Inflammation as a Cancer Co-Initiator: New Mechanistic Model Predicts Low/Negligible Risk at Noninflammatory Carcinogen Doses. Issue 2 (16th May 2019)

• Record Type: Journal Article
• Authors: Bogen, Kenneth T.
• Is Part Of: Dose-response. Volume 17:Issue 2(2019:Apr./Jun.)
• Publication Date: 2019-05-16
• Subjects: biological mechanism -- conditional multistage model -- inflammation -- low-dose nonlinearity -- stem cells -- cancer; Dose-response relationship (Biochemistry) -- Periodicals; Drugs -- Dose-response relationship -- Periodicals; Drugs -- Physiological effect -- Periodicals; Hormesis -- Periodicals; Dose-Response Relationship, Drug -- Periodicals; Dose-response relationship (Biochemistry); Drugs -- Dose-response relationship; Drugs -- Physiological effect; Periodicals; 571.634
• DOI: 10.1177/1559325819847834
• Languages: English
• ISSNs: 1559-3258

Abstract

Linear-no-threshold (LNT) risk extrapolation has long been applied to estimate risks posed by low-level environmental carcinogen exposures, based on the 60-year-old multistage somatic mutation/clonal expansion (MSM) cancer theory. Recent evidence supports an alternative theory: Malignant tumors arise most efficiently from a stem cell that incurs requisite mutations and also is activated by inflammation to an epigenetically mediated and maintained state of adaptive hyperplasia (AH). This new inflammation-MSM (ISM) theory posits that inflammation-activated stem cells normally restricted to sites of injury-induced inflammation and tissue repair become uniquely susceptible to efficient carcinogenesis if normal post-inflammation AH termination is blocked by mutation. This theory posits that inflammation generally thus co-initiates cancer and transiently amplifies activated stem cells, implying that MSM theory (eg, the 2-stage stochastic "Moolgavkar, Venzon, Knudson [MVK]" model) is incomplete. Because inflammation dose–response typically is not LNT, the ISM theory predicts this is also true for most (perhaps all) carcinogens. The ISM (but not the MVK) model is shown to be consistent with recent data showing ∼100% carcinoma incidence (but not DNA adducts) in livers of rats exposed to aflatoxin B1 and was eliminated when that dose was co-administered with a highly potent anti-inflammatory agent. Experimental approaches to test ISM theory more robustly are discussed.