Advances in bladder cancer biology and therapy

Abstract

The field of research in bladder cancer has seen significant advances in recent years. Next-generation sequencing has identified the genes most mutated in bladder cancer. This wealth of information allowed the definition of driver mutations, and identification of actionable therapeutic targets, as well as a clearer picture of patient prognosis and therapeutic direction. In a similar vein, our understanding of the cellular aspects of bladder cancer has grown. The identification of the cellular geography and the populations of different cell types and quantifications of normal and abnormal cell types in tumours provide a better prediction of therapeutic response. Non-invasive methods of diagnosis, including liquid biopsies, have seen major advances as well. These methods will likely find considerable utility in assessing minimal residual disease following treatment and for early-stage diagnosis. A significant therapeutic impact on patients with bladder cancer is found in the use of immune checkpoint inhibitor therapeutics. These therapeutics have been shown to cure some patients with bladder cancer and significantly decrease adverse events. These developments provide patients with better monitoring opportunities, unique therapeutic options and greater hope for prolonged survival.

Fig. 1 |. Pathological and molecular features of human bladder cancer.

Urothelial carcinoma of the bladder is comprised of two major groups on the basis of clinical staging with different clinical outcomes and therapy options: non-muscle-invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Staging of urothelial bladder carcinoma is shown according to the tumour, lymph node, metastasis (TNM) system. The UROMOL study classified NMIBC into three classes: class 1, luminal-like signature; class 2, luminal-like, epithelial–mesenchymal transition (EMT) and cancer stem cell signatures; and class 3, basal-like signature. Six subgroups of MIBC are shown: luminal papillary (LumP), luminal non-specified (LumNS), luminal unstable (LumU), stroma-rich, basal/squamous (Ba/Sq) and neuroendocrine-like (NE-like). APOBEC, apolipoprotein B mRNA editing catalytic polypeptide-like family of proteins; FGFR3, fibroblast growth factor receptor 3; UPK, uroplakin; TMB tumour mutation burden.

Fig. 2 |. Major genomic alterations in human bladder cancer.

Whole-transcriptome mRNA profiling of patient samples identified frequently altered genes and pathways that drive bladder cancer (The Cancer Genome Atlas (TCGA)). The data shown in this figure were retrieved from TCGA Pan Cancer Atlas in CBioPortal, and represent the frequency of altered genes in patient samples (n = 406) and the proportions of the different types of alterations per gene. Somatic alterations of genes are most common in pathways related to p53, the cell cycle, receptor tyrosine kinase (RTK)–RAS–PI3K and epigenetic modifications. Alterations in TP53 and cell cycle genes are common in muscle-invasive bladder cancer (MIBC), including CDKN2A, CDKN2B, RB1, STAG2, E2F3, ATM, CDKN1A, ERCC2, MDM2 and FBXW7. Common mutations for TP53 are missense and truncating mutations (frameshift, insertion/deletion and splice site mutation), which induce loss of funtion. Genes limiting cell cycle activity such as CDKN2A, CDKN2B, RB1 and CDKN1A are commonly inactivated by homologous deletion and truncating mutations. Progrowth signalling genes E2F3 and MDM2 commonly exhibit amplification. STAG2 encodes a subunit of the cohesin complex, which regulates sister chromatid separation during cell division and is frequently silenced by truncating mutations in MIBC. ATM encodes a DNA damage sensor protein and exhibits loss of function when mutated (mostly missense and truncating mutations) in 14% of patients with MIBC. The protein product of ERCC2 is involved in nucleotide excision repair, ERCC2 is mutated in 11% of patients with MIBC and missense mutations drive MBIC cisplatin sensitivity. FBXW7 encodes a protein that functions in cell cycle exit and stem cell maintenance and is often found mutated in MIBC. Activating mutations in FGFR3, PIK3CA, ERBB2 and ERBB3 enhance tumour growth. TSC1 negatively regulates mechanistic target of rapamycin complex 1 signalling and the gene is frequently inactivated by truncating mutations. Bladder cancer often has truncating and missense mutations in chromatin remodelling genes such as ARID1A, KDM6A, KMT2D, KMT2C, EP300, CREBBP and ASXL2.

Fig. 3 |. Non-tumour cell types implicated in bladder cancer progression.

Signalling between cancer, stromal and immune cells modulates tumour growth and aggressiveness. Many of these cell types have been correlated with therapeutic resistance and lower survival outcome for patients. Green arrows indicate protumorigenic associations, while red bars indicate antitumour activity. CAF, cancer-associated fibroblast; CCL2, C-C motif chemokine ligand 2; DC, dendritic cell; DC-SIGN, dendritic cell-specific C-type lectin; EMT, epithelial–mesenchymal transition; FAP, fibroblast activation protein; FOXP3, forkhead box protein P3; Gal-9, galectin 9; MDSC, myeloid-derived suppressor cell; TAM, tumour-associated macrophage; TIL, tumour-infiltrating lymphocyte; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor; T_reg cell, regulatory T cell.