Effects of Nicotine on Urinary Bladder Carcinogenesis.

Epidemiological evidence has consistently demonstrated an association between tobacco smoking and an increased risk of urinary bladder cancer. However, the specific role of nicotine, independent from established genotoxic carcinogens such as aromatic amines, has not been clarified. This review summarises experimental evidence regarding the carcinogenic effects of nicotine and the underlying molecular mechanisms in urinary bladder carcinogenesis. In a two-stage rat carcinogenesis model, nicotine administration significantly increased the incidence and multiplicity of invasive urothelial carcinoma. In contrast, nicotine treatment alone increased hyperplasia but did not induce the formation of tumors, suggesting that nicotine functions as an enhancing agent for tumorigenesis, rather than as a DNA reactive agent. Mechanistically, nicotine has been shown to induce cell proliferation through two distinct pathways. One involves the activation of nicotinic acetylcholine receptors (nAChRs), particularly the α7 subunit, leading to activation of STAT3 and ERK1/2 signalling pathway. The other involves urothelial cytotoxicity followed by regenerative increased cell proliferation. In addition, cotinine, the major urinary metabolite of nicotine, was found to induce proliferation via nAChRs, without inducing cytotoxicity. These findings indicate that nicotine exposure may contribute to bladder cancer risk through mechanisms involving increased cell proliferation, either due to direct mitogenesis or secondary to cytotoxicity and regeneration.