Serum Cystatin C, a New Marker of Glomerular Filtration Rate, Is Increased during Malignant Progression

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 α2-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0.0001) in patients at all Dukes stages, correlating weakly with patient age and gender (unpublished data).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. Determination of cystatin C in sera of healthy controls and cancer patients, using ELISA as described by Kos et al. (7). Ratio 1:2, not significant; ratio 1:3, P = 0.02; ratio 1:4, P <0.0001. Error bars represent mean + 2 SE. 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.