Inflammasomes in tumorigenesis: Implications in bladder cancer

The term inflammasome was coined over a decade ago to describe the molecular platform activated by pathogens or stressor molecules where inflammatory caspases are triggered and cleavage of IL-1β takes place. Since then, many efforts have been made to characterize its mechanisms of molecular action. Inflammasome regulation is critical for the maintenance of homeostasis: an imbalance in this fine-tuning is responsible for the establishment of infectious, autoimmune, metabolic and neurodegenerative diseases, besides cancer. The intimate correlation between inflammasome and tumorigenesis is without doubt: inflammation contributes to the establishment of a pro-oncogenic microenvironment where IL-1β exerts a crucial role. Tumor-promoting inflammation is an imprint of the tumor microenvironment and it is principally triggered by tumor-associated macrophages. Scientific evidence concerning the importance of inflammasome in carcinogenesis is not currently supported by a profound knowledge of its actual behavior. Many scientific incongruities raise the hypothesis of a dual role of inflammasome depending on many variables, such as tumor type and surrounding conditions. Considering these premises, dissecting inflammasome behavior during carcinogenesis could provide benefits for diagnostic purposes, on one hand, and for the development of effective therapies, on the other. Recent studies have highlighted the role of inflammasomes in immunosuppression during tumorigenesis and metastatic processes, which suggests that a common therapeutic strategy could be adopted to act on cancer-related inflammation. Inflammasometargeting molecules (IL-1β neutralizing antibodies, recombinant IL-1RN and IL-18 binding protein) have been developed. Studies on caspase-1- targeting molecules are in progress. The real challenge is to understand those specific situations when quenching inflammation is the right choice. Moreover, discriminating inflammasome effects deriving from either infiltrating inflammatory cells or from cancer cells will allow the exploitation of this mechanism towards clinical development. Inflammasomes have been described in almost all malignancies: with regards to tumors, bladder cancer deserves particular attention, since transitional cancer cells have a high immunogenic potential and consistent amounts of myeloid cells infiltrate during cancer onset. Furthermore, immunotherapy with an attenuated form of Mycobacterium tubercolosis (Bacillus Calmette-Guerrin, BCG) is the treatment of choice for non-muscle invasive urothelial carcinoma subtypes after surgery. An increased expression of several inflammasome members has been described in non-muscle invasive urothelial cell carcinoma. Molecular and cellular heterogeneity observed in bladder cancer highlight the importance of characterizing inflammatory molecular networks favoring tumor growth and progression. In this chapter we will focus on inflammasome involvement in carcinogenesis, with particular emphasis on bladder cancer.