This study examined possible mechanisms for
hypoxia-increased
metastasis in a
green fluorescent protein-labeled human
fibrosarcoma cell line (HT1080). The efficiency of the lung arrest of
tumor cells, which can be dependent on the adhesive potential of the
tumor cells, was assessed by measuring the level of
integrin alpha3beta1 protein and by adhesion assays, whereas the extravasation potential was examined by an invasion assay. These properties were not changed by exposure to
hypoxia, indicating that lung arrest and extravasation are unlikely to play a major role in the effect of
hypoxia on
metastasis in this model. The main effect of hypoxic exposure was found to be increased survival after lung arrest as determined by clonogenic assay of
tumor cells recovered from mouse lungs after i.v. injection. Concomitantly, apoptosis was identified as responsible for the death of lung-arrested cells, suggesting the involvement of an altered apoptotic response following hypoxic exposure of these cells. Consistent with this finding, we found that the effect of
hypoxia on both increased
metastasis and survival of arrested cells was inhibited by treatment with
farnesylthiosalicylic acid. However, this effect was not due to down-regulation of
hypoxia-inducible factor-1alpha, a mechanism of action of this
drug reported by previous studies. Further detailed studies of the mechanisms of action of the
drug are needed.