PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma

Jacob Thomsen, Rikke Hjortebjerg, Ulrick Espelund, Gitte Ørtoft, Poul Vestergaard, Nils E. Magnusson, Cheryl A Conover, Trine Tramm, Henrik Hager, Claus Høgdall, Estrid Høgdall, Claus Oxvig, Jan Frystyk

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)32266-32278
Number of pages13
JournalOncotarget
Volume6
Issue number31
DOIs
StatePublished - 2015

Fingerprint

Pregnancy-Associated Plasma Protein-A
Somatomedins
Ascites
Insulin-Like Growth Factor Binding Protein 4
Carcinoma
Insulin-Like Growth Factor II
Neoplasms
Insulin-Like Growth Factor I
Animal Pregnancy
Serum
IGF Type 1 Receptor
Growth
Proteolysis
Immunohistochemistry

Keywords

  • IGF-I
  • IGFBP-4
  • KIRA assay
  • Malignant ascites
  • PAPP-A

ASJC Scopus subject areas

  • Oncology

Cite this

Thomsen, J., Hjortebjerg, R., Espelund, U., Ørtoft, G., Vestergaard, P., Magnusson, N. E., ... Frystyk, J. (2015). PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma. Oncotarget, 6(31), 32266-32278. https://doi.org/10.18632/oncotarget.5010

PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma. / 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.

In: Oncotarget, Vol. 6, No. 31, 2015, p. 32266-32278.

Research output: Contribution to journalArticle

Thomsen, J, Hjortebjerg, R, Espelund, U, Ørtoft, G, Vestergaard, P, Magnusson, NE, Conover, CA, Tramm, T, Hager, H, Høgdall, C, Høgdall, E, Oxvig, C & Frystyk, J 2015, 'PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma', Oncotarget, vol. 6, no. 31, pp. 32266-32278. https://doi.org/10.18632/oncotarget.5010
Thomsen J, Hjortebjerg R, Espelund U, Ørtoft G, Vestergaard P, Magnusson NE et al. PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma. Oncotarget. 2015;6(31):32266-32278. https://doi.org/10.18632/oncotarget.5010
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. / PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma. In: Oncotarget. 2015 ; Vol. 6, No. 31. pp. 32266-32278.
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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.",
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