Solid tumors display an altered microenvironment (such as regions of ischemia), primarily due to insufficient vascular supply. Recent studies have suggested that DNA repair is impaired under hypoxia and similar conditions, providing a possible mechanism for the known mutagenicity of the tumor microenvironment. Colorectal cancer is a prevalent human neoplasm for which K-ras mutation is a significant, yet not initiating, event. As K-ras mutations frequently arise in established early colorectal cancers, this study explored the possibility that the developing abnormal tumor microenvironment is a significant triggering event. Employing human CRC cell lines with differing mismatch repair and K-ras mutation status, the role of tumor microenvironment in such mutagenesis was evaluated. There was de novo generation of K-ras mutation under in vitro conditions of combined hypoxia and hypoglycemia (but neither alone), and in vivo xenograft tumor growth, with concomitant reduction of expression of the MMR protein MSH2. This image of a tumor xenograft dual stained for an ischemia marker (green) and MSH2 protein (red) shows nearly mutually exclusive localization of both markers. This study thus establishes a novel linkage between a fundamentally important and common genetic event in cancer (activating mutation of the K-ras oncogene) and properties of the tumor microenvironment (hypoxia/ischemia, glucose deprivation), and implies that tumor blood supply and hence vascularity may serve as an important modulator of the efficiency of MMR mechanisms, genetic instability, and rate of oncogenic events in cancer. For details, see the article by Shahrzad et al. on page 8134 of this issue.