Alterations in complex cellular phenotype each typically involve multistep activation of an ultrasensitive molecular switch (e.g., to adaptively initiate an apoptosis, inflammasome, Nrf2-ARE anti-oxidant, or heat-shock activation pathway) that triggers expression of a suite of target genes while efficiently limiting false-positive switching from a baseline state. Such switches exhibit nonlinear signal-activation relationships. In contrast, a linear no-threshold (LNT) dose-response relationship is expected for damage that accumulates in proportion to dose, as hypothesized for increased risk of cancer in relation to genotoxic dose according to the multistage somatic mutation/clonal-expansion theory of cancer, e.g., as represented in the Moolgavkar-Venzon-Knudsen (MVK) cancer model by a doubly stochastic nonhomogeneous Poisson process. Mesothelioma and lung cancer induced by exposure to carcinogenic (e.g., certain asbestos) fibers in humans and experimental animals are thought to involve modes of action driven by mutations, cytotoxicity-associated inflammation, or both, rendering ambiguous expectations concerning the nature of model-implied shape of the low-dose response for above-background increase in risk of incurring these endpoints. A recent Inflammation Somatic Mutation (ISM) theory of cancer posits instead that tissue-damage-associated inflammation that epigenetically recruits, activates and orchestrates stem cells to engage in tissue repair does not merely promote cancer, but rather is a requisite co-initiator (acting together with as few as two somatic mutations) of the most efficient pathway to any type of cancer in any reparable tissue (Dose-Response 2019; 17(2):1-12). This theory is reviewed, implications of this theory are discussed in relation to mesothelioma and lung cancer associated with chronic asbestos inhalation, one of the two types of ISM-required mutations is here hypothesized to block or impede inflammation resolution (e.g., by doing so for GPCR-mediated signal transduction by one or more endogenous autacoid specialized pro-resolving mediators or SPMs), and supporting evidence for this hypothesis is discussed.
Keywords: Asbestos; Cytotoxicity; Inflammation; Lung cancer; Mesothelioma; Mutation.
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