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.

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.