Insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) proteolysis in patients with colorectal cancer: possible association with the metastatic potential of the tumor.
The limited proteolysis of insulin-like growth factor (IGF)-binding protein (IGFBP)-3 is a key event in the regulation of endocrine bioavailability of IGFs. Here, we investigated IGFBP-3 and IGFBP-3 proteolysis in serum from patients with colorectal cancer both before and at different times following surgery. In vivo IGFBP-3 proteolysis, estimated by immunoblot analysis of IGFBP-3 fragments in serum, and in vitro IGFBP-3 protease activity of serum, estimated by a 125I-IGFBP-3 degradation assay, allowed us to identify 2 groups of patients (IGF-M vs. IGF-NM) with respect to their status for mobilizing the IGF system. In IGF-M patients, in vivo and in vitro IGFBP-3 proteolysis were significantly elevated (156% and 181% of the age-matched control pool, respectively) and accompanied by a decrease in intact IGFBP-3 (38% of the control pool). The IGFBP-3 proteolytic processing was further increased in response to surgical ablation of the tumor (mean increase 45-55%), then gradually returned to levels comparable with controls. In contrast, IGF-NM patients exhibited a minimal alteration of in vitro IGFBP-3 protease activity and even an inhibition of in vivo IGFBP-3 proteolysis, whereas intact IGFBP-3 was unaltered when compared with controls. Moreover, this pattern was not further significantly altered in response to the surgical stress. None (0/6) of the IGF-M patients vs. 70% (5/7) of the IGF-NM patients developed a metastatic disease (median duration of follow-up 26 months). Neither elevated amounts of pro-IGF-II nor presence of detectable IGFBP-3 protease inhibitors in the circulation could explain the observed suppression of IGFBP-3 proteolytic processing in IGF-NM patients. These results indicate that inhibition of IGFBP-3 proteolysis and invasive properties of cancer cells are related in colorectal cancer patients.
Baciuchka
M
M
Service d'Oncologie Médicale, Hôpital de la Timone, Marseille, France.
Remacle-Bonnet
M
M
Garrouste
F
F
Favre
R
R
Sastre
B
B
Pommier
G
G
D000230:Adenocarcinoma / Q000097:blood* / Q000473:pathology / Q000601:surgery; D000368:Aged; D015179:Colorectal Neoplasms / Q000097:blood* / Q000473:pathology / Q000601:surgery; D018572:Disease-Free Survival; D010450:Endopeptidases / Q000097:blood*; D005260:Female; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010446:Peptide Fragments / Q000097:blood*; D011480:Protease Inhibitors / Q000097:blood
D018972:Insulin-Like Growth Factor Binding Protein 3; D010446:Peptide Fragments; D011480:Protease Inhibitors; D007335:Insulin-Like Growth Factor II; D010450:Endopeptidases; C080473:insulin-like growth factor binding protein-3 protease