INFLAMMATION, CHROMOSOMAL INSTABILITY, AND CANCER - THE SCHISTOSOMIASIS MODEL

Evidence is accumulating in support of a role for reactive oxygen spec ies in the etiology of cancer. Inflammatory cells, such as neutrophils , macrophages, and eosinophils, are an important endogenous source of oxygen radicals. Stimulation of these cells by tumor promoters or by f oreign bodies (parasites, bacteria, etc.) causes the release of reacti ve oxygen species. Laboratory studies have shown that genetic damage a nd neoplastic transformation are induced in vitro in cells cocultured with activated inflammatory cells. We have recently begun to study the role of inflammatory reactions in inducing genetic damage in a human population. This paper describes our initial studies of Egyptian patie nts infected with Schistosoma haematobium. This infection induces chro nic inflammation and irritation in the urinary bladder and is associat ed with increased cancer at this site. We describe a recently complete d population study that shows that infected individuals have elevated levels of genetic damage in their bladders, as measured by the exfolia ted cell micronucleus test. Treatment that kills the parasite also red uces the micronucleus frequencies. We also explore the hypothesis that altered sensitivity of clones of cells in these patients to reactive oxygen species could be a force that drives the development of neoplas ia by facilitating clonal expansion. Evidence is presented for the pos sible involvement of loci on chromosome II in controlling the level of chromosomal breakage caused by oxidative damage. We have shown that b ladder carcinoma cells are sensitive to micronucleus induction by prom oter-activated neutrophils and that they can be protected from this da mage by insertion of a normal chromosome 11. Further work is in progre ss to define the source of chromosomal breakage in schistosomiasis pat ients and to begin to develop an understanding of the host factors pro tecting bladder cells in these individuals from genetic damage.