INSULIN-LIKE-GROWTH-FACTOR (IGF)-BINDING PROTEIN-3 (IGFBP-3) PROTEOLYSIS IN PATIENTS WITH COLORECTAL-CANCER - POSSIBLE ASSOCIATION WITH THEMETASTATIC POTENTIAL OF THE TUMOR

The limited proteolysis of insulin-like growth factor (IGF)-binding pr otein (IGFBP)-3 is a key event in the regulation of endocrine bioavail ability of IGFs. Here, we investigated IGFBP-3 and IGFBP-3 proteolysis in serum from patients with colorectal cancer both before and at diff erent times following surgery. In vivo IGFBP-3 proteolysis, estimated by immunoblot analysis of IGFBP-3 fragments in serum, and in vitro IGF BP-3 protease activity of serum, estimated by a I-125-IGFBP-3 degradat ion assay, allowed us to identify 2 groups of patients (IGF-M vs. IGF- NM) with respect to their status for mobilizing the ICF system, In IGF -M patients, in vivo and in vitro IGFBP-3 proteolysis were significant ly elevated (156% and 181% of the age-matched control pool, respective ly) and accompanied by a decrease in intact IGFBP-3 (38% of the contro l pool). The IGFBP-3 proteolytic processing was further increased in r esponse to surgical ablation of the tumor (mean increase 45-55%), then gradually returned to levels comparable with controls, In contrast, I GF-NM patients exhibited a minimal alteration of in vitro IGFBP-3 prot ease activity and even an inhibition of in vivo IGFBP-3 proteolysis, w hereas intact IGFBP-3 was unaltered when compared with controls. Moreo ver, 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) o f the IGF-NM patients developed a metastatic disease (median duration of follow-up 26 months). Neither elevated amounts of pro-IGF-II nor pr esence of detectable IGFBP-3 protease inhibitors in the circulation co uld 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 co lorectal cancer patients. Int. J. Cancer (Pred. Oncol.) 79:460-467, 19 98, (C) 1998 Wiley-Liss, Inc.