The role of ROS/RNS during inflammation-associated.. (ROSCAN)
The role of ROS/RNS during inflammation-associated and sporadic carcinogenesis
Start date: Oct 1, 2011,
End date: Sep 30, 2016
"A link between inflammation and cancer has been suspected over a long period of time and in recent years genetic evidence supporting such notion could be obtained. Several signaling pathways, such as NF-κB and STAT3, could be identified by our group as well as other groups to play important roles during tumor promotion and progression. Chronic inflammation leads to the formation of reactive oxygen and nitrogen species, which are known to cause DNA damage and inactivation of DNA repair mechanisms, thereby presumably inducing tumor-initiating mutations. On the other hand, oxidative stress has been documented to trigger apoptosis and cellular senescence. However, in vivo evidence demonstrating the consequences of increased oxidative stress on tumor development in a distinct genetic model is lacking. Selenoproteins of the glutathione peroxidase and thioredoxin reductase family are important anti-oxidant scavenger systems. Using cell type specific inactivation (epithelial cells an myeloid cells) of several of these family members in various well established and relevant models of inflammation-associated and sporadic colon tumorigenesis we will directly examine the role of these anti-oxidant systems. These models will allow us to genetically determine the outcome of increased lipid peroxidation and accumulation of reactive oxygen species in each cell type and to address whether cancer development is supported or inhibited under such conditions and will help to identify which phase of tumor development is affected. Furthermore, we expect to obtain results that will determine whether increased levels of ROS/RNS found during chronic inflammation are capable of initiating tumorigenesis. Our proposed experiments are supposed to provide fundamental insight into the molecular changes in the tumor microenvironment, which will ultimately help to identify novel strategies to prevent and treat colorectal cancer."
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