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INTRODUCTION AND OBJECTIVES: Cystoscopy is a standard diagnostic and follow-up tool of bladder cancer (BCa), but it is invasive and painful for patients. Therefore, novel urinary molecular markers which are non-invasive but have a high sensitivity even for lowgrade tumors have been explored. Here, we show an improved accuracy at measuring urinary CXCL1 (uCXCL1) by a newly developed ELISA system and at predicting the presence and prognosis of bladder cancer. METHODS: We produced a monoclonal antibody against human CXCL1 by immunization of BALB/c mice with CXCL1 fusion protein and developed new ELISA system using that antibody. As a first part, CXCL1 levels were determined in the set of urine samples from total of 68 BCa patients (22 of low grade pTa, 21 of high grade pTa, 21 of pT1-pT3 and 4 of pTis), 43 other urological disease control samples and 20 healthy control samples. The sensitivity and specificity of uCXCL1 concentration normalized by urine creatinine (CXCL1/Cre) were compared with those of commercially available markers (NMP22 and BTATRAK). As a second part, urine CXCL1/Cre in 175 patients with BCa was measured and the predictive ability for intravesical recurrence after transurethral resection (TUR) was examined. RESULTS: In the first part, the values of uCXCL1 increased according to stage of BCa. uCXCL1 was superior to NMP22 and BTA in sensitivity (81%, 37% and 79% for CXCL1, NMP22 and BTA, respectively) and had a high specificity (80%, 95% and 60%, respectively). AUC values of ROC curves were 0.875, 0.656 and 0.814 for CXCL1, NMP22 and BTA, respectively. Even for distinguishing BCa with other urological disease subjects, CXCL1 gave higher AUC values (0.633) than the conventional markers (0.514 and 0.621 for NMP22 and BTA, respectively). In the latter part, patients who showed higher CXCL1/Cre were significantly more likely to develop intravesical recurrence after TUR. CXCL1/Cre was also able to separate BCa patients with EORTC intermediate-risk into high and low probabilities of post-TUR recurrence equivalent to EORTC highand low-risk group, respectively. In multivariate analysis, CXCL1/Cre was an independent predictor for postTUR intravesical recurrence (p 1⁄4 0.009). CONCLUSIONS: We showed the usefulness of urinary CXCL1 as a novel urinary molecular marker for BCa detection and prediction of NMIBC recurrence using a new ELISA system, which would be able to reduce the frequency of cystoscopy and compensate for low sensitivity of urinary cytology in BCa patients.

INTRODUCTION AND OBJECTIVES: Given that the harms of prostate (PCa) and breast (BCa) cancer screening may outweigh the benefits for individuals with limited life expectancy, current guidelines do not recommend screening in these individuals. However, there is limited nationwide data addressing the prevalence of nonrecommended screening for PCa and BCa. The objective of this study is to estimate the US nationwide, and state-by-state prevalence of non-recommended PCa and BCa screening in individuals with a life expectancy

More effective therapeutic approaches for castration-resistant prostate cancer (CRPC) are urgently needed, thus reinforcing the need to understand how prostate tumors progress to castration resistance. We have established a novel mouse xenograft model of prostate cancer, KUCaP-2, which expresses the wild-type an- drogen receptor (AR) and which produces the prostate-specific antigen (PSA). In this model, tumors regress soon after castration, but then reproducibly restore their ability to proliferate after 1 to 2 months without AR mutation, mimicking the clinical behavior of CRPC. In the present study, we used this model to identify novel therapeutic targets for CRPC. Evaluating tumor tissues at various stages by gene expression profiling, we discovered that the prostaglandin E receptor EP4 subtype (EP4) was significantly upregulated during progression to castration resistance. Immunohistochemical results of human prostate cancer tissues con- firmed that EP4 expression was higher in CRPC compared with hormone-naive prostate cancer. Ectopic overexpression of EP4 in LNCaP cells (LNCaP-EP4 cells) drove proliferation and PSA production in the ab- sence of androgen supplementation in vitro and in vivo. Androgen-independent proliferation of LNCaP-EP4 cells was suppressed when AR expression was attenuated by RNA interference. Treatment of LNCaP-EP4 cells with a specific EP4 antagonist, ONO-AE3-208, decreased intracellular cyclic AMP levels, suppressed PSA production in vitro, and inhibited castration-resistant growth of LNCaP-EP4 or KUCaP-2 tumors in vivo. Our findings reveal that EP4 overexpression, via AR activation, supports an important mechanism for castration-resistant progression of prostate cancer. Furthermore, they prompt further evaluation of EP4 antagonists as a novel therapeutic modality to treat CRPC. Cancer Res; 70(4); 1606-15. ©2010 AACR.