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 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.
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark.
Jacob
J
Thomsen
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark.
Rikke
R
Hjortebjerg
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark.
Ulrick
U
Espelund
Department of Gynecology, Aarhus University Hospital, DK-8200 Aarhus N, Denmark.
Gitte
G
Ørtoft
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark.|Department of Endocrinology and Internal Medicine, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
Poul
P
Vestergaard
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark.
Nils E
NE
Magnusson
Division of Endocrinology and Metabolism, Endocrine Research Unit, Mayo Clinic, Rochester, MN 55905, USA.
Cheryl A
CA
Conover
Department of Pathology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
Trine
T
Tramm
Department of Pathology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
Henrik
H
Hager
Clinic of Gynecology, Juliane Marie Centret, Rigshospitalet, DK-2100 Copenhagen, Denmark.
Claus
C
Høgdall
Department of Pathology, Herlev University Hospital, DK-2730 Herlev, Denmark.
Estrid
E
Høgdall
Department of Molecular Biology and Genetics, Faculty of Science & Technology, Aarhus University, DK-8000 Aarhus C, Denmark.
Claus
C
Oxvig
Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, DK-8000 Aarhus C, Denmark.|Department of Endocrinology and Internal Medicine, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
Jan
J
Frystyk
D000368:Aged; D001202:Ascitic Fluid / Q000201:enzymology*; D002277:Carcinoma / Q000201:enzymology*; D016022:Case-Control Studies; D003718:Denmark; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000201:enzymology*; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation
C583557:IGF1 protein, human; C000597236:IGF1R protein, human; C035170:IGF2 protein, human; D018974:Insulin-Like Growth Factor Binding Protein 4; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; D011266:Pregnancy-Associated Plasma Protein-A; C579283:PAPPA protein, human
IGF-I; IGFBP-4; KIRA assay; PAPP-A; malignant ascites