Inflammation as a Cancer Co-Initiator: New Mechanistic Model Predicts Low/Negligible Risk at Noninflammatory Carcinogen Doses

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 B 1 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.

Carcinogenesis: Failure of resolution of inflammation?

“…Virchow studied the four signs of inflammation (redness, swelling, heat and pain) and hypothesized a link between microinflammation and subsequent tumor progression ( Heidland, Klassen, Rutkowski, & Bahner, 2006 ). Experimental studies have indeed confirmed that inflammation can stimulate or induce tumor initiation, growth, and metastasis ( Bogen, 2019 ; Chang et al, 2019 ; Coussens & Werb, 2002 ; Fishbein et al, 2020 ; Gartung et al, 2019 ; Gilligan et al, 2019 ; Guerra et al, 2007 ; Mantovani et al, 2008 ; Panigrahy et al, 2019 ; Sulciner et al, 2018 ; Wang & Dubois, 2010 ). Cancers arise frequently at sites of chronic inflammation and injury as the observation that secondary tumors occur at the points of injury (e.g.…”

“…Carcinogens may induce a specific gene mutation frequently observed in a particular cancer increasing the risk of cancer ( Moore et al, 2008 ). While carcinogen-induced DNA damage can cause cancer, some studies suggest that DNA adducts alone or mutations alone may not be sufficient to cause cancer ( Bogen, 2019 ; Johnson et al, 2014 ). Non cell-autonomous mechanisms such as inflammation and angiogenesis may also be critical to tumor initiation and progression ( Folkman, 2007 ).…”

“…aflatoxins, nitrosamines, asbestos, dioxins, tobacco, and alcohol) can initiate and stimulate cancer progression through various mechanism including inflammation, oxidative stress, DNA damage , cytotoxicity, acute or chronic injury, and subsequent regenerative proliferation via cell death (e.g. apoptosis) ( Bogen, 2019 ; Klaunig, Hocevar, & Kamendulis, 2012 ; Yao & Zhong, 2005 ). Environmental and occupational exposure to carcinogenic metals (e.g.…”

“…Interestingly, both genotoxic, and non-genotoxic carcinogens generate oxidative stress as an underlying cause for carcinogenesis ( Deferme, Wolters, Claessen, Briede, & Kleinjans, 2015 ). A new highly innovative model of carcinogenesis has been proposed as the Inflammation Somatic Model (ISM) based off the 2-stage somatic mutation model suggesting genotoxic effects are not sufficient to promote carcinogenesis and that inflammation as well as oxidative stress can prime tissues for cancer growth ( Bogen, 2019 ). Importantly, AFB 1 -induced hepatocarcinogenesis was prevented in rats with systemic administration of an anti-inflammatory and antioxidant CDDO-Im despite significant DNA adduct burden suggesting a protective effect and a DNA damage threshold ( Eaton & Schaupp, 2014 ; Johnson et al, 2014 ).…”

“…Cellular debris (apoptotic cells) and inflammation-induced cellular damage can induce cellular proliferation to activate a “Phoenix Rising” Pathway) to promote wound healing and tissue regeneration of the damaged tissue ( Li et al, 2010 ). Cytotoxicity-induced pro-inflammatory activity of carcinogens and tissue damage/injury may lead to inflammation as a cancer co-initiator and predict low or negligible risk at noninflammatory carcinogen doses ( Bogen, 2019 ). Inflammation activated-stem cells involved in tissue repair in damaged tissue and may lead to cancer if the normal termination of inflammation is suppressed by mutations ( Bogen, 2019 ).…”