Beyaert et al. Molecular Cancer 2013, 12:98 http://www.molecular-cancer.com/content/12/1/98 REVIEW Open Access Cancer risk in immune-mediated inflammatory diseases (IMID) Rudi Beyaert1,2, Laurent Beaugerie3,4, Gert Van Assche5, Lieve Brochez6, Jean-Christophe Renauld7, Manuelle Viguier8,9, Veronique Cocquyt10, Guy Jerusalem11, Jean-Pascal Machiels12,13, Hans Prenen14, Pierre Masson15, Edouard Louis16 and Filip De Keyser17* Abstract Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors. This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors. Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce. This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history. This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86. Keywords: Antirheumatic agents, Autoimmune diseases, Biological products, Cancer, Inflammation, Tumor necrosis factor Introduction disease. This is achieved using corticosteroids, immuno- Immune-mediated inflammatory diseases (IMIDs) are a suppressants, and “biologicals”, especially those targeting group of chronic and highly disabling diseases involving tumor necrosis factor (TNF). inappropriate or excessive immune responses caused or Because immunosurveillance is thought to help sup- accompanied by cytokine dysregulation and acute or press the development of cancer, there are concerns that chronic inflammation [1]. This includes a wide variety of immunotherapies might increase cancer risk in patients illnesses, such as Crohn’s disease (CD), ulcerative colitis with IMIDs. Furthermore, inflammation is known to (UC), psoriasis, rheumatoid arthritis (RA), and systemic have both pro- and anti-tumorigenic effects, and cancer- lupus erythematosus (SLE). IMIDs are fairly common, related inflammation is now considered the seventh hall- affecting an estimated 5% to 7% of the population in mark of cancer [2]. Western countries. Treatment of IMIDs focuses on the In this article, we discuss the current state of know- rapid control of inflammation, prevention of tissue ledge concerning the relationship between IMIDs and damage, and where possible, long-term remission of the cancer. This information should help clinicians decide about the safety of giving immunosuppressive therapies * Correspondence: [email protected] to IMID patients with a history of tumors. 17Department of Rheumatology, Ghent University, 0K12, De Pintelaan 185, Ghent B-9000, Belgium Full list of author information is available at the end of the article © 2013 Beyaert et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Beyaert et al. Molecular Cancer 2013, 12:98 Page 2 of 12 http://www.molecular-cancer.com/content/12/1/98 Dual relationship between inflammation and tumor cell variants have become resistant to elimination cancer by the immune system. Inflammation can occur in response to dietary or envir- Efficient inhibition of tumor growth was recently onmental factors, infection, and autoimmune diseases shown to involve not only defined cell death and clear- including IMIDs. Inflammatory cells are present in most, ance mechanisms by CD8+ cytotoxic T lymphocytes and if not all, solid tumors [3]. Tumor-associated macro- natural killer cells, but also the induction of tumor cell phages can comprise up to as much as half of the mass senescence by interferon-γ and TNF producing CD4+ of a solid tumor [4]. These cells promote tumor cell sur- T-helper 1 cells. In addition, T-helper 1 immunity can vival, proliferation, and dissemination, and a high level also induce anti-angiogenic chemokines that protect of them is associated with a poor prognosis. Tumor- against cancer [14]. associated inflammatory cells appear to be actively recruited, possibly as part of an anti-tumor response, but Pro-tumorigenic effects of inflammation this inflammatory response may be usurped by the A wide range of studies indicate that inflammation also tumor to promote tumorigenesis [3]. contributes more directly to tumorigenesis [15]. Nearly one in five cancers is linked to infections: e.g. Helicobacter pylori and Hepatitis C virus infections Anti-tumorigenic effects of inflammation eventually lead to gastric and liver cancers, respectively Activation of inflammatory cells as part of an immune [16,17]. Also, many cancers are associated with persist- response to eliminate mutant cells, a process called ent inflammation due to environmental factors or auto- immunosurveillance, was originally suggested by Ehrlich immune reactions: e.g. lung cancer is associated with and later formalized by Burnet and Thomas [5]. Aber- asbestosis and smoking, colon cancer with inflammatory rant proteins or peptide-MHC complexes on the sur- bowel disease (IBD), and lymphoma with celiac disease faces of transformed or malignant cells are recognized [8,17]. Furthermore, numerous experimental and epide- and targeted for elimination by the immune system. Evi- miologic studies, along with randomized clinical trials dence that the immune system recognizes and eliminates showed that long-term daily use of the nonsteroidal tumor cells was originally obtained in mice, but this is anti-inflammatory drug aspirin reduced the incidence of also supported by several lines of clinical evidence: can- several cancers, especially those of the gastrointestinal cer incidence is increased in transplant patients treated tract [18-21]. The mechanism of action of the with immunosuppressants; cancer patients develop im- chemopreventive and anticancer effects of aspirin is not mune responses to tumors; immune responses in tumors fully understood, but it has been attributed to its correlate with improved prognosis in colorectal cancer; anti-inflammatory effects, specifically inhibition of survival positively correlates with the presence of tumor- prostaglandin-endoperoxide synthase 2 (formerly named infiltrating lymphocytes, CD8+ T cells, and natural killer cyclooxygenase 2), which is the rate-limiting step for the cells in various cancers; higher natural cytotoxic activity conversion of arachidonic acid to prostaglandins. Be- of peripheral blood lymphocytes correlates with a re- cause aspirin can cause stomach upset and dangerous duced cancer risk [6-8]. internal bleeding, its use as anticancer drug for the gen- Murine studies found that tumors formed in the eral population is still under debate [22]. Together, these absence of an intact immune system are more immuno- findings suggest that when inflammation becomes per- genic in wild-type mice than those formed in the pres- sistent or dysfunctional, it can promote tumor growth, ence of an intact immune system [9-13]. In other words, as inflammatory cells, normally recruited to control the immune response eliminated the more immunogenic damage, are diverted by the tumor for pro-tumorigenic cells and selected less immunogenic cells, a process that purposes [3,23]. Dunn and colleagues refer to as “immunologic sculpting” How chronic inflammation increases cancer risk is be- or “immunoediting” [7]. Immunoediting is composed of ginning to come into focus [3,15]. Chronic inflammation three phases: “elimination”, “equilibrium”, and “escape”. can initiate tumors by directly causing DNA changes or The initial phase of an immune response to a tumor, making cells more susceptible to mutagens. In addition, elimination, is the same as immunosurveillance and inflammation can act as a tumor promoter. Inflamma- results in destruction of (part of) the tumor cells [7]. tory mediators, including cytokines like TNF, interleukin Dunn and colleagues envision that the tumor thereafter (IL)-1, and IL-6, growth factors, chemokines, and prote- remains in equilibrium with the immune system, ases produced by tumor-associated lymphocytes and wherein selection pressure continues but is unable to macrophages can enhance tumor cell growth and metas- eliminate the tumor. In this equilibrium phase, some tasis by promoting their survival, proliferation, migration tumor cells are eliminated and others, including new to and invasion of other tissues. Tumor-associated mac- variants, survive. In the final escape phase, the selected rophages release inflammatory mediators that stimulate