[Stress proteins in prostate cancer. Challenge and promise]. / Stressproteine bei der Pathogenese des Prostatakarzinoms. Herausforderung und Versprechen an die Zukunft.

Therapeutic resistance is the underlying basis for most cancer deaths. Exposure to anticancer therapies induces expression of many stress proteins, including heat shock proteins and clusterin. These molecular chaperones interact with various client proteins to assist in their folding and enhance cellular recovery from stress conditions. Cellular stress and cell death are linked, as the induction of chaperones appear to function at key regulatory points in the control of apoptosis. On this basis and on the role of stress proteins in the regulation of steroid receptors, kinases, caspases, and other protein remodeling events, it is not surprising that molecular chaperones have been implicated in resistance to anticancer treatments. Recently, several chaperones have been reported to be involved in development and progression of hormone-refractory prostate cancer. In this review, we address some of the events initiated by treatment-induced stress and discuss the potential role of chaperone inhibitors in prostate cancer treatment.

The best local therapy for unfavorable risk prostate cancer: the role of surgery.

High-risk prostate cancer has an increased rate of local and systemic recurrence after locally definitive therapy. High-risk prostate cancer is defined by using a combination of pretreatment tumor related factors (prostatic specific antigen [PSA] level, stage, Gleason score, and extent of involved biopsy cores) and by pathological findings. Pretreatment PSA kinetics may allow the identification of more patients at high risk of treatment failure who otherwise would have been included in lower risk groups according to conventional risk assignment systems. Eight months of neoadjuvant androgen deprivation therapy prior to radical prostatectomy has been shown in a randomized trial to significantly reduce rates of positive margins compared to 3 months of therapy; however, no significant difference in PSA recurrence rates is apparent 5 years postsurgery. The use of early chemotherapy in prostate cancer has until recently been limited by lack of evidence of an effective chemotherapeutic agent for more advanced disease. Recent data, confirming a survival advantage of docetaxel based regimes in metastatic disease, has focused attention on the use of early chemotherapy in these men with high-risk disease. The technical requirements of surgery on high-risk patients are now better defined and one challenge for the specialty is to take this knowledge and apply it successfully in the laparoscopic setting. However, the limit of surgery alone in reducing recurrence in high-risk disease from technical advancements has plateaued. In order to take the field forward, successful multimodal treatment strategies are needed to improve the outcomes over surgical monotherapy for high-risk disease. Novel nucleotide therapy targeting the production of cell survival proteins has provided promising phase 1 data in prostate cancer. This experimental therapy has been built on an understanding of the observed effects that androgen deprivation therapy has on cancer cell survival proteins produced during periods of cellular stress.

Comparative genomic hybridization detects multiple chromosomal amplifications and deletions in undifferentiated embryonal sarcoma of the liver.

Undifferentiated embryonal sarcoma (UES) is the third most common hepatic malignancy in children. Previous reports have described a broad range of complex cytogenetic abnormalities in individual cases of hepatic UES. Herein we report the cytogenetic findings of six cases of hepatic UES at our institution analyzed by conventional cytogenetic methods and comparative genomic hybridization (CGH). The CGH demonstrated several chromosomal gains and deletions in each case, but there was no specific abnormality seen in every case. Patterns of chromosomal changes included gains of chromosome 1q (four cases), 5p (four cases), 6q (four cases), 8p (three cases), and 12q (three cases), and losses of chromosome 9p (two cases), 11p (two cases), and chromosome 14 (three cases). The three cases in which CGH showed gains in the 12q region were studied specifically for amplifications of MDM2 and CDK4, two genes that have been shown to be amplified in other soft tissue sarcomas. However, Southern analysis showed no amplification of MDM2 or CDK4 in these three cases. Further analysis will be needed to determine the critical events in the pathogenesis of these malignant pediatric liver tumors.

Isolation and characterization of the eighth component of the bovine complement system.

OBJECTIVE: To isolate and characterize the eighth component of the complement system (C8) in cattle. SAMPLE POPULATION: Fresh plasma obtained from beef cattle. PROCEDURES: Plasma samples were fractionated, using sequential precipitation and ion-exchange and gel-filtration chromatography, to yield C8. The protein was identified throughout the procedure on the basis of its hemolytic function. Electrophoresis in polyacrylamide gels was used to determine molecular weight and composition of polypeptide chains. Reconstitution of classical and alternative complement pathways was used to characterize the hemolytic function of bovine C8. RESULTS: The bovine C8 protein consisted of a disulfide-bonded alpha-gamma heterodimer that was noncovalently associated with a beta chain. Apparent molecular weight of the alpha, beta, and gamma chains under reducing conditions were 66, 61, and 23 kd, respectively. In the classical pathway of activation, bovine C8 and the ninth component of the complement system (C9) had species incompatibility with human C8 and C9 on sheep erythrocyte target cells. CONCLUSIONS: A simple 4-step fractionation procedure provided good yield of bovine C8 from plasma. The isolated protein was structurally comparable to C8 from other species. Purified bovine C8 may be useful in functional hemolytic assays to investigate the roles of complement-mediated lysis in the pathogenesis of inflammatory diseases and the killing of susceptible microorganisms.