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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.

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Fig. 1: Pathological and molecular features of human bladder cancer.
Fig. 2: Major genomic alterations in human bladder cancer.
Fig. 3: Non-tumour cell types implicated in bladder cancer progression.

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Acknowledgements

This work was supported in part by NIH grants CA075115 and CA143971 to D.T.

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L.T., J-F.X., N.A. and J.E.D. contributed to researching data for and writing the article. J.E.D. also substantially contributed to discussion of the content. D.T. contributed to all aspects of the article.

Corresponding author

Correspondence to Dan Theodorescu.

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D.T. is on the scientific advisory board for Urogen. J.E.D. receives compensation from Invitae. The other authors declare no competing interests.

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Nature Reviews Cancer thanks L. Derre, L. Dyrskjøt and C. L. Mendelsohn for their contribution to the peer review of this work.

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Supplementary information

Glossary

Cystoscopy

A process whereby an imaging device is inserted into a patient’s urethra for the purpose of imaging the urethra and bladder lining to look for abnormalities.

Uroplakins

Protein complexes normally expressed on the surface of luminal cells of the bladder and that are an indicator of terminal differentiation. Loss of uroplakin III expression is therefore indicative of disease progression and is correlated with poor prognosis.

Regulons

Groups of genes regulated as a unit and controlled by the same regulatory gene that expresses a protein acting as a repressor or activator.

Gene promoter

Sequence of DNA to which RNA polymerase and transcription factors bind to initiate RNA synthesis of a gene.

Telomere

Cap made of a repetitive nucleotide sequence at the ends of a chromosome to protect it from deterioration.

Plasmacytoid variant

Infiltrating urothelial carcinoma that is characterized by tumour cells that have a striking morphologic resemblance to and immunohistochemical overlap with plasma cells, and that harbours a CDH1 mutation.

Nested variant

A rare neoplasm that is histologically characterized by large numbers of small, closely packed, haphazardly arranged nests of urothelial cells infiltrating the lamina propria and the muscularis propria.

Papillary urothelial carcinomas

Tumours with thin, finger-like growths that start in the bladder lining and extend into the centre of the bladder.

Glandular lesions

An intriguing group of clinically and morphologically diverse neoplasms, encompassing benign processes to malignant growths.

Inverted papillomas

Rare yet benign neoplasms that is are moderate significance due to their similarity to inverted urothelial carcinoma, which has a much more aggressive prognosis.

Complex of proteins associated with Set1

(COMPASS). Methyltransferase protein complex that controls gene transcription by specifically methylating histone H3 on the lysine at position 4 of the protein.

Immune checkpoint inhibitors

(ICIs). A class of therapies (antibodies) that reactivate dormant or exhausted cytotoxic T cells.

Intravesical instillations

Administration of therapeutics directly to the bladder through a soft catheter inserted through the urethra.

Bacillus Calmette–Guérin

(BCG). A live attenuated strain of Mycobacterium bovis. Used as a vaccine against tuberculosis (first given to patients in 1921). Since 1977, it has been used as an immunotherapeutic agent in patients with bladder cancer.

Radical cystectomy

Complete removal of the bladder in cases of advanced muscle-invasive bladder cancer with the aim of removing bladder cancer entirely from the patient.

Androgen deprivation therapy

A clinical approach to inhibit signalling of the hormone androgen, either by chemical or surgical castration, with the goal of preventing androgen-dependent cancer cells from growing.

5α-Reductase

Enzyme that catalyses conversion of testosterone to dihydrotestosterone.

Hydroxyflutamide

An active metabolite of flutamide used as an androgen antagonist.

Urine cytology

A process whereby cells from a patient’s urine are collected and analysed under a microscope to look for cellular abnormalities such as those found in bladder cancer.

Metastatic relapse

Relapse of cancer after treatment with the cancer spreading to distant organs.

Transurethral resection of the bladder

A surgical technique used to harvest tissue samples for pathology analysis and remove non-muscle-invasive bladder cancer tumours.

Photodynamic therapy

A therapy involving localized activation of photosensitive molecules that are selectively taken up by cancer cells, reducing toxicity to normal cells.

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Tran, L., Xiao, JF., Agarwal, N. et al. Advances in bladder cancer biology and therapy. Nat Rev Cancer 21, 104–121 (2021). https://doi.org/10.1038/s41568-020-00313-1

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