Inflamación y cancer

insight review articles

Inflammation and cancer
Lisa M. Coussens*†§ & Zena Werb‡§
*Cancer Research Institute, Departments of †Pathology and ‡Anatomy, and the §UCSF Comprehensive Cancer Center, University of California, San Francisco, California 94143 USA (e-mail: coussens@cc.ucsf.edu; zena@itsa.ucsf.edu)

Recent data have expanded the concept that inflammation is a critical component oftumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of theinnate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new antiinflammatory therapeutic approaches to cancer development.

he functional relationship between inflammation and cancer is not new. In 1863, Virchow hypothesized that the origin of cancer was at sites of chronic inflammation, in part based on hishypothesis that some classes of irritants, together with the tissue injury and ensuing inflammation they cause, enhance cell proliferation1. Although it is now clear that proliferation of cells alone does not cause cancer, sustained cell proliferation in an environment rich in inflammatory cells, growth factors, activated stroma, and DNA-damage-promoting agents, certainly potentiates and/or promotesneoplastic risk. During tissue injury associated with wounding, cell proliferation is enhanced while the tissue regenerates; proliferation and inflammation subside after the assaulting agent is removed or the repair completed. In contrast, proliferating cells that sustain DNA damage and/or mutagenic assault (for example, initiated cells) continue to proliferate in microenvironments rich ininflammatory cells and growth/survival factors that support their growth. In a sense, tumours act as wounds that fail to heal2. Today, the causal relationship between inflammation, innate immunity and cancer is more widely accepted; however, many of the molecular and cellular mechanisms mediating this relationship remain unresolved — these are the focus of this review. Furthermore, tumour cells may usurpkey mechanisms by which inflammation interfaces with cancers, to further their colonization of the host. Although the acquired immune response to cancer is intimately related to the inflammatory response, this topic is beyond the scope of this article, but readers are referred to several excellent reviews3,4.

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An overview of inflammation
To understand the role of inflammation in theevolution of cancer, it is important to understand what inflammation is and how it contributes to physiological and pathological processes such as wound healing and infection (Fig. 1). In response to tissue injury, a multifactorial network of chemical signals initiate and maintain a host response designed to ‘heal’ the afflicted tissue. This involves activation and directed migration of leukocytes(neutrophils, monocytes and eosinophils) from the venous system to sites of damage (Box 1), and tissue mast cells also have a significant role. For neutrophils, a four-step mechanism is believed to coordinate recruitment of these inflammatory cells to sites of tissue injury and to the provisional extracellular matrix (ECM) that forms a scaffolding upon which fibroblast and endothelial cells proliferateand migrate, thus providing a nidus for
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reconstitution of the normal microenvironment5. These steps involve: activation of members of the selectin family of adhesion molecules (L- P-, and E-selectin) that facilitate rolling along the vascular endothelium; triggering of signals that activate and upregulate leukocyte integrins mediated by cytokines and leukocyte-activating molecules;...