Age-promoted creation of a pro-cancer microenvironment by inflammation: pathogenesis of dyscoordinated feedback control

Aging and local chronic inflammation are established risk factors for epithelial tumorigenesis. These risk factors can act individually and/ or synergistically to increase the incidence of age-related carcinomas. The basis for this co-stimulatory response has not yet been defined, nor have the feedback mechanisms that are responsible for this synergism. This review provides insight into the age-stimulated dysregulation of coordination of feedbacks in oxygen-, heme-, and proteolysis-dependent metabolic pathways caused by acute and chronic inflammation, and its role as a possible pathological basis for the creation of a pro-cancer microenvironment (PCM). The PCM facilitates the selective survival and growth of transformed cells (in a manner similar to a cancer-supportive microenvironment (CM)). The cancer-induced environment has certain features in common with chronic inflammtory-induced PCM. Namely, there are: enhanced oxidative cell resistance against apoptosis, increased production of matrix-degrading enzymes, switching to glycolytic metabolism, angiogenesis and vasorelaxation thus providing nutrient delivery, but restriction of the immune cell mobilization and/or its activation. The hypothetical model of PCM-genesis is presented as a result of enzymatic dysregulation of feedback control including oxygen-, heme-, prostaglandin E-2-, metalloproteinase-9-, and NO/COdependent pathways. PCM-genesis takes place between the growth-inhibiting (cytotoxic) and growth promoting (regenerative) stages of inflammatory response. According to this model, age-related metabolic changes create opportunities for chronic (not acute) inflammatory response, which supports the PCM-condition with the non-healing wound state that often occurs around carcinomas. (C) 2004 Elsevier Ireland Ltd. All rights reserved.