The skin not only acts as a physical barrier to pathogens and toxins, but also functions as an immunological barrier constantly responding to environmental insults (e.g., UV radiation, chemical carcinogens, and oncogenic viruses). Resident and recruited immune cells respond to these types of insults by directly or indirectly inducing secretion of damage response molecules (e.g., proinflammatory cytokines, chemokines, matrix remodeling enzymes, reactive oxygen mediators, and so on) in an attempt to clear damaged cells and pathogens such that tissue homeostasis can be reinstated. Instead, when damage is chronic and/or results in somatic alterations leading to altered proliferative or apoptotic programming of epithelial cells, inflammation that was initially an acute response instead becomes chronic. In this scenario, chronic inflammation acts as a promoting force that fosters early neoplastic progression and underscores data revealing that chronic exposure to environmental toxins and pathogens is a risk factor for cancer development (Coussens and Werb, 2002). How does activation of what should be an acute response instead foster neoplasia? The series of events discussed above is initiated by tissue-resident innate immune cells (dendritic cells, mast cells, macrophages, and γδ T cells) responding to damage response proteins, including damage-associated molecular patterns, pathogen-associated molecular patterns, Toll-like receptor ligands, colony stimulating factors, cytokines (tumor necrosis factor-α), and chemokines released from “damaged” epithelial cells (Balkwill et al., 2005; Balkwill, 2009). Upon engagement of these damage signals, resident immune cells are activated, and they respond by degranulation or secretion of a diversity of mediators that in turn results in activation of resident mesenchymal support cells (fibroblasts, adipocytes, mural, and endothelial cells), recruitment of peripheral blood leukocytes into “damaged” tissue, as well as engagement of cells of the adaptive immune system, both locally and peripherally (Balkwill et al., 2005). Dendritic cells, and to a lesser extent macrophages, are antigen-presenting cells that activate B and T cells to mount an adaptive immune response. Upon antigen recognition, B cells, as well as CD4+ and CD8+ T cells, undergo clonal expansion and mount responses specific to presented antigens. Although all of these tissue responses are otherwise entirely “normal,” during early neoplasia, they fail to resolve (Dvorak, 1986). Thus, chronic inflammation underlies the earliest stages of cancer development (Balkwill and Mantovani, 2001; Coussens and Werb, 2001, 2002). As such, chronic inflammation is now accepted as a hallmark of cancer development (Hanahan and Weinberg, 2011), where both innate and adaptive immune cells exert either pro- or anti-tumor activities dependent on their activation state and the microenvironment in which they reside (Balkwill et al., 2005; de Visser et al., 2006; Hanahan and Coussens, 2012). Although early studies of skin focused on the suppressive effects of leukocytes on carcinogenesis, we now recognize that proliferation and survival of epithelial cells harboring genomic alterations are sustained by chronic inflammatory pathways; understanding the nuances of these support mechanisms has yielded a diversity of new anticancer targets currently being utilized in the clinic.
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Jul 1, 2017
Ryan S Lane + 7
Open Access