The tumor suppressor PTEN, a critical regulator for multiple cellular processes, is mutated or deleted frequently in various human cancers. Subtle reductions in PTEN expression levels have profound impacts on carcinogenesis. Here we show that PTEN level is regulated by ubiquitin-mediated proteasomal degradation, and purified its ubiquitin ligase as HECT-domain protein NEDD4-1. In cells NEDD4-1 negatively regulates PTEN stability by catalyzing PTEN polyubiquitination. Consistent with the tumor-suppressive role of PTEN, overexpression of NEDD4-1 potentiated cellular transformation. Strikingly, in a mouse cancer model and multiple human cancer samples where the genetic background of PTEN was normal but its protein levels were low, NEDD4-1 was highly expressed, suggesting that aberrant upregulation of NEDD4-1 can posttranslationally suppress PTEN in cancers. Elimination of NEDD4-1 expression inhibited xenotransplanted tumor growth in a PTEN-dependent manner. Therefore, NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53.

Models of bladder tumor progression have suggested that genetic alterations may determine both phenotype and clinical course.We have applied expression microarray analysis to a divergent set of bladder tumors to further elucidate the course of disease progression and to classify tumors into more homogeneous and clinically relevant subgroups. cDNA microarrays containing 10,368 human gene elements were used to characterize the global gene expression patterns in 80 bladder tumors, 9 bladder cancer cell lines, and 3 normal bladder samples. Robust statistical approaches accounting for the multiple testing problem were used to identify differentially expressed genes. Unsupervised hierarchical clustering successfully separated the samples into two subgroups containing superficial (pT a and pT 1 ) versus muscle-invasive (pT 2 -pT 4 ) tumors. Supervised classification had a 90.5% success rate separating superficial from muscle-invasive tumors based on a limited subset of genes. Tumors could also be classified into transitional versus squamous subtypes (89% success rate) and good versus bad prognosis (78% success rate). The performance of our stage classifiers was confirmed in silico using data from an independent tumor set. Validation of differential expression was done using immunohistochemistry on tissue microarrays for cathepsin E, cyclin A2, and parathyroid hormone^related protein. Genes driving the separation between tumor subsets may prove to be important biomarkers for bladder cancer development and progression and eventually candidates for therapeutic targeting.

BACKGROUND. By using the age‐adjusted Charlson comorbidity index (ACCI), the authors characterized the impact of age and comorbidity on disease progression and overall survival after radical cystectomy (RC) for transitional cell carcinoma of the bladder. Also evaluated was whether ACCI was associated with clinicopathologic and treatment characteristics. METHODS. The authors evaluated 1121 patients treated by RC for transitional cell carcinoma of the bladder at a single institution (1990–2004). Logistic regression was used to determine the relation between ACCI and clinical features. They evaluated the association between ACCI and overall and progression‐free survival by using multivariate survival‐time models with pathologic stage and nodal status as covariates. RESULTS. ACCI scores increased during the study period (P = .009). Extravesical disease was present in 43% of patients with ACCI ≤2, 49% with ACCI 3–5, and 56% with ACCI >5 (P = .051). Despite their higher prevalence of extravesical disease, patients with higher ACCI were less likely to have lymph‐node dissection (odds ratio, 0.55 and 0.35, respectively, for ACCI 3–5 and >5 vs ≤2; P = .005), and when it was performed, fewer lymph nodes were evaluated (P < .0005). Patients with higher ACCI were also less likely to have postoperative chemotherapy (odds ratio, 0.70 and 0.66, respectively, for ACCI 3–5 and >5 vs ≤2; P = .04). Higher ACCI was significantly associated with lower overall (P < .005) but not recurrence‐free (P = .17) survival after RC. CONCLUSIONS. Age and comorbidity among patients who underwent RC at a cancer referral hospital increased with time. Both age and comorbidity were associated with treatment selection and survival and should, therefore, be considered when comparing outcomes after RC. Cancer 2008. © 2008 American Cancer Society.

BACKGROUND. Perioperative cisplatin‐based chemotherapy has shown benefit in patients with high‐risk localized urothelial bladder cancer, but it is not widely used. Renal impairment may be a major factor limiting its use. The current study was designed to determine the proportion of patients ineligible to receive adjuvant cisplatin‐based chemotherapy based on inadequate renal function alone. METHODS. Patients who underwent radical cystectomy for urothelial cancer of the bladder with evidence of extravesical disease (≥pT3 or any N+) were identified. Patients who received neoadjuvant chemotherapy were excluded. Serum creatinine immediately before and nadir serum creatinine after cystectomy were used to calculate creatinine clearance (CrCl) or glomerular filtration rate (GFR) using the Cockroft‐Gault (CG), Jelliffe, and Modification of Diet in Renal Disease (MDRD) study formulas. A cutoff of CrCl <60 mL/min or GFR <60 mL/min/1.73 m2 was used to determine ineligibility for cisplatin‐based chemotherapy. The proportion of patients ineligible by each formula was compared by univariate logistic regression. Univariate linear regression was performed to determine the effect of age on CrCl or GFR. RESULTS. Most patients were pT3 or greater; 39% were lymph node‐positive. The overall proportion of patients ineligible for cisplatin‐based chemotherapy was 28% by the CG formula, 52% by Jelliffe, and 24% by MDRD. Concordance between formulas was low. With all formulas the probability of ineligibility increased with age: by the CG equation, >40% of patients age >70 years were ineligible. CONCLUSIONS. The widespread use of cisplatin‐based perioperative chemotherapy in patients with high‐risk localized bladder cancer may be significantly limited by the high prevalence of baseline renal insufficiency in this population. This finding is most striking in the elderly. Better selection of patients who may safely receive cisplatin and more effective regimens devoid of cisplatin are required to optimize outcomes in this group of patients. Cancer 2006. © 2006 American Cancer Society.

Purpose To assess the association of lymphovascular invasion (LVI) with cancer recurrence and survival in a large international series of patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). Patients and Methods Data were collected on 1,453 patients treated with RNU at 13 academic centers and combined into a relational database. Pathologic slides were rereviewed by genitourinary pathologists according to strict criteria. LVI was defined as presence of tumor cells within an endothelium-lined space. Results LVI was observed in 349 patients (24%). Proportion of LVI increased with advancing tumor stage, high tumor grade, presence of tumor necrosis, sessile tumor architecture, and presence of lymph node metastasis (all P < .001). LVI was an independent predictor of disease recurrence and survival (P < .001 for both). Addition of LVI to the base model (comprising pathologic stage, grade, and lymph node status) marginally improved its predictive accuracy for both disease recurrence and survival (1.1%, P = .03; and 1.7%, P < .001, respectively). In patients with negative lymph nodes and those in whom a lymphadenectomy was not performed (n = 1,313), addition of LVI to the base model improved the predictive accuracy of the base model for both disease recurrence and survival by 3% (P < .001 for both). In contrast, LVI was not associated with disease recurrence or survival in node-positive patients (n = 140). Conclusion LVI was an independent predictor of clinical outcomes in nonmetastatic patients who underwent RNU for UTUC. Assessment of LVI may help identify patients who could benefit from multimodal therapy after RNU. After confirmation, LVI should be included in staging of UTUC.