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Cysteine Proteinase Inhibitors Stefin A, Stefin B, and Cystatin C in Sera from Patients with Colorectal Cancer: Relation to Prognosis¹

Janko Kos², Marta Kraovec, Nina Cimerman, Hans Jørgen Nielsen, Ib Jarle Christensen and Nils Brünner

Joef Stefan Institute, Department of Biochemistry and Molecular Biology, 1000 Ljubljana, Slovenia [J. K.]; KRKA, d.d., Research and Development Division, Department of Biochemical Research and Drug Design, 1000 Ljubljana, Slovenia [J. K., M. K., N. C.]; Hvidovre University Hospital, Department of Surgical Gastroenterology, Hvidovre, Denmark 2650 [H. J. N.]; and Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark 2100 [I. J. C., N. B.]

The levels of cysteine proteinase inhibitors stefin A, stefin B, and cystatin C were determined using ELISAs in sera obtained preoperatively from 345 patients with colorectal cancer and in control sera from 125 healthy blood donors. The levels of stefin A and cystatin C were found to be moderately increased in patient sera (1.4-fold and 1.6-fold, respectively; P < 0.0001), whereas the level of stefin B remained statistically unchanged when compared with controls. The medians were 4.3 ng/ml versus 3.2 ng/ml for stefin A, 1.2 ng/ml versus 1.7 ng/ml for stefin B, and 679 ng/ml versus 425 ng/ml for cystatin C. In patient sera, a weak correlation of cystatin C with age (r = 0.34; P < 0.001) and gender (P = 0.01) was found. Stefin A and cystatin C levels were independent of Dukes’ stage, whereas stefin B correlated significantly with Dukes’ stage, its level being the highest in stage D (P < 0.007). Stefin B and cystatin C correlated with survival, whereas stefin A was not a significant prognostic factor in this study. Using medians as cutoff values, patients with high levels of stefin B and patients with high levels of cystatin C exhibited a significantly higher risk of death than those with low levels of inhibitors (hazard ratio = 1.6; 95% confidence interval, 1.2–2.2; P = 0.002 for stefin B; hazard ratio = 1.3; 95% confidence interval, 1.0–1.8; P = 0.04 for cystatin C). Our results reveal a correlation between high levels of extracellular cysteine proteinase inhibitors and short survival in patients with colorectal cancer, and the data thus support previous studies suggesting a contributing role of protease inhibitors in the progression of cancer.

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