Urothelial bladder cancer progression: lessons learned from the bench

Urothelial bladder carcinoma(UBC)is an intricate malignancy with a variable natural history and clinical behavior.Despite developments in diagnosis/prognosis refi nement and treatment modalities,the recurrence rate is high,and progression from non-muscle to muscle invasive UBC commonly leads to metastasis.Moreover,patients with muscle-invasive or extra-vesical disease often fail the standard chemotherapy treatment,and overall survival rates are poor.Thus,UBC remains a challenge in the oncology fi eld,representing an ideal candidate for research on biomarkers that could identify patients at increased risk of recurrence,progression,and chemo-refractoriness.However,progress toward personalized medicine has been hampered by the unique genetic complexity of UBC.Recent genome-wide expression and sequencing studies have brought new insights into its molecular features,pathogenesis and clinical diversity,revealing a landscape where classical pathology is intersected by the novel and heterogeneous molecular groups.Hence,it seems plausible to postulate that only an integrated signature of prognostic/predictive biomarkers inherent in different cancer hallmarks will reach clinical validation.In this review,we have summarized ours and others’research into novel putative biomarkers of progression and chemoresistance that encompass several hallmarks of cancer:tumor neovascularization,invasion and metastasis,and energy metabolism reprogramming of the tumor microenvironment.

Reduction of Tat-interacting Protein 30 Expression Could be a Prognostic Marker in Bladder Urothelial Cancer

Background： Tat-interacting protein 30 （TIP30） has been reported to be a tumor suppressor, with reduced or absent expression in various tumors. However, its role in bladder urothelial cancer （BUC） has not been investigated. Therefore, herein, we investigated the expression of T1P30 protein in BUC and normal bladder mucosa and the clinical significance of TIP30 expression in the prognosis of BUC. Methods： We reviewed data from 79 cases of BUC and 15 adjacent tissue samples from 79 patients treated at our institution between 2004 and 2007. TIP30 expression was examined by immunohistochemistry. The relationship between TIP30 expression and tumor stage, histological grade, and survival was analyzed. Differences between groups were evaluated using the t-test or matched-pairs test, and differences in the survival rates were analyzed with the log-rank test. Results： TIP30 protein expression was significantly reduced in BUC tissue （t = -6.91, P 〈 0.05） compared with normal tissue samples, and in invasive bladder cancer （t = 10.89, P 〈 0.05） compared with superficial bladder cancer. TIP30 protein expression differed significantly among different differentiated groups classified either according to the World Health Organization （2004, F = 17.48, P 〈 0.01） or World Health Organization （1973, F = 10.68, P 〈 0.01）. TIP30 protein expression was significantly reduced in high-grade papillary urothelial carcinoma compared with papillary urothelial neoplasm of low malignant potential （P 〈 0.05） and low-grade papillary urothelial carcinoma （P 〈 0.05）. Meanwhile, TIP30 protein expression was significantly reduced in Grade 111 BUC, compared with Grade I （P 〈 0.05） and Grade 11 （P 〈 0.05）. Patients with low T1P30 expression showed a higher incidence of disease progression than those with high TIP30 expression （t - 2.63, P 〈 0.05）. Kaplan-Meier survival analysis showed a strong positive relationship between TIP30 expression and overall survival （OS） （x^2 = 17.29, P 〈 0.05）. Conclusions： TIP30 expression was associated with clinical tumor stage in BUC, suggesting that it might play an important role in disease progression. Furthermore, TIP30 might predict postoperative OS. Thus, its evaluation might be useful lbr predicting prognosis.

What we have learned from urinary bladder cancer models

Urinary bladder cancer(UBC)is a heterogeneous disease with highly variable clinical outcomes and responses to chemotherapy.Despite some advances in the molecular understanding of UBC,this knowledge still has not been translated to the clinic in terms of improvements in the prognosis and treatment of patients.Suitable urinary bladder tumor models representative of the human disease in terms of histology and behavior are needed to study factors involved in tumor initiation,progression and metastasis.Further,accurate model systems would facilitate identification of new therapeutic targets and predictive markers that could lead to optimization of existing therapies and development of new ones.Many established cancer cell lines derived from human urinary bladder tumors representing different grades and stages have been used as experimental models for UBC study.These cell lines reflect some of the genetic and morphologic alterations observed in human urothelial carcinoma and serve as simplified models to study the behavior of cancer cells in vitro.However,their translational potential is limited due to the artificial conditions,in which the cells are maintained,grown and tested.Animal models offer a more complex and realistic model for the establishment,development,and progression of tumors as well as to evaluate new therapeutic approaches.Over the years,the authors'group has worked with several UBC cell lines,established and characterized chemically induced UBC models,and patient-derived xenografts models.In this study,the authors will provide a summary of the UBC models developed by their group,analyze their translational potential and weaknesses,and define areas that remain to be explored.