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...

Summary Background First-line chemotherapy for patients with cisplatin-ineligible locally-advanced or metastatic urothelial carcinoma (mUC) is associated with short response duration, poor survival, and high toxicity. This multicenter, 2-cohort phase 2 study evaluated atezolizumab (anti–programmed death-ligand 1 [PD-L1]) as treatment for mUC in this setting, as well as in later lines. Methods In a cohort of previously untreated patients who were cisplatin ineligible, atezolizumab was given 1200 mg every 3 weeks until progression. The primary endpoint was independently confirmed objective response rate per Response Evaluation Criteria In Solid Tumors v1.1 (central review), evaluated in pre-specified subgroups based on PD-L1 expression and in all patients. Secondary endpoints included response duration, progression-free survival, overall survival, and safety. Exploratory analyses included biomarker correlates of response and survival. This study is registered with ClinicalTrials.gov, number NCT02108652. Findings Of 119 patients who received atezolizumab in the first-line setting, 83 (70%) had baseline renal impairment, and 24 (20%) had Eastern Cooperative Oncology Group performance status 2. At 17·2 months’ median follow-up, the objective response rate was 23% (95% CI 16–31), the complete response rate was 9%, and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months. Median overall survival was 15·9 months. Tumour mutation load was associated with response. Treatment-related adverse events ≥10% were fatigue, diarrhoea, and pruritus. One treatment-related death (sepsis) occurred. Nine patients (8%) had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients. Interpretation Atezolizumab demonstrated encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated mUC. Funding F. Hoffmann-La Roche Ltd./Genentech, Inc., a member of the Roche Group.

Recent studies have established distinctive serum polypeptide patterns through mass spectrometry (MS) that reportedly correlate with clinically relevant outcomes. Wider acceptance of these signatures as valid biomarkers for disease may follow sequence characterization of the components and elucidation of the mechanisms by which they are generated. Using a highly optimized peptide extraction and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) MS-based approach, we now show that a limited subset of serum peptides (a signature) provides accurate class discrimination between patients with 3 types of solid tumors and controls without cancer. Targeted sequence identification of 61 signature peptides revealed that they fall into several tight clusters and that most are generated by exopeptidase activities that confer cancer type-specific differences superimposed on the proteolytic events of the ex vivo coagulation and complement degradation pathways. This small but robust set of marker peptides then enabled highly accurate class prediction for an external validation set of prostate cancer samples. In sum, this study provides a direct link between peptide marker profiles of disease and differential protease activity, and the patterns we describe may have clinical utility as surrogate markers for detection and classification of cancer. Our findings also have important implications for future peptide biomarker discovery efforts.

Purpose: To better direct targeted therapies to the patients with tumors that express the target, there is an urgent need for blood-based assays that provide expression information on a consistent basis in real time with minimal patient discomfort.We aimed to use immunomagnetic-capture technology to isolate and analyze circulating tumor cells (CTC) from small volumes of peripheral blood of patients with advanced prostate cancer. Experimental Design: Blood was collected from 63 patients with metastatic prostate cancer. CTCs were isolated by the CellSearch system, which uses antibodies to epithelial cell adhesion marker and immunomagnetic capture. CTCs were defined as nucleated cells positive for cytokeratins and negative for CD45. Captured cells were analyzed by immunofluorescence, Papanicolau staining, and fluorescence in situ hybridization. Results: Most patients (65%) had 5 or more CTCs per 7.5 mL blood sample. Cell counts were consistent between laboratories (c = 0.99) and did not change significantly over 72 or 96 h of storage before processing (c = 0.99). Their identity as prostate cancer cells was confirmed by conventional cytologic analysis. Molecular profiling, including analysis of epidermal growth factor receptor (EGFR) expression, chromosome ploidy, and androgen receptor (AR) gene amplification, was possible for all prostate cancer patients with z5 CTCs. Conclusions: The analysis of cancer-related alterations at the DNA and protein level from CTCs is feasible in a hospital-based clinical laboratory. The alterations observed in EGFR and AR suggest that the methodology may have a role in clinical decision making.