Nasal cavity carcinogenesis by N-nitrosamines: a critical appraisal

This review is a critical appraisal of our current knowledge on nasal cavity carcinogenesis by nitrosamines. The pathology and pathogenesis of nitrosamine-induced tumors in the nasal cavity of rodents is summarized while controversies on the underlying molecular mechanisms are discussed in more detail. Investigations on the distribution of metabolically competent cell types, the cellular site(s) of nitrosamine metabolism, as well as reports on the cellular distribution and persistence of DNA-adducts strongly suggest that DNA-adducts formed from reactive metabolites are not immediately responsible for the genesis of nasal cavity tumors. A preexisting high proliferative ability has also been suggested as a factor rendering certain cell types more susceptible to the carcinogenic actions of nitrosamines in the nasal cavity. However, this hypothesis has been clearly rejected by more recent investigations. Recent studies have shown that nitrosamines can stimulate the secretion of growth factors via interaction with neurotransmitter receptors in the lungs and that this molecular mechanism is an important factor in determining the histological phenotype of the developing lung tumors. In light of the fact that secretory cells are the main sites of DNA-adduct accumulation and toxic lesions in the nasal cavities of nitrosamine treated rodents, it is suggested that similar mechanisms may mediate the genesis of nitrosamine-induced nasal cavity tumors.