What causes bladder cancer?

Updated: Apr 03, 2019
  • Author: E Jason Abel, MD; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
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The etiology of bladder cancer, a frequent indication for bladder resection, is unknown. Postulated theories include environmental carcinogens (eg, chemicals, ultraviolet light, radiation), aberration of normal cell growth regulation (eg, oncogene induction, suppressor gene negation), and abnormalities in the genetic composition of malignant cells.

Chemical exposures that may increase the risk of bladder cancer include aromatic amines, dietary nitrites, and nitrates. These include aniline dyes (eg, 2-naphthylamine, 4-aminobiphenyl, 4-nitrobiphenyl, 4-4-diaminobiphenyl [benzidine], 2-amino-1-naphthol), combustion gases, coal soot, chlorinated aliphatic hydrocarbons, and acrolein dyes. Smoking is associated with an up to 4-fold increase in the risk of bladder cancer. Other implicated factors include coffee and tea, phenacetin (an analgesic), chronic cystitis, the presence of chronic indwelling catheters, bladder calculi, pelvic irradiation, and exposure to cyclophosphamide. Schistosomiasis of the urinary bladder is associated with a higher incidence of squamous cell carcinoma. Currently, no evidence links bladder cancer to heredity.

Recent investigations have addressed the arsenic content of drinking water. International studies in Taiwan, Chile, and Argentina have suggested that as little as 10.1 mcg/L of arsenic in drinking water increases the risk. [4, 5] In Taiwan, population studies of 8102 residents found that concentrations of 10-50, 50-100, and more than 100 mcg/L of arsenic in drinking water (compared with levels < 10 mcg/L) increase the relative risk of developing transitional cell carcinoma to 1.9, 8.2, and 15.3, respectively. [4] In Chile, studies of arsenic levels from 100-570 mcg/L revealed an elevated standardized mortality ratio of bladder cancer of 6 in men and 8.2 in women. [5] In the United States, it is estimated that 350,000 persons are exposed to arsenic levels of more than 50 mcg/L and that 2.5 million are exposed to levels higher than 25 mcg/L. In one study, the relative risk estimate for an average level of arsenic in US drinking water was 1 in 1000 persons. [6]

Oncogenes and tumor suppressor genes implicated in bladder cancer include TP53, retinoblastoma gene (Rb), p15, and p16. Alterations in TP53, a normal tumor suppressor gene found on chromosome 17p which controls apoptosis, lead to more aggressive bladder cancers. Ongoing studies are exploring the clinical implications of these tumor suppressor genes. Currently, conventional staging and grading are sufficient.

The tumor suppressor gene, Rb, is found on chromosome 13q. A mutated Rb gene or phosphorylated Rb gene leads to dissociation of its product protein, pRB, from the normally complexed transcription factor, E2F. Dissociated E2F drives the transition from G1 to S phase in cellular mitosis.

Two more protein regulators encoded on chromosome 9p, p15 and p16, inhibit nuclear cyclin-dependent kinases from phosphorylating pRB. When p15 and p16 mutate, they can no longer prevent phosphorylation of pRB, resulting in dissociation of the pRB-E2F complex, and free E2F is allowed to stimulate the cell's G1- to S-phase proliferation. Very aggressive high-grade bladder tumors have been associated with alterations in TP53. Mutations in Rb, p15, and p16 have been associated with low-grade superficial tumors.

Bladder cancer often behaves as a field disease; the entire urothelium, from the renal pelvis to the urethra, is susceptible to malignant transformation. Urothelial carcinoma cells may also have the ability to migrate and implant at different sites along the urothelium.

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