Tumor Heterogeneity and Consequences for Bladder Cancer Treatment

SIMPLE SUMMARY: Bladder cancer is a heterogeneous disease that is composed of epithelia with varying transcriptional, mutational and lineage signatures. The epithelia of bladder tumors can also undergo pronounced changes in transcriptional and phenotypical qualities in response to progression, treatment related stresses and cues from the tumor microenvironment (TME). We hypothesize that changes in epithelial tumor heterogeneity (EpTH) occur due to the evolving content of epithelial subpopulations through both Darwinian and Lamarckian-like natural selection processes. We further conjecture that lineage-defined subpopulations can change through nongenomic and genomic cellular mechanisms that include cellular plasticity and acquired driver mutations, respectively. We propose that such processes are dynamic and contribute towards clinical treatment challenges including progression to drug resistance. In this article, we assess mechanisms that may support dynamic tumor heterogeneity with the overall goal of emphasizing the application of these concepts to the clinical setting. ABSTRACT: Acquired therapeutic resistance remains a major challenge in cancer management and associates with poor oncological outcomes in most solid tumor types. A major contributor is tumor heterogeneity (TH) which can be influenced by the stromal; immune and epithelial tumor compartments. We hypothesize that heterogeneity in tumor epithelial subpopulations—whether de novo or newly acquired—closely regulate the clinical course of bladder cancer. Changes in these subpopulations impact the tumor microenvironment including the extent of immune cell infiltration and response to immunotherapeutics. Mechanisms driving epithelial tumor heterogeneity (EpTH) can be broadly categorized as mutational and non-mutational. Mechanisms regulating lineage plasticity; acquired cellular mutations and changes in lineage-defined subpopulations regulate stress responses to clinical therapies. If tumor heterogeneity is a dynamic process; an increased understanding of how EpTH is regulated is critical in order for clinical therapies to be more sustained and durable. In this review and analysis, we assess the importance and regulatory mechanisms governing EpTH in bladder cancer and the impact on treatment response.