Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function

Cancer cachexia is a multifactorial syndrome characterized by anorexia, weight loss and muscle wasting that impairs patients' quality of life and survival. Aim of this work was to evaluate the impact of either autophagy inhibition (knocking-down beclin-1) or promotion (overexpressing TP53INP2/DOR) on cancer-induced muscle wasting. In C26 tumor-bearing mice, stress-induced autophagy inhibition was unable to rescue the loss of muscle mass and worsened muscle morphology. Treating C26-bearing mice with formoterol, a selective β2-agonist, muscle sparing was paralleled by reduced static autophagy markers although the flux was maintained. Conversely, the stimulation of muscle autophagy exacerbated muscle atrophy in tumor-bearing mice. TP53INP2 further promoted atrogene expression and suppressed mitochondrial dynamics-related genes. Excessive autophagy might impair mitochondrial function through mitophagy. Consistently, tumor-induced mitochondrial dysfunction was detected by reduced ex vivo muscle fiber respiration. Overall, the results evoke a central role for muscle autophagy in cancer-induced muscle wasting

Recent trends in the use of radical prostatectomy in England: the epidemiology of diffusion

OBJECTIVE To describe recent trends in the use of radical prostatectomy (RP) in England, as there is currently no consensus on the most effective treatment for localized prostate cancer, although RP is the treatment of choice among urological surgeons for men aged < 70 years. METHODS Routine data were assessed to establish the number of RPs performed in England in 1991–99. Age-standardized operation rates were compared by region and socio-economic group, and the geographical spread of use mapped. RESULTS The number of RPs performed annually increased nearly 20-fold between 1991 and 1999. Rates of surgery were greatest in the London National Health Service (NHS) regions and lowest in the Trent region. Outside London, the risk of surgery in a NHS hospital was significantly greater for men living in the least deprived areas; in London this trend was reversed. CONCLUSION Rapid increases in the use of RP showed marked regional variations, most likely related to access to prostate-specific antigen testing and the location of surgeons able to carry out radical surgery. By 1999, a third of procedures were still being undertaken in 'low-volume' hospitals, with implications for the quality of care and outcomes. Crucially, these developments occurred in the absence of robust information about the effectiveness of RP. Recent funding of a randomized trial of treatment options in this area is welcome, but wider questions remain about the timing of the evaluation of surgical technologies

The tumor suppressor activity of IKKα in stratified epithelia is exerted in part via the TGF-β antiproliferative pathway

The transforming growth factor type β-1 (TGF-β) signaling pathway is a major tumor suppressor during early carcinogenesis, and its growth-suppressive activity is commonly lost during early tumor progression. IκB kinase α (IKKα) also acts as a tumor suppressor in stratified epithelia, and its expression and nuclear localization are progressively down-regulated during malignant progression of squamous cell carcinoma (SCC) and acquisition of an invasive phenotype. A critical role for IKKα in TGF-β signaling in stratified epithelia was identified recently during normal keratinocyte differentiation, and both IKKα and components of the TGF-β signaling pathway are required for induction of antiproliferative Myc antagonists in such cells. We now describe that the interaction between IKKα and the TGF-β signaling pathway is also important in a subset of SCCs. In SCCs that are unable to shuttle IKKα to the nucleus, defective TGF-β-induced growth arrest was rescued by introduction of a constitutively nuclear IKKα variant. These results suggest that the tumor-suppressive activity of IKKα in stratified epithelia may be exerted in part via the TGF-β signaling pathway