For this project our group will continue using non-small cell lung cancer. NSCLC metastasizes to the adrenal gland, bone, brain, liver and the other lung. For a tumor cell to grow and expand into other cells it needs a stable blood supply and a hypoxic environment. In tumor cells, hypoxia is regulated by hypoxia-induced factor 1 alpha. HIF1α can be translocated to the nucleus, bind with HIF1β and increase transcription of vascular endothelial growth factor (VEGF). VEGF leads to the formation of more blood vessels which supply the tumor cells with more nutrients.
Hypoxia also stimulates growth factors such as IGF and EGF which inhibit apoptosis. Cells can also escape death in the hypoxic areas by reducing cell division and lowering their metabolism. Tumor cells also have their own level of selection occurring. After generations of cell formation, the cells in the hypoxic areas are the ones that can survive hypoxia based apoptosis. These tumors will have a more aggressive phenotype and be significantly harder to treat than their earlier stage counterparts.
HIF1α can initiate apoptosis but can be overwhelmed in the hypoxic environment. HIF1α has the ability to release proapoptotic proteins such as BNIP3 to stabilize p53 and start the process of apoptosis. However, during hypoxia, IAP-2, an antiapoptotic protein is released. This neutralizes BNIP3 and other proapoptotic protein such as BAX are down regulated. Our goal is to reduce the level of hypoxia in the environment for HIF1α to perform apoptosis while IAP-2 cannot function.