CYSTATIN C AND NEUROENDOCRINE DIFFERENTIATION IN THE MALE REPRODUCTIVE SYSTEM AND IN PROSTATE CANCER

Cystatins are endogenous protease inhibitors that regulate the proteolytic activities of family C1 (papain-like) cysteine proteases, such as human cathepsins B, H, K, L, and S. Cystatin C shows the fastest inhibition and the highest affinity of all cystatins towards lysosomal cysteine proteases in general and is widespread in human tissues and body fluids. Alterations in the balance between the cysteine proteases and the cystatins have been associated with cancer cell invasion and metastasis. Neuroendocrine cells, containing growth stimulatory hormones, are found in various degrees in the vast majority of prostatic adenocarcinomas, and neuroendocrine differentiation has been correlated with tumor progression and resistance to hormonal therapy. Recent immunohistochemical studies suggest that there may be a relationship between cystatin C and the neuroendocrine system. The aim of this thesis was to examine cystatin C and neuroendocrine differentiation in the male genital tract and in prostate cancer. RESULTS AND CONCLUSIONS: 1. Cystatin C is highly expressed and widely distributed in benign tissues throughout the male genital tract, indicating that cystatin C is an important local protease inhibitor in these tissues. 2. Cystatin C is produced by prostate cancer cells in vivo and in vitro. 3. The expression of cystatin C is altered in prostate cancer relative to that in benign prostatic tissues, and there is an association between increased cathepsin B / cystatin C ratio and cancer progression and advanced disease. 4. The number of prostatic neuroendocrine cells increases during hormonal treatment, indicating that androgen-deprivation therapy enhances the selection and progression of androgen-independent neuroendocrine tumor cells. 5. Our finding of scattered, strongly cystatin C-positive neuroendocrine-like cells in prostate cancer tissues suggests that cystatin C may be a useful tissue marker for neuroendocrine differentiation in prostate cancer