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- Jiborn, Thomas
(författare)
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CYSTATIN C AND NEUROENDOCRINE DIFFERENTIATION IN THE MALE REPRODUCTIVE SYSTEM AND IN PROSTATE CANCER
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 3. |
- Secin, Fernando P, et al.
(författare)
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Multi-institutional Study of Symptomatic Deep Venous Thrombosis and Pulmonary Embolism in Prostate Cancer Patients Undergoing Laparoscopic or Robot-Assisted Laparoscopic Radical Prostatectomy
- 2008
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Ingår i: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 53:1, s. 134-145
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The true incidence of symptomatic deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients undergoing laparoscopic radical prostatectomy is unknown. Our aim was to determine the incidence of symptomatic DVT and PE and the risk factors for these complications. METHODS: Fourteen surgeons from 13 referral institutions from both Europe and the United States provided retrospective data for all 5951 patients treated with laparoscopic radical prostatectomy (LRP), with or without robotic assistance, since the start of their institution's experience. Symptomatic DVT and PE within 90 d of surgery were regarded as venous thromboembolism (VTE). DVT was diagnosed mostly by Doppler ultrasound or contrast venography and PE by lung ventilation/perfusion scan or chest computed tomography or both. Statistical analysis included evaluation of incidence of symptomatic DVT and PE and risk factors as determined by exact methods and logistic regression. RESULTS: Of 5951 patients in the study, 31 developed symptomatic VTE (0.5%; 95% confidence interval [CI], 0.4%, 0.7%). Among patients with an event, 22 (71%) had DVT only, 4 had PE without identified DVT, and 5 had both. Two patients died of PE. Prior DVT (odds ratio [OR]=13.5; 95%CI, 1.4, 61.3), current tobacco smoking (OR=2.8; 95%CI, 1.0, 7.3), larger prostate volume (OR=1.18; 95%CI, 1.09, 1.28), patient re-exploration (OR=20.6; 95%CI, 6.6, 54.0), longer operative time (OR=1.05; 95%CI, 1.02, 1.09), and longer hospital stay (OR=1.05; 95%CI, 1.01, 1.09) were associated with VTE in univariate analysis. Neoadjuvant therapy, body mass index, surgical experience, surgical approach, pathologic stage, perioperative transfusion, and heparin administration were not significant predictors. CONCLUSIONS: The incidence of symptomatic VTE after LRP is low. These data do not support the administration of prophylactic heparin to all patients undergoing LRP, especially those without risk factors for VTE.
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| 4. |
- Wegiel, Barbara, et al.
(författare)
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Cystatin C is downregulated in prostate cancer and modulates invasion of prostate cancer cells via MAPK/Erk and androgen receptor pathways
- 2009
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Ingår i: PLOS ONE. - San Francisco : Public Library of Science. - 1932-6203. ; 4:11
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Tidskriftsartikel (refereegranskat)abstract
- Cystatin C is believed to prevent tumor progression by inhibiting the activities of a family of lysosomal cysteine proteases. However, little is known about the precise mechanism of cystatin C function in prostate cancer. In the present study, we examined the expression of cystatin C and its association with matrix metalloproteinases 2 (MMP2) and androgen receptor (AR) in a tissue microarray comparing benign and malignant specimens from 448 patients who underwent radical prostatectomy for localized prostate cancer. Cystatin C expression was significantly lower in cancer specimens than in benign tissues (p<0.001) and there was a statistically significant inverse correlation between expression of cystatin C and MMP2 (r(s) (2) = -0.056, p = 0.05). There was a clear trend that patients with decreased level of cystatin C had lower overall survival. Targeted inhibition of cystatin C using specific siRNA resulted in an increased invasiveness of PC3 cells, whereas induction of cystatin C overexpression greatly reduced invasion rate of PC3 in vitro. The effect of cystatin C on modulating the PC3 cell invasion was provoked by Erk2 inhibitor that specifically inhibited MAPK/Erk2 activity. This suggests that cystatin C may mediate tumor cell invasion by modulating the activity of MAPK/Erk cascades. Consistent with our immunohistochemical findings that patients with low expression of cystatin C and high expression of androgen receptor (AR) tend to have worse overall survival than patients with high expression of cystatin C and high AR expression, induced overexpression of AR in PC3 cells expressing cystatin C siRNA greatly enhanced the invasiveness of PC3 cells. This suggests that there may be a crosstalk between cystatin C and AR-mediated pathways. Our study uncovers a novel role for cystatin C and its associated cellular pathways in prostate cancer invasion and metastasis.
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