Because of our prior studies of the role of antioxidant defense systems in carcinogenesis and inflammation, we began to investigate the origins of pro-inflammatory oxidant stress in tumors and pre-malignant conditions. When these experiments were initiated, potential sources of oxidant production (beyond inflammatory cell infiltrates) in such conditions as pancreatitis or inflammatory bowel disease were not clear. In particular, it did not seem likely that mitochondrial or microsomal metabolism alone could account for the extent of the reactive oxygen production that could be measured in cultured tumor cells; furthermore, if additional sources of oxidant stress in tumors existed, it was unclear what they might be and how they were regulated. We have, therefore, focused our attention on identifying potential sources of reactive oxygen generation in cancer.

Our laboratory has made noteworthy observations regarding the presence, function, and regulation of members of a recently discovered family of NADPH oxidase genes in human malignancies; these oxidases (that generate superoxide and H2O2) appear to contribute significantly to the development of a proliferative, pro-angiogenic milieu both in tumor cells and in their associated microenvironment (Antioxid. Redox Signal. 20: 2873, 2014). The NADPH oxidase 1 isoform plays an essential role in colorectal inflammation, at least in the mouse (Free Rad. Biol. Med. 68: 315, 2014); the dual oxidase 2 isoform contributes to chronic pancreatitis in man (J. Immunol. 190: 1859, 2013); and inhibitors of these oxidases have therapeutic activity against human colon cancers both in vitro and in vivo (Free Rad. Biol. Med. 57: 162, 2013). Our investigations suggest that it might be possible to develop novel therapeutic agents capable of interdicting at least some clinical sources of pro-carcinogenic oxidant stress.