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

17 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Oncology

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    Thomsen, J., Hjortebjerg, R., Espelund, U., Ørtoft, G., Vestergaard, P., Magnusson, N. E., Conover, C. A., 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, 6(31), 32266-32278. https://doi.org/10.18632/oncotarget.5010