Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro 1-3 , but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer 4,5 . Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription 6-10 . Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers nonlethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age. Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, we detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of Pten-deficient tumours.'Cellular senescence' describes a permanent form of cell cycle arrest in primary cultured cells, which can be triggered by DNA damage or activated oncogenes 1-3 . Although it has been implicated in mediating the response to anti-tumour treatments 11 , there is still no evidence that senescence opposes tumorigenesis.Up to 70% of primary prostate tumours lose one PTEN allele and retain the other copy 12-15 . Similarly, p53 is found completely lost or mutated almost exclusively in advanced prostate cancer 16,17 . Because complete loss of Pten in the mouse seems to be crucial for the development of invasive prostate tumours 18,19 , why human invasive prostate cancer wouldCorrespondence and requests for materials should be addressed to P.P.P. (p-pandolfi@ski.mskcc.org). Author Information Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.Supplementary Information is linked to the online version of the paper at www.nature.com/nature. (Supplementary Fig. S1). As expected, in the presence of Pb-Cre4, recombination of Pten and Trp53 was restricted to the three prostatic lobes, namely the anterior prostate (AP), ventral prostate (VP) and dorsolateral prostate (DLP), with minor recombination occurring in seminal vesicles ( Supplementary Fig. S2a). NIH Public AccessTo study early effects of Pten and/or Trp53 inactivation in the prostate, mice were killed at 9 weeks of age and histopathological analysis was performed. Wild-type (WT) mice displayed normal prostate histology, whereas age-matched Pten pc−/− littermate...

Complete inactivation of the PTEN tumor suppressor gene is extremely common in advanced cancer, including prostate cancer (CaP). However, one PTEN allele is already lost in the vast majority of CaPs at presentation. To determine the consequence of PTEN dose variations on cancer progression, we have generated by homologous recombination a hypomorphic Pten mouse mutant series with decreasing Pten activity: Ptenhy/+ > Pten+/− > Ptenhy/− (mutants in which we have rescued the embryonic lethality due to complete Pten inactivation) > Pten prostate conditional knockout (Ptenpc) mutants. In addition, we have generated and comparatively analyzed two distinct Ptenpc mutants in which Pten is inactivated focally or throughout the entire prostatic epithelium. We find that the extent of Pten inactivation dictate in an exquisite dose-dependent fashion CaP progression, its incidence, latency, and biology. The dose of Pten affects key downstream targets such as Akt, p27Kip1, mTOR, and FOXO3. Our results provide conclusive genetic support for the notion that PTEN is haploinsufficient in tumor suppression and that its dose is a key determinant in cancer progression.

Purpose-A postoperative nomogram for prostate cancer recurrence after radical prostatectomy (RP) has been independently validated as accurate and discriminating. We have updated the nomogram by extending the predictions to 10 years after RP and have enabled the nomogram predictions to be adjusted for the disease-free interval that a patient has maintained after RP.Methods-Cox regression analysis was used to model the clinical information for 1,881 patients who underwent RP for clinically-localized prostate cancer by two high-volume surgeons. The model was externally validated separately on two independent cohorts of 1,782 patients and 1,357 patients, respectively. Disease progression was defined as a rising prostate-specific antigen (PSA) level, clinical progression, radiotherapy more than 12 months postoperatively, or initiation of systemic therapy. Results-The 10-year progression-free probability for the modeling set was 79% (95% CI, 75% to 82%). Significant variables in the multivariable model included PSA (P = .002), primary (P < . 0001) and secondary Gleason grade (P = .0006), extracapsular extension (P < .0001), positive surgical margins (P = .028), seminal vesicle invasion (P < .0001), lymph node involvement (P = . 030), treatment year (P = .008), and adjuvant radiotherapy (P = .046). The concordance index of the nomogram when applied to the independent validation sets was 0.81 and 0.79. Conclusion-We have developed and validated as a robust predictive model an enhanced postoperative nomogram for prostate cancer recurrence after RP. Unique to predictive models, the nomogram predictions can be adjusted for the disease-free interval that a patient has achieved after RP.

An existing preoperative nomogram predicts the probability of prostate cancer recurrence, defined by prostate-specific antigen (PSA), at 5 years after radical prostatectomy based on clinical stage, serum PSA, and biopsy Gleason grade. In an updated and enhanced nomogram, we have extended the predictions to 10 years, added the prognostic information of systematic biopsy results, and enabled the predictions to be adjusted for the year of surgery. Cox regression analysis was used to model the clinical information for 1978 patients treated by two high-volume surgeons from our institution. The nomogram was externally validated on an independent cohort of 1545 patients with a concordance index of 0.79 and was well calibrated with respect to observed outcome. The inclusion of the number of positive and negative biopsy cores enhanced the predictive accuracy of the model. Thus, a new preoperative nomogram provides robust predictions of prostate cancer recurrence up to 10 years after radical prostatectomy.

BCR defined as a PSA value of at least 0.4 ng/mL followed by another increase best explains the development of distant metastasis among 10 candidate definitions, after controlling for clinical variables and the use of secondary therapy. On the basis of this evidence, we propose that this definition be adopted as the standard for reporting the outcome of RP.

Predictors of disease specific survival include local disease at presentation, complete tumor resection and tumor grade, size, location and histological subtype. With adequate surgical treatment most patients who presented with primary disease and underwent complete surgical resection achieved prolonged disease specific survival.

Neoadjuvant chemotherapy followed by radical cystectomy and complete pelvic lymph node dissection is the optimal curative strategy in most patients presenting with muscle invasive bladder cancer.

Risk factors for positive soft tissue surgical margins are female gender, locally advanced cancer, presence of vascular invasion and mixed histology. Patients with positive soft tissue surgical margins have poor prognosis, and positive soft tissue surgical margins were found to be independently associated with disease specific death.