Clinical Research Papers:
PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma
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Jacob Thomsen1, Rikke Hjortebjerg1, Ulrick Espelund1, Gitte Ørtoft2, Poul Vestergaard1,3, Nils E. Magnusson1, Cheryl A. Conover4, Trine Tramm5, Henrik Hager5, Claus Høgdall6, Estrid Høgdall7, Claus Oxvig8, Jan Frystyk1,3
1Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark
2Department of Gynecology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark
3Department of Endocrinology and Internal Medicine, Aarhus University Hospital, DK-8000 Aarhus C, Denmark
4Division of Endocrinology and Metabolism, Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA
5Department of Pathology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark
6Clinic of Gynecology, Juliane Marie Centret, Rigshospitalet, DK-2100 Copenhagen, Denmark
7Department of Pathology, Herlev University Hospital, DK-2730 Herlev, Denmark
8Department of Molecular Biology and Genetics, Faculty of Science & Technology, Aarhus University, DK-8000 Aarhus C, Denmark
Jan Frystyk, e-mail: Frystyk@clin.au.dk
Keywords: IGF-I, PAPP-A, KIRA assay, IGFBP-4, malignant ascites
Received: February 15, 2015 Accepted: August 14, 2015 Published: August 24, 2015
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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