Mitostatin is down-regulated in human prostate cancer and suppresses the invasive phenotype of prostate cancer cells.

MITOSTATIN, a novel putative tumor suppressor gene induced by decorin overexpression, is expressed in most normal human tissues but is markedly down-regulated in advanced stages of mammary and bladder carcinomas. Mitostatin negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27. In this study, we demonstrated that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells not only induced a significant reduction in cell growth, but also inhibited migration and invasion. Moreover, Mitostatin inhibited colony formation in soft-agar of PC3 and LNCaP cells as well as tumorigenicity of LNCaP cells in nude mice. Conversely, targeting endogenous Mitostatin by siRNA and anti-sense strategies in PC3 and DU145 prostate cancer cells enhanced the malignant phenotype in both cell lines. In agreement of these anti-oncogenic roles, we discovered that Mitostatin was absent in ∼35% (n = 124) of prostate tumor samples and its overall reduction was associated with advanced cancer stages. Collectively, our findings indicate that MITOSTATIN may acts as a tumor suppressor gene in prostate cancer and provide a novel cellular and molecular mechanism to be further exploited and deciphered in our understanding of prostate cancer progression.

Prevention of urinary bladder cancer in the FHIT knock-out mouse with Rofecoxib, a Cox-2 inhibitor.

OBJECTIVES: Aberrant or increased expression of cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of many diseases, including cancer. However, the exact mechanism by which COX-2 may influence tumorigenesis has yet to be described. To investigate the chemopreventive role of a COX-2 inhibitor, rofecoxib, in the development of urinary bladder cancer, we studied the effect of this drug in heterozygous and nullizygous fragile histidine triad (FHIT) gene-deficient mice in a chemically induced carcinogenesis model. MATERIALS AND METHODS: Two-hundred eight mice consisting of 50 FHIT +/+, 63 FHIT +/- and 95 FHIT -/-, were divided into five treatment groups and followed up for 15 weeks. Mice were treated with freshly prepared solution of 0.1% or 0.01% N-butyl-N-(-4-hydroxybutyl)-nitrosamine (BBN) in their drinking water and rofecoxib was administered in mouse chow at 150 parts per million concentration. Mice were sacrificed, and accurate histological analysis of the bladder was performed. RESULTS: Rofecoxib treatment significantly reduced the incidence of preneoplastic lesions/bladder tumors (P = 0.016). Comparing the incidence of neoplastic lesions in mice treated with rofecoxib and BBN (22/56, 39.3%) and mice treated only with BBN (32/57, 56.1%), a protective role of rofecoxib on the BBN tumor induction has been observed (P = 0.024). A similar result (P = 0.002) has been reached observing the incidence of mild and moderate dysplasia in mice treated with a lower concentration of BBN (8/16, 50.0% vs. 20/24, 83.3%).Moreover, as previously observed, a significant increase in neoplastic lesions in the FHIT +/- and FHIT -/- vs. FHIT +/+ mice after BBN treatment has been observed (P = 0.003). CONCLUSIONS: These findings suggest that rofecoxib provides a therapeutic defense against bladder carcinogenesis in our model and confirmed that the FHIT knock-out mouse is a suitable system to study in vivo bladder carcinogenesis.

Leukocyte subtypes in electroejaculates of spinal cord injured men.

OBJECTIVES: To determine the level of leukocytospermia and seminal leukocyte subtypes in men with spinal cord injury (SCI) and to compare the findings with those of fertile, able-bodied controls. DESIGN: Prospective, controlled clinical trial. SETTING: University infertility practice. PARTICIPANTS: Thirteen able-bodied fertile men age matched to 17 men with SCI seeking reproductive rehabilitation. INTERVENTIONS: Vibratory stimulation and antegrade electroejaculation for SCI group; manual ejaculation for controls. MAIN OUTCOME MEASURES: Immunoperoxidase technique on a panel of antileukocyte monoclonal antibodies to obtain the leukocyte subpopulations: B cells, T cells, neutrophils, and macrophages. Immunohistochemical staining and scoring to obtain the mean number of leukocytes and spermatozoa per high power field. The ratios of leukocyte to sperm and leukocyte subtype to sperm were tabulated. RESULTS: Total white blood cells, neutrophils, and macrophages in the SCI population were significantly higher than those in the ejaculates of controls. Although not significantly elevated, all the other evaluated subsets were higher in the SCI group then in the controls. CONCLUSIONS: Leukocytospermia appears to be a pervasive abnormality in the semen recovered from men with SCI. The SCI group had significant elevations of total seminal leukocytes after electroejaculation. Compared with controls, men with SCI had significantly more seminal neutrophils and macrophages. Asthenospermia, universally observed in men with SCI, may be attributable, among other causes, to leukocytospermia.