Inflammation-Induced Cell Proliferation Potentiates DNA Damage-Induced Mutations In Vivo

Abstract

Mutations are a critical driver of cancer initiation. While extensive studies have focused on exposure-induced mutations, few studies have explored the importance of tissue physiology as a modulator of mutation susceptibility in vivo. Of particular interest is inflammation, a known cancer risk factor relevant to chronic inflammatory diseases and pathogen-induced inflammation. Here, we used the fluorescent yellow direct repeat (FYDR) mice that harbor a reporter to detect misalignments during homologous recombination (HR), an important class of mutations. FYDR mice were exposed to cerulein, a potent inducer of pancreatic inflammation. We show that inflammation induces DSBs (γH2AX foci) and that several days later there is an increase in cell proliferation. While isolated bouts of inflammation did not induce HR, overlap between inflammation-induced DNA damage and inflammation-induced cell proliferation induced HR significantly. To study exogenously-induced DNA damage, animals were exposed to methylnitrosourea, a model alkylating agent that creates DNA lesions relevant to both environmental exposures and cancer chemotherapy. We found that exposure to alkylation damage induces HR, and importantly, that inflammation-induced cell proliferation and alkylation induce HR in a synergistic fashion. Taken together, these results show that, during an acute bout of inflammation, there is a kinetic barrier separating DNA damage from cell proliferation that protects against mutations, and that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations. These studies demonstrate a fundamental mechanism by which inflammation can act synergistically with DNA damage to induce mutations that drive cancer and cancer recurrence.

Helicobacter saguini, a Novel Helicobacter Isolated from Cotton-Top Tamarins with Ulcerative Colitis, Has Proinflammatory Properties and Induces Typhlocolitis and Dysplasia in Gnotobiotic IL-10 −/− Mice

“…Chronically inflamed tissues which are continuously regenerating are at an increased risk for mutagenesis and tumor transformation. It has been reported that inflammation-induced cell proliferation greatly potentiates exposure-induced mutations; inflammation can act synergistically with DNA damage to induce mutations that promote cancer and cancer recurrence (49). Reactive oxygen species (ROS) are associated with the inflammatory response and frequently contribute to the tissue-damaging effects of inflammatory reactions.…”

Overt Increase of Oxidative Stress and DNA Damage in Murine and Human Colitis and Colitis-Associated Neoplasia

“…As a consequence, nucleotides can be oxidized (such as guanine to 8-oxoG) resulting in base transversion (GC-TA), abasic sites and DNA single-and double-strand breaks. (7)(8)(9)(10)(11)(12) For cellular integrity, DNA double-strand breaks (DSB) can be fatal and their repair is initiated by the cellular DNA damage response (DDR) consisting of a multi-protein signalling cascade. (13,14) An early event in DSB response is phosphorylation of the H2A subtype histone H2AX at ser-139 (also known as γH2AX) by the phosphatidylinositol 3-like kinases ATM, ATR and DNA-PK.…”

Age Species of Women With Chronic Salpingoforitis

“…Более того, длительный воспалительный процесс отличается спектром возможностей провоцировать ДНК-индуцированную гибель клеток: от специфических повреждений ДНК до процессов вследствие повреждения ДНК и апоптоза [6]. Пролиферация клеток, индуцированная воспалением, потенцирует мутации, вызванные повреждением ДНК in vivo [7]. [10].…”