Aberrant expression of cystatin C in prostate cancer is associated with neuroendocrine differentiation.
OBJECTIVE
To investigate the expression of cystatin C and the relationship with neuroendocrine differentiation and proliferation in benign and malignant prostatic tissues, as cystatin C, the most important inhibitor of human lysosomal cysteine proteases, is considered to be a major regulator of pathological protein degradation in inflammatory and neoplastic diseases.


METHODS
Immunoreactivity for cystatin C, prostate-specific antigen, Ki-67 and the neuroendocrine marker chromogranin A was examined in whole-mount radical prostatectomy specimens and using tissue microarrays. Cystatin C in tissue homogenates was analysed by Western blotting and enzyme-linked immunosorbent assay (ELISA). The expression and relative levels of cystatin C mRNA were assessed by in situ hybridization and quantitative real-time polymerase chain reaction (QRT-PCR).


RESULTS
The intensity of cystatin C immunostaining in Gleason grade 2 and 3 prostate cancer was significantly higher than in benign prostatic tissues, but decreased significantly with increasing Gleason grades. There was strong expression of cystatin C in neuroendocrine-like cells, which increased significantly with increasing Gleason grades. The Ki-67 immunoreactivity also increased significantly during de-differentiation. In situ hybridization showed staining patterns in concordance with the immunohistochemical results. ELISA showed high concentrations of cystatin C in benign and malignant tissue extracts and QRT-PCR further corroborated that the cystatin C gene is highly expressed in both benign and malignant prostatic tissues.


CONCLUSIONS
There was a significant decrease in the immunohistochemical expression of cystatin C in non-neuroendocrine prostate cancer cells, concomitant with increasing Gleason grades. That there were more strongly cystatin C-positive neuroendocrine-like cells in prostate cancer than in benign prostatic tissue suggests a connection between cystatin C and neuroendocrine differentiation in prostate cancer progression.
Jiborn
Thomas
T
Department of Clinical Sciences, Division of Urological Research and Laboratory Sciences, Malmö University Hospital, Malmö, Sweden. thomas.jiborn@skane.se
Abrahamson
Magnus
M
Gadaleanu
Virgil
V
Lundwall
Ake
A
Bjartell
Anders
A
D000368:Aged; D002471:Cell Transformation, Neoplastic; D053379:Chromogranin A; D002864:Chromogranins / Q000378:metabolism*; D055316:Cystatin C; D015891:Cystatins / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*
C525030:CST3 protein, human; D053379:Chromogranin A; D002864:Chromogranins; D055316:Cystatin C; D015891:Cystatins; D019394:Ki-67 Antigen