We previously reported that reactive stroma grading in prostate cancer (PCa) is predictive of biochemical recurrence in prostatectomies and biopsies. In this study, we tested whether quantifying the percentage of reactive stromal grade 3 (RSG 3; stromogenic carcinoma pattern) in the entire tumor is predictive of PCa-specific death. Whole-mount prostatectomies operated by a single surgeon obtained between 1983 and 1998 were reviewed. Reactive stroma was evaluated as described previously, and areas of RSG 3 in the entire tumor were registered as percentages of total tumor. Statistical analysis was performed using Spearman, Kaplan-Meier, and Cox analyses. In all, 872 cases were Prostate cancer (PCa) remains the most common malignancy affecting men and is the second-leading cause of cancer-related death of men in the United States. 1,2 The most accepted and internationally used histological classification to predict the behavior of PCa is the Gleason scoring system. 3-7 Tools such as the Kattan nomogram or the Partin tables combine predictive information to optimize the prediction of time to biochemical recurrence (BCR). 8 -11 However, all of these histological parameters examine the epithelial component of the cancer, and not the interaction between the tumor and the host.The most common histological interaction between the tumor and the native host stroma in many tumors is desmoplasia, or reactive stroma (RS). Reactive stroma in PCa was described in our previous studies and characterized at the phenotypic, 12-15 morphological, 16,17 and genomic levels. 18 We immunophenotyped RS as cells coexpressing vimentin and smooth muscle ␣-actin, with loss of terminal muscle differentiation markers such as desmin and/or calponin. Other studies described RS as a mixture of fibroblasts, myofibroblasts, endothelial cells, and immune cells in breast cancer. 19 -21 We recently demonstrated that RS is promising as a new marker to predict a patient's time to progression in PCa, using both biopsies and tissue microarrays from radical prostatectomy specimens. [12][13][14] To determine whether RS carries predictive information, we charac-

Heat shock protein 90 (HSP90) inhibition is an attractive strategy for cancer treatment. Several HSP90 inhibitors have shown promising effects in clinical oncology trials. However, little is known about HSP90 inhibition-mediated bladder cancer therapy. Here, we report a quantitative proteomic study that evaluates alterations in protein expression and histone post-translational modifications (PTMs) in bladder carcinoma in response to HSP90 inhibition. We show that 5 HSP90 inhibitors (AUY922, ganetespib, SNX2112, AT13387, and CUDC305) potently inhibited the proliferation of bladder cancer 5637 cells in a dose- and time-dependent manner. Our proteomic study quantified 518 twofold up-regulated and 811 twofold down-regulated proteins common to both AUY922 and ganetespib treatment. Bioinformatic analyses revealed that those differentially expressed proteins were involved in multiple cellular processes and enzyme-regulated signaling pathways, including chromatin modifications and cell death-associated pathways. Furthermore, quantitative proteome studies identified 14 types of PTMs with 93 marks on the core histones, including 34 novel histone marks of butyrylation, citrullination, 2-hydroxyisobutyrylation, methylation, O-GlcNAcylation, propionylation, and succinylation in AUY922- and ganetespib-treated 5637 cells. Together, this study outlines the association between proteomic changes and histone PTMs in response to HSP90 inhibitor treatment in bladder carcinoma cells, and thus intensifies the understanding of HSP90 inhibition-mediated bladder cancer therapeutics.

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