One of the major advances in cancer research over the last several decades has been the growing (but still far from universal) recognition that adaptation of the cancer cell to its microenvironment is a driving force in the clonal selection leading to invasive and metastatic disease. In particular, cancer cells are often confronted with a significant reduction in oxygen availability (intratumoral hypoxia), which is a major obstacle to cell survival. Vaupel and Mayer review the clinical studies (many of which were performed by Dr. Vaupel’s group) in which O2 concentrations within cancers were measured directly and found to be reduced compared to surrounding normal tissue, with severe hypoxia correlating with invasion, metastasis, and patient death. Since the pioneering work of Gray and colleagues over a half century ago, radiation biologists have known that intratumoral hypoxia reduces the efficacy of radiation therapy. This resistance is due in part to a reduction in free radical generation in hypoxic tissue after irradiation. However, it is now clear that exposure of cancer cells to hypoxia prior to radiation is associated with reduced radiosensitivity. Moeller, Richardson, and Dewhirst summarize the results of their recent work establishing the effect of changes in gene expression that are mediated by the transcriptional activator hypoxia-inducible factor 1 (HIF-1) on the radiosensitivity of hypoxic cancer cells. The role of hypoxia in cancer has broadened considerably since the time of Gray. It is now appreciated that intratumoral hypoxia affects every major aspect of cancer biology. The other members of the “dream team” of hypoxia researchers that have been assembled for this special issue of Cancer and Metastasis Reviews have each focused on one of these key areas. Bindra, Crosby, and Glazer summarize data concerning the alterations in DNA repair that occur in hypoxic cancer cells and contribute to genetic instability. Barnhart and Simon discuss the properties of cancer stem cells that are promoted by hypoxia. Lukashev, Ohta, and Sitkovsky describe the mechanisms by which hypoxia promotes the evasion of cancer cells from the immune system.

Hypoxia induces two important adaptive responses in most cells. One important response involves the production of vascular endothelial growth factor and other hypoxiainduced angiogenic cytokines that promote increased tissue vascularization, thereby increasing tissue oxygenation. The pioneering work of Folkman led to recognition of the