Impact of therapeutically induced reactive oxygen species and radical scavenging by α-tocopherol on tumor cell adhesion

Many tumor treatment modalities such as ionizing radiation or some chemotherapy induce reactive oxygen species (ROS) resulting in therapeutic cell damage. The aim of this study was to analyze whether such ROS induction may affect the mechanical stability of solid tumor tissue by degradation of the extracellular matrix proteins or by a loss of cell adhesion molecules. Additionally, the protective impact of α-tocopherol treatment on these processes was studied. Experimental DS-sarcomas in rats were treated with a combination of localized 44°C hyperthermia, inspiratory hyperoxia and xanthine oxidase in order to induce pronounced oxidative stress. A second group of animals were pretreated with α-tocopherol. The in vivo expression of E- and N-cadherin, α-catenin, integrins αv, β3 and β5 as well as the expression of the integrin dimer αvβ3 were assessed by flow cytometry. The activity of the matrix metalloproteinases MMP-2 and -9 and the activity of the urokinase-type plasminogen activator (uPA) were determined by zymography. The expression of E-cadherin, the αv-, β3-integrin and the αvβ3-integrin dimer was significantly reduced by ROS induction, an effect which was at least partially reversible by α-tocopherol. N-cadherin, α-catenin and the β5-integrin expression was not affected by ROS. In addition, MMP-2, MMP-9 and uPA activities were markedly reduced immediately after hyperthermia. Whereas 24 h later the effects on MMP-2 and -9 were no longer evident, for uPA the impact of oxidative stress became even more pronounced at this time. These results show that several processes responsible for the structural stability of the tumor tissue are affected by therapeutic ROS generation. Changes in some of the markers assessed suggested a decrease in tissue stability upon ROS induction, whereas others indicated changes which could lead to a more stable tumor cell cluster. Depending on the individual tumor entity ROS may therefore influence the mechanical stability of solid tumors and by this affect metastatic behavior.