PAPP-A proteolytic activity enhances IGF bioactivity in ascites from women with ovarian carcinoma

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.

Pregnancy-Associated Plasma Protein-A2 Is Associated With Mortality in Patients With Lung Cancer

“…A subgroup of five patients who were operable provided tumor tissue for IHC, which was performed as previously described ( 20 ) using antibodies specific for PAPP-A (PAC1-D8-mIgG2a) ( 24 ) and PAPP-A2 (P257) ( 22 ) at 10 and 20 mg/L, respectively.…”

“…Thus, PAPP-A causes a release of bioactive IGF in close proximity to the IGF-IR. Shifts in PAPP-A levels have been suggested to modify the relationship between bound and free IGF in various neoplasms ( 8 , 18 – 20 ). In patients with lung cancer, serum PAPP-A levels have been shown to be elevated ( 19 ), and down-regulation of PAPP-A expression decreases lung cancer progression in vivo ( 21 ).…”

“…In patients with lung cancer, serum PAPP-A levels have been shown to be elevated ( 19 ), and down-regulation of PAPP-A expression decreases lung cancer progression in vivo ( 21 ). The present authors previously described a cohort of women with ovarian cancer, in which PAPP-A levels were investigated in serum and malignant ascites ( 20 ). In ascites, which surrounds the ovarian tumor in the abdominal cavity and is a negative prognostic factor, PAPP-A levels were 46-fold higher as compared to serum from the same patient.…”

Prognostic relevance and performance characteristics of serum IGFBP‐2 and PAPP‐A in women with breast cancer: a long‐term Danish cohort study

“…Previous studies show that circulating IGFBP-2 levels in women with ovarian cancer correlate with tumour tissue IGFBP-2 mRNA levels [38], and in patients with colorectal cancer undergoing resection, elevated presurgery concentrations return to normal after resection [9]. Furthermore, in ascites from women with ovarian cancer, IGFBP-2 levels were higher and correlated positively with serum IGFBP-2 [39]. Collectively, these studies suggest that circulating IGFBP-2 levels partly reflect tumor secreted protein.…”

PAPP-A: a promising therapeutic target for healthy longevity

“…These beneficial effects of inhibiting the proteolytic activity of PAPP‐A were only manifested in tumors expressing moderate‐to‐high levels of PAPP‐A. Thus, PAPP‐A expression in patient tumors, or ascites (Thomsen et al ., ), may be a biomarker for patient response to PAPP‐A therapies. We also have unpublished data indicating that mAb‐PA treatment can prevent ovarian tumor metastases to intraperitoneal lining and perigonadal fat, these being prime sites for metastases via ascites.…”