Intestinal carcinogenesis: IKK can go all the way

Chronic inflammation has long been suspected to support tumorigenesis in a variety of cancers. The IκB kinase (IKK)/NF-κB pathway is the critical signal transduction pathway regulating inflammation, and loss-of-function studies have demonstrated its involvement in tumorigenesis. In this issue of the JCI, Vlantis et al. present evidence that persistent genetic activation of IKK/NF-κB signaling in intestinal epithelial cells not only accelerates tumorigenesis in models of both carcinogen-and mutation-induced colorectal cancer, but also is sufficient to induce intestinal tumors. Inflammation and colorectal cancerColorectal cancer is one of the most common malignancies and causes of death worldwide.Each year, more than 1.2 million new cases are registered, and it is estimated that approximately 600,000 people die from the disease (1).The etiological factors for colorectal cancer include genetic mutations, chronic inflammation, diet, and lifestyle (2).Among the dietary and lifestyle risk factors that have been defined are a diet rich in unsaturated fats and red meat, consumption of alcohol, and reduced physical activity (2), all of which are associated with the higher incidence of colorectal cancer in developed countries.Critical mutations underlying the pathogenesis of colorectal cancer have been identified by molecular genetic studies.The main targets of genetic change are the oncogene KRAS and several tumor suppressor genes, most prominently adenomatous polyposis coli (APC) and P53 (2, 3).Many observations now indicate that chronic inflammation is important in the pathogenesis of colorectal cancer (2, 4).For example, inflammatory cells are often found infiltrated in human tumors and preneoplastic lesions (5).These cells produce cytokines and chemokines involved in propagation of the inflammatory response and support the growth and survival of premalignant cells (4).In addition, one of the best established rodent models of intestinal carcinogenesis, the azoxymethane/dextran sulfate sodium model (AOM/DSS model), involves the use of a chronic inflammatory stimulant (DSS), which is critically