Environmental immune disruptors, inflammation and cancer risk

Abstract

An emerging area in environmental toxicology is the role that chemicals and chemical mixtures have on the cells of the human immune system. This is an important area of research that has been most widely pursued in relation to autoimmune diseases and allergy/asthma as opposed to cancer causation. This is despite the well-recognized role that innate and adaptive immunity play as essential factors in tumorigenesis. Here, we review the role that the innate immune cells of inflammatory responses play in tumorigenesis. Focus is placed on the molecules and pathways that have been mechanistically linked with tumor-associated inflammation. Within the context of chemically induced disturbances in immune function as co-factors in carcinogenesis, the evidence linking environmental toxicant exposures with perturbation in the balance between pro- and anti-inflammatory responses is reviewed. Reported effects of bisphenol A, atrazine, phthalates and other common toxicants on molecular and cellular targets involved in tumor-associated inflammation (e.g. cyclooxygenase/prostaglandin E2, nuclear factor kappa B, nitric oxide synthesis, cytokines and chemokines) are presented as example chemically mediated target molecule perturbations relevant to cancer. Commentary on areas of additional research including the need for innovation and integration of systems biology approaches to the study of environmental exposures and cancer causation are presented.

Figure 1.

Graphic representation of ‘yin’ and ‘yang’ arms of acute inflammation. The scheme depicts two, tightly controlled and biologically opposing arms of self-terminating acute inflammatory responses. Stimuli induce activation of innate and/or adaptive immune cells by expression of appropriate ‘death factors’ in yin (apoptosis, growth-arrest) processes to destroy foreign elements and injured tissue; while yang simultaneously produces ‘growth factors’ (wound healing, growth-promote) to terminate and resolve inflammation. Yin and yang processes are intimately facilitated by activation of a vasculature response and expression of apoptotic and wound-healing mediators. Reproduced with permission (3) [Exp. Opin. Biol. Ther. 2008, All Rights Reserved.]

Figure 2.

The activation of NFκB is a potent stimuli for IL-6 and IL-6 activates the STAT3 protein. Cancer cells and surrounding inflammatory immune cells have been shown to produce excessive and continuous amounts of IL-6 and other cytokines promoting chronic stimulation of STAT3. If unchecked, this leads to an uncontrolled pro-inflammatory/pro-tumorigenesis state mediated by the effects of STAT3 on gene transcription that promote proliferation, resistance to apoptosis, angiogenesis, immune evasion, invasion and metastasis; all hallmarks of cancer.