Chronic immune activation and inflammation as the cause of malignancy

Abstract

Summary Several chronic infections known to be associated with malignancy have established oncogenic properties. However the existence of chronic inflammatory conditions that do not have an established infective cause and are associated with the development of tumours strongly suggests that the inflammatory process itself provides the prerequisite environment for the development of malignancy. This environment includes upregulation of mediators of the inflammatory response such as cyclo-oxygenase (COX)-2 leading to the production of inflammatory cytokines and prostaglandins which themselves may suppress cell mediated immune responses and promote angiogenesis. These factors may also impact on cell growth and survival signalling pathways resulting in induction of cell proliferation and inhibition of apoptosis. Furthermore, chronic inflammation may lead to the production of reactive oxygen species and metabolites such as malondialdehyde within the affected cells that may in turn induce DNA damage and mutations and, as a result, be carcinogenic. Here it is proposed that the conditions provided by a chronic inflammatory environment are so essential for the progression of the neoplastic process that therapeutic intervention aimed at inhibiting inflammation, reducing angiogenesis and stimulating cell mediated immune responses may have a major role in reducing the incidence of common cancers. 473-483 © 2001 Cancer Research Campaign doi: 10.1054/ bjoc.2001.1943, available online at http://www.idealibrary.com on http://www.bjcancer.com (Kirk and Clements, 1999;Lewis et al, 1999). Furthermore, in the majority of colorectal tumours not associated with inflammatory bowel disease, histology shows that the precursor lesions, whether adenomas or polyps, are often inflammatory in nature (Higaki et al, 1999). THE INFLAMMATORY ENVIRONMENT ASSOCIATED WITH THE SUBSEQUENT DEVELOPMENT OF CANCERWhereas the association between chronic immune activation and the development of cancer has been recognized for some years, only recently have we begun to understand the mechanisms underlying this phenomenon. The first concerns the nature of the local and systemic immune response seen in patients with chronic inflammatory conditions known to be associated with the development of malignant disease. Immune responses may be broadly divided into two categories -cell mediated immunity and humoral immunity. Cell mediated immunity (CMI) is associated with CD4 + T-lymphocytes which characteristically produce the cytokines interleukin(IL)-2, interferon-γ and tumour necrosis factor(TNF)-α (Thl-lymphocytes). Humoral immunity (HI) is associated with CD4+ T-lymphocytes which characteristically produce IL-4, IL-6 and IL-10 (Th2) (Mosmann and Coffman, 1989).Recent experimental evidence suggests that exposure to a foreign antigen results in upregulation of the non-specific pro-inflammatory cytokines IL-1α and -β and the Th1 cytokines in inflammatory cells. Cyclooxygenase (COX)-1 and COX-2 are among the most important enzymes involved in the regulation of th...

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