Hypoxia exists in many solid tumors due to the structural and functional abnormality of tumor vasculature. Both clinical and experimental studies have indicated tumor hypoxia as a negative prognostic factor associated with increased metastasis and failure of local control. The purpose of this project is to understand the mechanisms involved in the effect of hypoxia on metastasis. Our hypothesis is that hypoxia can modify the sensitivity of tumor cells to apoptosis through epigenetic changes; the altered apoptotic potential contributes to hypoxia-mediated metastatic efficiency. To test the hypothesis, experiments were performed to investigate the role of apoptosis in hypoxia-enhanced metastases and the molecular mechanisms involved.The studies in this project provide better understanding of hypoxia-promoted tumor progression by revealing that increased metastasis can be due to increased tumor cell survival, which may also contribute to the resistance of some tumors to certain therapies. Although the importance of these mechanisms in hypoxia-enhanced metastatic efficiency need to be further investigated in different tumor types and at different organs, studies in this project underscore the importance of targeting hypoxia-increased tumor cell survival in the treatment for patients with hypoxic tumors.Our initial studies using KHT-C cells identified apoptosis to be a mechanism responsible for the death of tumor cells in lungs, and hypoxia pretreatment increased the survival of lung arrested tumor cells. Additional studies indicated that hypoxia could decrease tumor cell apoptotic potential by suppressing p53 activity through a p53-independent upregulation of Mdm2, thereby increasing tumor cell metastatic efficiency.The role of hypoxia-suppressed p53 in increased tumor cell survival was further investigated using ionizing radiation and/or hyperthermia. The suppression of p53 activity and increased resistance to radiation and/or hyperthermia was observed in KHT-C and SCC VII cells after chronic or cyclic hypoxia pretreatment, but not in HT 1080-GFP cells, in which hypoxia induced, rather than suppressed, p53 activity.Although hypoxia did not suppress p53 activity in HT1080-GFP cells, hypoxia pretreatment still increased their metastatic efficiency. Increased survival of lung arrested cells was again identified to be the responsible mechanism. However, the molecular mechanisms are different from previously identified in KHT-C cells.