Integrating inflammation.

PL01-01

Inflammation promotes neoplastic transformation and progression. However, the remarkable complexity of the inflammatory process provides a barrier to the design of strategies for cancer prevention based on reducing inflammation. The goals of this talk are first, to suggest a functionally useful way of conceptualizing inflammation that helps rationalize phenomena that otherwise appear paradoxical; second, to illustrate how widespread chronic inflammation has become in industrialized societies, with an attendant risk of an increased incidence of cancer, with special reference to epidemic obesity; and third, to draw lessons for intervention. According to a conventional view, inflammation is a response to emergent, intermittent stimuli, and anti-inflammatory mechanisms come into play late in the process to wind inflammation down. In this view, persistent inflammation results from failure to eliminate stimuli. An alternative view is that inflammatory stimuli are ubiquitous and continual and that anti-inflammatory mechanisms operate constitutively to prevent inflammation from starting unless dual criteria are fulfilled, namely, sustained receipt of signals for both infection and injury. The latter view is concordant with experimental evidence that disruption of an anti-inflammatory mechanism is enough to lead to spontaneous inflammation, which in turn can lead to oncogenesis. We can recognize at least 5 physiologic anti-inflammatory mechanisms: default-off: ongoing verification of emergency is generally required to avoid defaulting to the resting state; prevent-on: the resting state reflects a tonic anti-inflammatory tone maintained through positive actions of numerous gene products; active-off: the resting state is partly maintained by constitutive off signals; neo-stop: inflammation itself generates stop signals; and sense-switch: certain signals switch sense from pro- to anti-inflammatory during the course of the response. In conclusion, prevention and treatment of chronic inflammation have the potential to reduce substantially the incidence of cancer. Behavioral approaches to reduction of inflammation have the greatest potential for epidemiologic impact. Pharmacologic approaches will be important as well, but if their anti-inflammatory effects are profound and prolonged, mechanism-based complications can be anticipated. These include increased incidence of infections; reduced immunocompetence, possibly with pro-oncogenic effects; paradoxical exacerbations of inflammation; and even paradoxical oncogenic effects. Theoretical problems potentially associated with long-term anti-inflammatory interventions should inform rather than discourage trials of chemoprevention based on reducing inflammation.