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.
Highlights
Insulin-like growth factor I (IGF-I) and its primary target, the insulin-like growth factor (IGF)-I receptor (IGF-IR) stimulate malignant transformation, tumor progression and metastasis [1,2,3,4]
The comparison showed that patients had borderline reductions in bioactive IGF (P = 0.09) and total IGF-II (P = 0.06), significant reductions in total IGF-I (P = 0.005), pro-IGF-II (P < 0.001) and IGF-binding protein (IGFBP)-3 (P < 0.001), and significant increases in plasma protein-A (PAPP-A) (P = 0.03) and IGFBP-2, the latter being more than 7-fold elevated (P < 0.001)
The present study confirmed this hypothesis as the IGF bioactivity of ascites from women with ovarian cancer was 31% higher than that of serum
Summary
Insulin-like growth factor I (IGF-I) and its primary target, the IGF-I receptor (IGF-IR) stimulate malignant transformation, tumor progression and metastasis [1,2,3,4]. This holds true for ovarian carcinoma, where up-regulated IGF-I and IGF-IR expression has been demonstrated in surgical specimens from patients with advanced stages as well as with poorly differentiated ovarian tumors [5]. These clinical observations gain support from experimental studies. Clinical as well as pre-clinical data support a pathogenic role for IGF-I and the IGF-IR in the development and progression of ovarian carcinoma
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
