Evidence is gathered that the tumor microenvironment has a profound effect upon tumor cell development. Physiologic stresses of low oxygen (hypoxia), low glucose, and low growth factors are all found within a tumor and can exert selective pressures upon the tumor cell population. Specifically, hypoxia can induce genomic instability, cell cycle arrest, resistance to chemotherapy, apoptosis, and increased production of angiogenic factors; all of which can lead to a more aggressive tumor. In order to determine the mechanism by which hypoxia exerts these effects, novel hypoxia-induced messenger RNAs were identified. The goals of this study are 1) to identify the specific stresses that induce two related, hypoxia-induced messages, 2) to determine the mechanism for their accumulation, and 3) to investigate the role that the protein product plays in the hypoxic phenotype. The experimental design will utilize Northern blots, run-off transcript analysis, message stability studies, expression of mRNAs under heterologous promoters, expression of tagged protein products, and cell biologic investigation for hypoxia-like phenotypes. These studies may provide insight into novel targets for cancer therapy, or novel reagents for cancer-specific gene- therapy.
