metabolism</subject><subject>Signal Transduction</subject><subject>Transfection</subject><subject>Up-Regulation</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUUtP3DAQtlARIMqdU-VjLwE7jp3kUmmFCkVCYg_lbE0mE9Yosbe2d9H-e1IeWzqXGel7jfQxdi7FhWyMKi-Dx5AhPlK-0EKKA3Yi26otSq3Vl0_3MTtL6UnMo6u6KdsjdlwapUxT6hMGy8VyWSz4OoZMYdxlhxwwu63LO05-BR4p8duba965sAec55DQ5RkaYpj4c5jI82eXVzxsITrwHCGi82GCr-xwgDHR2fs-ZQ_XP39f_Sru7m9urxZ3BarW5KJqzUCtIOpBKi0I-04hDVCXqGHoJLYaSUsDtSHV9F1Faqi1JiqrUjQ9qlP24813vekm6pF8jjDadXQTxJ0N4Oz_iHcr-xi2tqoraWozG3x_N4jhz4ZStpNLSOMInsImWVnPUbo1Qs5U8UbFGFKKNOxjpLCv5dh_5di_5cySb5_f2ws-qlAvdx2Q3Q</recordid><startdate>20151013</startdate><enddate>20151013</enddate><creator>Thomsen, Jacob</creator><creator>Hjortebjerg, Rikke</creator><creator>Espelund, Ulrick</creator><creator>Ørtoft, Gitte</creator><creator>Vestergaard, Poul</creator><creator>Magnusson, Nils E</creator><creator>Conover, Cheryl A</creator><creator>Tramm, Trine</creator><creator>Hager, Henrik</creator><creator>Høgdall, Claus</creator><creator>Høgdall, Estrid</creator><creator>Oxvig, Claus</creator><creator>Frystyk, Jan</creator><general>Impact Journals LLC</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><scope>5PM</scope></search><sort><creationdate>20151013</creationdate><title>PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma</title><author>Thomsen, Jacob ; Hjortebjerg, Rikke ; Espelund, Ulrick ; Ørtoft, Gitte ; Vestergaard, Poul ; Magnusson, Nils E ; Conover, Cheryl A ; Tramm, Trine ; Hager, Henrik ; Høgdall, Claus ; Høgdall, Estrid ; Oxvig, Claus ; Frystyk, Jan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c396t-496fe90eeda1350ecdb3cefa72c5afb1c95ce516a76e38db4e3f755ee24208dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Aged</topic><topic>Ascitic Fluid - enzymology</topic><topic>Carcinoma - enzymology</topic><topic>Case-Control Studies</topic><topic>Clinical Research Paper</topic><topic>Denmark</topic><topic>Female</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Insulin-Like Growth Factor Binding Protein 4 - metabolism</topic><topic>Insulin-Like Growth Factor I - metabolism</topic><topic>Insulin-Like Growth Factor II - metabolism</topic><topic>Middle Aged</topic><topic>Ovarian Neoplasms - enzymology</topic><topic>Pregnancy-Associated Plasma Protein-A - metabolism</topic><topic>Receptor, IGF Type 1</topic><topic>Receptors, Somatomedin - genetics</topic><topic>Receptors, Somatomedin - metabolism</topic><topic>Signal Transduction</topic><topic>Transfection</topic><topic>Up-Regulation</topic><toplevel>online_resources</toplevel><creatorcontrib>Thomsen, Jacob</creatorcontrib><creatorcontrib>Hjortebjerg, Rikke</creatorcontrib><creatorcontrib>Espelund, Ulrick</creatorcontrib><creatorcontrib>Ørtoft, Gitte</creatorcontrib><creatorcontrib>Vestergaard, Poul</creatorcontrib><creatorcontrib>Magnusson, Nils E</creatorcontrib><creatorcontrib>Conover, Cheryl A</creatorcontrib><creatorcontrib>Tramm, Trine</creatorcontrib><creatorcontrib>Hager, Henrik</creatorcontrib><creatorcontrib>Høgdall, Claus</creatorcontrib><creatorcontrib>Høgdall, Estrid</creatorcontrib><creatorcontrib>Oxvig, Claus</creatorcontrib><creatorcontrib>Frystyk, Jan</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Thomsen, Jacob</au><au>Hjortebjerg, Rikke</au><au>Espelund, Ulrick</au><au>Ørtoft, Gitte</au><au>Vestergaard, Poul</au><au>Magnusson, Nils E</au><au>Conover, Cheryl A</au><au>Tramm, Trine</au><au>Hager, Henrik</au><au>Høgdall, Claus</au><au>Høgdall, Estrid</au><au>Oxvig, Claus</au><au>Frystyk, Jan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2015-10-13</date><risdate>2015</risdate><volume>6</volume><issue>31</issue><spage>32266</spage><epage>32278</epage><pages>32266-32278</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>Pregnancy-associated plasma protein-A (PAPP-A) stimulates insulin-like growth factor (IGF) action through proteolysis of IGF-binding protein (IGFBP)-4. In experimental animals, PAPP-A accelerates ovarian tumor growth by this mechanism. To investigate the effect of PAPP-A in humans, we compared serum and ascites from 22 women with ovarian carcinoma. We found that ascites contained 46-fold higher PAPP-A levels as compared to serum (P < 0.001). The majority (80%) of PAPP-A was enzymatically active. This is supported by the finding that ascites contained more cleaved than intact IGFBP-4 (P < 0.03). Ascites was more potent than serum in activating the IGF-I receptor (IGF-IR) in vitro (+31%, P < 0.05); in 8 of 22 patients by more than two-fold. In contrast, ascites contained similar levels of immunoreactive IGF-I, and lower levels of IGF-II (P < 0.001). Immunohistochemistry demonstrated the presence of IGF-IR in all but one tumor, whereas all tumors expressed PAPP-A, IGFBP-4, IGF-I and IGF-II. Addition of recombinant PAPP-A to ascites increased the cleavage of IGFBP-4 and enhanced IGF-IR activation (P < 0.05). In conclusion, human ovarian tumors express PAPP-A, IGFBP-4 and IGFs and these proteins are also present in ascites. We suggest that both soluble PAPP-A in ascites and tissue-associated PAPP-A serve to increase IGF bioactivity and, thereby, to stimulate IGF-IR-mediated tumor growth.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>26336825</pmid><doi>10.18632/oncotarget.5010</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aged Ascitic Fluid - enzymology Carcinoma - enzymology Case-Control Studies Clinical Research Paper Denmark Female HEK293 Cells Humans Insulin-Like Growth Factor Binding Protein 4 - metabolism Insulin-Like Growth Factor I - metabolism Insulin-Like Growth Factor II - metabolism Middle Aged Ovarian Neoplasms - enzymology Pregnancy-Associated Plasma Protein-A - metabolism Receptor, IGF Type 1 Receptors, Somatomedin - genetics Receptors, Somatomedin - metabolism Signal Transduction Transfection Up-Regulation |
| title | PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma |
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