Tumor hypoxia and heterogeneity: Challenges and opportunities for the future

Many human tumors contain a significant fraction of hypoxic cells that can directly affect responsiveness to therapy. Evidence is increasing that hypoxia may also contribute to malignant progression through effects on signal transduction pathways and regulation of transcription of various genes. New methods for detecting and mapping tumor hypoxia are being applied to directly assess the significance of hypoxia in relation to biological characteristics and responsiveness to therapy. Knowledge of which tumors are hypoxic is being used to test new therapies to exploit hypoxia, such as with new bioreductive drugs that are selectively cytotoxic in hypoxic environments. Recent advances in fundamental research are showing mechanisms and intracellular pathways involved in regulating cellular responses to hypoxia and reoxygenation. Response to hypoxic stress involves altering the expression of specific genes. Several different classes of hypoxic stress proteins have been identified. These include glucose regulated proteins that function as 'chaperones' in protein processing, glycolytic enzymes that maintain energy metabolism under anerobic conditions, proteins involved in oxidative stress responses and maintaining radox homeostasis, various transcription factors, including protooncogenes and suppressor genes, and molecules involved in the regulation of growth signal transduction pathways. There are many challenges and opportunities for basic research and translational research to apply this fundamental knowledge to the clinic.