SUBLETHAL OXIDATIVE STRESS INHIBITS TUMOR-CELL ADHESION AND ENHANCES EXPERIMENTAL METASTASIS OF MURINE MAMMARY-CARCINOMA

We have postulated that murine mammary tumor progression is fueled, in part, by tumor-associated macrophages that deliver sub-lethal oxidati ve stress to tumor cells. In the present study, we determined whether oxidative stress would affect murine mammary tumor cell attachment to laminin and fibronectin, critical functions in the metastatic process, Sublethal oxidative stress generated by exposure of cells to hydrogen peroxide (H2O2, 1-1000 mu M/L) inhibited tumor cell attachment to imm obilized laminin or fibronectin, This oxidant effect was blocked in th e presence of catalase which removes H2O2. The inhibitory effect on at tachment was rapid, with significant inhibition occurring at 5 min; to tal inhibition was achieved at 60 min with 1 mM H2O2. The oxidative st ress effect was partially reversible at 20 h post-treatment and occurr ed at concentrations of H2O2 that do not adversely affect cell viabili ty or growth. Pretreatment of tumor cells with H2O2 Or hypoxanthanine and xanthine oxidase (to generate superoxide radical and H2O2) prior t o intravenous injection, enhanced experimental lung tumor colony forma tion, The enhancement of experimental metastatic potential with enzyme -generated oxidative stress was completely reversed by catalase; the H 2O2-mediated enhancement was only partially reversed with catalase, Th us, treatments that inhibit tumor cell attachment to extracellular mat rix proteins in vitro enhance experimental metastasis in vivo.