Editorial [Hot Topic: Hypoxia and Tumor Progression (Guest Editors: Ranjit S. Bindra and Peter M. Glazer) Introduction: The Evolving Picture of the Hypoxic Tumor Microenvironment]

Hypoxia is a common feature of solid tumors, with significant effects on the responses to both chemotherapy and radiotherapy. It has now been well established that hypoxia is associated with a poor prognosis in multiple tumor types, and several mechanisms underlying this association have emerged over the last decade. Hypoxia appears to induce a diverse range of molecular changes in the tumor microenvironment that are manifested at the DNA, RNA and protein level, all of which contribute significantly to the unique, “hypoxic phenotype”. At the DNA level, hypoxia is associated with numerous genetic mutations and aberrations, which are in part a result of dynamic changes in the expression of key DNA repair genes. At the RNA level, it is now apparent that hypoxia induces both the transcriptional expression and repression of myriad target genes, and importantly, this regulation occurs via both HIF-dependent and -independent pathways. Finally, at the protein level, it is now clear that hypoxia alters the translation and post-translational stability of numerous proteins involved in diverse regulatory pathways. In this issue of Current Molecular Medicine, we present a series of reviews that address the multifaceted role of hypoxia in tumor progression and its clinical implications. Chan, Koch, and Bristow summarize data regarding the regulation of double-strand break (DSB) repair by hypoxia. In particular, they discuss the effects of both short-term and prolonged hypoxia on the two major DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ). The exciting potential for developing new agents specifically targeting these hypoxia-induced defects in HR and NHEJ is also discussed by the authors. In addition to HIFs, numerous other transcription factors appear to be specifically induced by hypoxia, thus highlighting the complexity of the transcriptome response to hypoxia. Ye and Koumenis discuss one such protein, ATF4, a basic leucine-zipper transcription factor involved in amino acid metabolism, regulation of cellular redox state, and anti-stress responses. Based on analyses of clinical tumor tissue, the authors propose that ATF4 plays a role in the adaptive response to hypoxia in the tumor microenvironment.