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tabuc3
1
Department of Biochemistry, and Molecular Biology, Jo
ef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia,
2
Research and Development Division, KRKA, d.d., 8000 Novo mesto, Slovenia,
3
Institute of Oncology, 1000 Ljubljana, Slovenia,
4
Finsen Laboratory, Rigshospitalet, Copenhagen 2100, Denmark
a Author for correspondence.etters
Cystatin C has recently been shown to be an accurate marker of glomerular filtration rate with advantages over serum creatinine(1, 2). Cystatin C, a potent inhibitor of cysteine proteases, is found mainly in extracellular fluids such as blood, cerebrospinal fluid, and seminal plasma. Its low molecular weight and stable production rate indicate that the blood concentration of cystatin C is determined mainly by glomerular filtration. The production rate of cystatin C is less altered by nonrenal factors than is the production of creatinine, and it has been reported that circulating cystatin C concentrations are not affected by inflammatory conditions or malignancy (3). Our observations, however, have revealed a significant correlation between increased serum cystatin C and malignant progression in melanoma and colorectal cancer.
In malignancy, an imbalance between cysteine proteases and their
inhibitors, associated with a metastatic tumor cell phenotype, is
thought to facilitate tumor cell invasion and metastasis
(4). Numerous studies have provided evidence of substantial
increases in mRNA, protein, and the activity of tumor cysteine
proteases, accompanied by only moderately increased or unchanged
concentrations of intracellular inhibitors (5). Enhanced
extracellular secretion of cysteine proteases is another feature
associated with tumor cell phenotype. We recently published evidence
that high serum concentrations of the cysteine proteases cathepsins B
and H are of prognostic importance in predicting the rate of death in
colorectal (6) and melanoma cancer (7). These
high concentrations were balanced by increased serum cystatin C, which
in addition to kininogens and 
2-macroglobulin is the
most important inhibitor for controlling the proteolytic activity of
extracellular cysteine proteases. In melanoma we found significant
increases (P = 0.02) in the cystatin C concentration
among patients with metastatic disease and smaller increases in
patients with primary melanoma (Fig. 1
), indicating the up-regulation of cystatin C in later events of
tumor progression. In colorectal cancer, serum concentrations of
cystatin C were significantly increased (P <0.0001) in
patients at all Dukes stages, correlating weakly with patient age and
gender (unpublished data). The correlation between cystatin C and
creatinine serum values (7), however, was much weaker in
cancer patients than that reported for healthy controls (3),
suggesting the influence of nonrenal factors on the concentration of
cystatin C in malignant sera. The creatinine values, not significantly
changed in cancer patients, suggest that patients' renal function had
not been altered at the time of sample collection.
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In our opinion the number of patients included in previous studies was too low to provide relevant information about changes in the cystatin C serum concentration during malignant progression. The results of our studies, which involved 401 patients with colorectal cancer, 97 patients with melanoma, and 124 healthy controls, strongly support the need for further evaluation of cystatin C as a marker for glomerular filtration rate determination, at least in cancer patients, to determine its potential for use in clinical practice.
References
ovec M, Christensen IJ, Cimerman N, Stephens RW, Brünner N. Prognostic values of cathepsin B and carcinoembryonic antigen in sera of patients with colorectal cancer. Clin Cancer Res 1998;4:1511-1516.
[Abstract]
tabuc B, Schweiger A, Kraovec M, Cimerman N, Kopitar-Jerala N, Vrhovec I. Cathepsins B, H, L, their inhibitors stefin A and cystatin C in sera of melanoma patients. Clin Cancer Res 1997;3:1815-1822.
[Abstract]
The following articles in journals at HighWire Press have cited this article:
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  J. P. Sokol and W. P. Schiemann Cystatin C Antagonizes Transforming Growth Factor {beta} Signaling in Normal and Cancer Cells Mol. Cancer Res., March 1, 2004; 2(3): 183 - 195. [Abstract] [Full Text] [PDF]
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 O. F. Laterza, C. P. Price, and M. G. Scott Cystatin C: An Improved Estimator of Glomerular Filtration Rate? Clin. Chem., May 1, 2002; 48(5): 699 - 707. [Abstract] [Full Text] [PDF]
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G. Filler, F. Priem, N. Lepage, P. Sinha, I. Vollmer, H. Clark, E. Keely, M. Matzinger, A. Akbari, H. Althaus, et al. {beta}-Trace Protein, Cystatin C, {beta}2-Microglobulin, and Creatinine Compared for Detecting Impaired Glomerular Filtration Rates in Children Clin. Chem., May 1, 2002; 48(5): 729 - 736. [Abstract] [Full Text] [PDF]
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R. P. Woitas, B. Stoffel-Wagner, S. Flommersfeld, U. Poege, P. Schiedermaier, H.-U. Klehr, U. Spengler, F. Bidlingmaier, and T. Sauerbruch Correlation of Serum Concentrations of Cystatin C and Creatinine to Inulin Clearance in Liver Cirrhosis Clin. Chem., May 1, 2000; 46(5): 712 - 715. [Full Text] [PDF]
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B. Stabuc, L. Vrhovec, M. Stabuc-Silih, and T. E. Cizej Improved Prediction of Decreased Creatinine Clearance by Serum Cystatin C: Use in Cancer Patients before and during Chemotherapy Clin. Chem., February 1, 2000; 46(2): 193 - 197. [Abstract] [Full Text] [PDF]
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D. Newman and J. Kos More on Cystatin C • One of the authors of the article cited above responds: Clin. Chem., May 1, 1999; 45(5): 718 - 719. [Full Text] [PDF]
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