S-6 : Parainflammation in cancer

Abstract

Inflammation has many faces, most commonly observed as an acute reaction in response to pathogen or another insult, or a chronic phase, accompanying chronic infection and chronic remittent inflammatory disease, such as inflammatory bowel disease [1] . Yet, there is another type of smoldering inflammation, harder to notice or monitor, which appears to underlie some of the major human diseases, cancer, diabetes type 2 and certain neurodegenerative diseases [2] . We have developed mouse models of cancer based on inducible CKIa knockout [3] , which exhibit smoldering inflammation, and demonstrate how a low grade, infiltrate-free inflammatory reaction to persistent DNA damage response translates to an aberrant growth. We determined this unusual inflammatory repertoire denoted parainflammation [4] in the knockout mice and gut explants, demonstrated its association with cellular senescence and showed how in the absence of p53, parainflammation is converted from a growth inhibitory to growth promoting mechanism, both in vitro and in vivo. Anti-inflammatory reagents capable of blocking parainflammation reverse a tumor-related crypt proliferative phenotype of mutant intestinal organoids in vitro and prevent carcinogenesis in mutant mice. We investigated the prevalence of parainflammation in human cancer and found that it characterizes fifty percent of the major cancer types, showing a tight association to p53 mutations and p53 pathway deficiencies. We will discuss the significance and implications of parainflammation in human cancer.