Major clinical issues in bladder cancer include the identification of prediction markers and novel therapeutic targets for invasive bladder cancer. In the current study, we describe the isolation and characterization of a tumor-initiating cell (T-IC) subpopulation in primary human bladder cancer, based on the expression of markers similar to that of normal bladder basal cells (Lineage-CD44 ؉ CK5 ؉ CK20 ؊ ). The bladder T-IC subpopulation was defined functionally by its enriched ability to induce xenograft tumors in vivo that recapitulated the heterogeneity of the original tumor. Further, molecular analysis of more than 300 bladder cancer specimens revealed heterogeneity among activated oncogenic pathways in T-IC (e.g., 80% Gli1, 45% Stat3, 10% Bmi-1, and 5% ␤-catenin). Despite this molecular heterogeneity, we identified a unique bladder T-IC gene signature by gene chip analysis. This T-IC gene signature, which effectively distinguishes muscle-invasive bladder cancer with worse clinical prognosis from non-muscle-invasive (superficial) cancer, has significant clinical value. It also can predict the progression of a subset of recurring non-muscleinvasive cancers. Finally, we found that CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder T-ICs compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro. In summary, we have identified a T-IC subpopulation with potential prognostic and therapeutic value for invasive bladder cancer.antibody therapy ͉ bladder cancer ͉ cancer stem cell ͉ CD44 ͉ CD47

HE PREVALENCE OF OBESITY IN the United States has dramatically increased in the past decade. 1 Increased body mass index (BMI) has been linked to death from colon, breast, and many other cancers. 2 Although there are biological bases for increased risk of certain cancers in obese persons, 3 delayed diagnosis may provide an explanation for advanced stage of disease and poor outcome. Obesity presents technical problems for cancer detection, since adiposity may hinder physical examination and interfere with imaging and ancillary tests. 4 Likewise, obesity may negatively affect early diagnosis through assessment of serum concentrations of soluble tumor markers. For example, recent evidence suggests that prostate cancer screening may be adversely affected by increased BMI. 5 In the United States, most prostate cancer cases are diagnosed by needle biopsy of the prostate prompted by a high serum prostate-specific antigen (PSA) concentration. The ability to accurately detect prostate cancer can be compromised by any factor that decreases PSA concentration in the circulation. Multiple studies have found that obese men have lower PSA con-Author Affiliations are listed at the end of this article.

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The percentage of obese men undergoing RP in our data set doubled in the last 10 years. Obesity was associated with higher-grade tumors, a trend toward increased risk of positive surgical margins, and higher biochemical failure rates among men treated with RP. A BMI > or = 35 kg/m(2) was associated with a higher risk of failure than a BMI between 30 and 35 kg/m(2).