title: Chronic inflammation and cancer: the role of the mitochondria.
abstract: Accumulating evidence shows that chronic inflammation can promote all stages of tumorigenesis, including DNA damage, limitless replication, apoptosis evasion, sustained angiogenesis, self-sufficiency in growth signaling, insensitivity to anti-growth signaling, and tissue invasion/metastasis. Chronic inflammation is triggered by environmental (extrinsic) factors (eg, infection, tobacco, asbestos) and host mutations (intrinsic) factors (eg, Ras, Myc, p53). Extensive investigations over the past decade have uncovered many of the important mechanistic pathways underlying cancer-related inflammation. However, the precise molecular mechanisms involved and the interconnecting crosstalk between pathways remain incompletely understood. We review the evidence implicating a strong association between chronic inflammation and cancer, with an emphasis on colorectal and lung cancer. We summarize the current knowledge of the important molecular and cellular pathways linking chronic inflammation to tumorigenesis. Specifically, we focus on the role of the mitochondria in coordinating life- and death-signaling pathways crucial in cancer-related inflammation. Activation of Ras, Myc, and p53 cause mitochondrial dysfunction, resulting in mitochondrial reactive oxygen species (ROS) production and downstream signaling (eg, NFkappaB, STAT3, etc.) that promote inflammation-associated cancer. A recent murine transgenic study established that mitochondrial metabolism and ROS production are necessary for K-Ras-induced tumorigenicity. Collectively, inflammation-associated cancers resulting from signaling pathways coordinated at the mitochondrial level are being identified that may prove useful for developing innovative strategies for both cancer prevention and cancer treatment.
authors.affiliation: Jesse Brown VA Medical Center, Chicago, Illinois, USA. d-kamp@northwestern.edu
authors.forename: David W
authors.initials: DW
authors.lastname: Kamp
authors.forename: Emily
authors.initials: E
authors.lastname: Shacter
authors.forename: Sigmund A
authors.initials: SA
authors.lastname: Weitzman
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009369:Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*