Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH

The tumor microenvironment is characterized by regions of fluctuating and c hronic hypoxia, low pH, and nutrient deprivation. It has been proposed that this unique tissue environment itself may constitute a major cause of the genetic instability seen in cancer. To In investigate possible mechanisms b y which the tumor microenvironment might contribute to genetic instability, we asked whether the conditions found in solid tumors could influence cell ular repair of DNA damage. Using an assay for repair based on host cell rea ctivation of UV-damaged plasmid DNA, cells exposed to hyposia and low pH we re found to have a diminished capacity for DNA repair compared with control cells grown under standard culture conditions. In addition, cells cultured under hypoxia at pH 6.5 immediately after UV irradiation had elevated leve ls of induced mutagenesis compared with those maintained in standard growth conditions. Taken together, the results suggest that cellular repair funct ions mag be impaired under the conditions of the tumor microenvironment, ca using hypermutability. to DNA damage, This alteration in repair capacity ma y constitute an important mechanism underlying the genetic instability of c ancer cells in vivo.