Microbial deprivation, inflammation and cancer

Monday, 01/08/2011  |   Inflammation  |  no comments

Sufficient exposure to a large variety of microbes is likely crucial for the development of a normally functioning immune system and for prevention of cancerous growths. The modern lifestyles may reduce this substantially, and, therefore, further studies to unravel the potential influence of microbial exposure on tumorigenesis are highly warranted and might pave a way for novel strategies for cancer prevention and therapy

Dysregulated immune function is involved in the pathogenesis of many common human diseases. Living in urban, microbe-poor environment may have a profound influence on the immune function and eventually also on carcinogenesis. Unfortunately, few studies have thus far addressed the role of exposure to the environmental microbiota on the risk of cancer. Which mechanisms are broken in individuals prone to develop chronic inflammation in response to exposure that does not cause harm in others? Recent work in immunology has revealed that Th17 cells, a third subset of Th cells, and inflammatory cytokines, particularly IL-23, are closely linked with tumour-associated inflammation. Albeit the precise role of Th17 cells in cancer is still unclear and a matter of debate, accumulating evidence shows that Th17 cells are enriched in a wide range of human tumours, and that these tumour-derived Th17 cells may promote angiogenesis, tumour growth and inflammation. Regulatory T cells, in turn, appear to have counter-regulatory effects on Th17 cells and can inhibit their function. Thus, the regulatory network, induced and strengthened by continuous exposure to environmental microbiota, may play an important role in tumour immunobiology in preventing the establishment of chronic inflammation in its early phases. In addition, the discovery of the Toll-like receptor (TLR) system has brought micro-organisms to new light; continuous signalling via these TLRs and other receptors that sense microbial components is necessary for epithelial cell integrity, tissue repair, and recovery from injury. In this communication, we summarise the epidemiological data of living in environments with diverse microbial exposures and the risk of cancer, and discuss the related immunological mechanisms, focusing on the links between environmental microbiota, the Th17/IL-23 axis and cancer-associated inflammation.

The link between cancer and inflammation was recognised by Virchow already in the 1860s (Balkwill & Mantovani, 2001). Epidemiological studies have further shown that chronic inflammation may predispose to some cancer (Vesterinen et al, 1993; Rubio et al, 2009) and in turn, that a regular use of non-steroidal anti-inflammatory drugs may reduce the risk of breast and colon cancer (Smyth et al, 2009; Wang et al, 2007). Inflammatory cells and mediators are present in the microenvironment of virtually all types of tumours in experimental settings and in humans from the early stages of development (Mantovani et al, 2008).
Carcinogenesis has been associated with chronic irritation, inflammation and tissue damage, and defective homeostatic mechanisms that govern tissue repair and stem cell renewal may be involved (Vakkila et al, 2004). Triggering factors include pathogens, irritants, toxic compounds and particles, and even components from changed tissues of the host (Medzhitov, 2008). The continuous state of repair and inflammation leads to the sustained presence of signalling molecules (cytokines, chemokines and non-cytokine mediators, such as Cox-2 and prostaglandins), angiogenesis and tissue remodelling. The states of repair and scarring continue as, due to defective homeostatic mechanisms, the cells are unable to return to quiescence that normally follows regeneration (Beachy et al, 2004). In this vicious circle, cancer-associated inflammation may further promote, rather than inhibit, tumour growth and progression (Mantovani, 2005).

Fig. 1 The involvement of environmental microbiota, receptors (TLRs, NLRs) on/in innate immune cells recognising microbial structures and the regulatory network in prevention of the Th17/IL-23-mediated chronic inflammation associated with carcinogenesis. Establishment of chronic inflammation can be prevented via at least two different mechanisms; via TLR/NLR triggering by microbial components which enhances epithelial cell homeostasis and tissue repair after injury (left arm), or via the regulatory network, primarily T reg cells and DCs secreting regulatory cytokines which prevent the production of pro-inflammatory cytokines and non-cytokine mediators by inflammatory cells (right arm). NLR, Nod nucleotide-binding oligomerisation domain-like receptor, TLR Toll-like receptor, DC dendritic cell, T reg regulatory T cell

Th1 immunity has traditionally been considered an important defence mechanism in immunosurveillance influencing tumour development and progression. T reg cells in turn have been viewed as deleterious promoting cancer progression. Novel data have added another level of complexity to this issue. Immune cells in human tumours have recently been found to produce high levels of IL-23, a cytokine linked with a new subset of Th cells, Th17 cells. Inflammation exerted by this Th17/IL-23 axis is associated with tumour progression, and suppressing this inflammation in early phases by T reg cells may hinder the progression (Figure). In advanced cancers, the presence of T reg cells could indicate the host’s attempt to limit the severe tumour-associated inflammation, and/or T reg cells may participate in the process by downregulating the antitumour activity of effector cells. In addition, both Th17 and T reg cells have shown considerable plasticity, albeit the relevance of this plasticity to tumorigenensis in humans is incompletely understood.
Epidemiological data suggest that exposure to environmental microbiota might be associated with protection against major cancers, but many other factors can also be involved. Experimental models using various microbial components lend some further support to this hypothesis. Continuous microbial exposure may be associated with
1. Activation of microbial receptors on/in immune and other cells, which may have direct antitumour effect and an indirect effect by endorsing innate immunity and homeostatic mechanisms,
2. Strengthening of the regulatory network, which in turn can prevent or dampen in early phases the development of Th17 cells and inflammatory mediators, such as Cox-2 and PGE2, central to cancer-promoting inflammation.

Source:
von Hertzen LC, Joensuu H & Haahtela T. Microbial deprivation, inflammation and cancer. Cancer and Metastasis Reviews. DOI: 10.1007/s10555-011-9284-1
References:
Balkwill, F., & Mantovani, A. (2001). Inflammation and cancer: Back to Virchow? Lancet, 357, 539–545.
Beachy, P. A., Karhadkar, S. S., & Berman, D. M. (2004). Tissue repair and stem cell renewal in carcino-genesis. Nature, 432, 324–331.
Mantovani, A. (2005). Cancer: Inflammation by remote control. Nature, 435, 752–753.
Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008). Cancer-related inflammation. Nature, 454, 436–444.
Medzhitov, R. (2008). Origin and physiological roles of inflammation. Nature, 454, 428–435.
Rubio, C. A., Kapraali, M., & Befrits, R. (2009). Further studies on the frequency of colorectal cancer in Crohn’s colitis: An 11-year survey in the Northwest Stockholm County. Anticancer Research, 29, 4291–4295.
Smyth, E. M., Grosser, T., Wang, M., Yu, Y., & FitzGerald, G. A. (2009). Prostanoids in health and disease. Journal of Lipid Research, 50, S423–S428.
Vakkila, J., & Lotze, M. T. (2004). Inflammation and necrosis promote tumour growth. Nature Reviews. Immunology, 4, 641–648.
Vesterinen, E., Pukkala, E., Timonen, T., & Aromaa, A. (1993). Cancer incidence among 78,000 asthmatic patients. International Journal of Epidemiology, 22, 976–982.
Wang, M. T., Honn, K. V., & Nie, D. (2007). Cyclooxygenases, prostanoids, and tumor progression. Cancer and Metastasis Reviews, 26, 525–534.

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