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Mech Ageing Dev. 2004 Sep;125(9):581-90.

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

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Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Pushchino, Moscow Region.


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 inflammatory-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/CO-dependent 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.

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