Fig. 8.
Schematic representation of a simplified narrative scenario model of uncontrolled dysregulated DAMP-promoted pathways in light of the exposome and AOP concepts. The figure illustrates the sequelae of key events proposed to leading to cancer, reflecting the adverse outcome. The stress/injury → DAMP-promoted, dysregulated pathways leading to immune diseases start with the sequelae of events (MIE → KE3→n) as described for the controlled pathway (Fig. 3). However, instead of proceeding to homeostatic events, the DAMP-induced pathways now provoke “pathogenic” KEs key events resulting in an adverse outcome in terms of cancer. The triggering “aberrant” event is the fifth KE that refers to (uncontrolled) chronic inflammation as characterized by the failure of an inflammation-resolution response. However, the exact mechanisms underlying chronic inflammatory microenvironment-promoted carcinogenesis are not fully understood. AO adverse outcome, cell./hum. cellular/humoral, DAMPs damage-associated molecular patterns, KE key event, KER key event relationship, MAMPs microbe-associated molecular patterns, MIE molecular initiating event, PRMs pattern recognition molecules, SAMPs suppressing DAMPs.
Sources: Balkwill and Mantovani (2001), Hecht (2002), Grivennikov et al. (2010), Ben-Neriah and Karin (2011), Wang et al. (2016) and Zhang and Xu (2017)