1. PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma.
- Author
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Thomsen J, Hjortebjerg R, Espelund U, Ørtoft G, Vestergaard P, Magnusson NE, Conover CA, Tramm T, Hager H, Høgdall C, Høgdall E, Oxvig C, and Frystyk J
- Subjects
- Aged, Case-Control Studies, Denmark, Female, HEK293 Cells, Humans, Insulin-Like Growth Factor Binding Protein 4 metabolism, Middle Aged, Receptor, IGF Type 1, Receptors, Somatomedin genetics, Receptors, Somatomedin metabolism, Signal Transduction, Transfection, Up-Regulation, Ascitic Fluid enzymology, Carcinoma enzymology, Insulin-Like Growth Factor I metabolism, Insulin-Like Growth Factor II metabolism, Ovarian Neoplasms enzymology, Pregnancy-Associated Plasma Protein-A metabolism
- 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.
- Published
- 2015
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