Oncogene (2010) 29, 3313–3323 & 2010 Macmillan Publishers Limited All rights reserved 0950-9232/10 www.nature.com/onc REVIEW Inflammatory bowel disease and intestinal cancer: a paradigm of the Yin–Yang interplay between inflammation and cancer

S Danese1 and A Mantovani2

1Inflammatory Bowel Disease Unit, Division of Gastroenterology, Milan, Italy and 2Laboratory of Inflammation and Immunology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy

Colon cancer represents a paradigm for the connection other tumors (Balkwill and Mantovani, 2001; Coussens between inflammation and cancer in terms of epidemio- and Werb, 2002; Mantovani et al., 2008). Inflammatory logy and mechanistic studies in preclinical models. Key cells and mediators are present in the microenvironment components of cancer promoting inflammation include of cancers epidemiologically related or unrelated to master factors (for example, nuclear factor inflammatory or infectious conditions. Leukocyte infil- jB, STAT3), proinflammatory (for example, tration and the presence of soluble mediators such as tumor necrosis factor, interleukin-6 (IL-6)), cyclooxygen- cytokines and chemokines, are key characteristics of ase-2 and selected chemokines (for example, CCL2). Of cancer-related inflammation. Conditions predisposing to no less importance are mediators that keep inflammation cancer (for example, IBD) or genetic events that cause in check, including IL-10, transforming growth factorb, neoplastic transformation orchestrate the construction toll-like receptor and the IL-1 receptor inhibitor TIR8/ of an inflammatory microenvironment. Indeed, altera- SIGIRR, and the chemokine decoy and scavenger tions of representative of all classes of oncogenes receptor D6. Dissection of molecular pathways involved drive the production of inflammatory mediators. Thus, in colitis-associated cancer may offer opportunities for an intrinsic pathway of inflammation (driven in tumor innovative therapeutic strategies. cells) as well as an extrinsic pathway driven by chronic Oncogene (2010) 29, 3313–3323; doi:10.1038/onc.2010.109; inflammatory conditions have been identified, both of published online 19 April 2010 which contribute to tumor progression (Mantovani et al., 2008). Cancer-related inflammation has therefore emerged Keywords: inflammation; colon cancer; chemokines as the seventh hallmark of cancer (Mantovani, 2009).

Introduction: the link between inflammation and cancer The relationship between IBD and CRC

Tumors of the provide a paradig- Crohn’s disease (CD) and ulcerative colitis (UC) are the matic connection between inflammation and cancer. two main forms of IBD. Because of chronic damage to Even though (CRC) does not always the colon and rectum, both types of IBD are at increased develop after a history of inflammatory bowel disease risk of developing CRC. CAC only accounts for B2% (IBD), a major building block of the current inflamma- of all the cases of CRC (Gyde et al., 1982; Choi and tion-and-cancer paradigm are epidemiological studies in Zelig, 1994); however, there is an incidence rate of colon cancer, including its high frequency in patients B2.75 and 2.64 in patients with UC and CD, with IBD, the protective function of nonsteroidal respectively (Bernstein et al., 2001). These studies went antiinflammatory drugs and genetic associations with on to identify the major factors involved in the genes that encode inflammatory mediators. Moreover, development of CAC in patients with IBD, such as the preclinical models of colitis-associated cancer (CAC) severity and extension of disease and duration of have provided an invaluable tool to dissect the mechani- inflammation. Indeed, the risk of developing CAC stic basis of cancer-related inflammation. increases by B0.5–1% after 10 years of chronic Smoldering, nonresolving inflammation is part of the inflammation, with a cumulative probability of 18% tumor microenvironment in gastrointestinal as well as after colonic disease of 30 years duration (Eaden et al., 2001). Colitis-associated cancer occurs when normal cell Correspondence: Dr A Mantovani, Laboratory of Inflammation and Immunology, Istituto Clinico Humanitas IRCCS, Rozzano, growth and tissue homeostasis is disrupted by sequential Via Manzoni56, Rozzano, Milan 20089, Italy. mutations and epigenetic alterations of cancer-related E-mail: [email protected] or Dr S Danese, genes, with DNA methylation, histone modification and Inflammatory Bowel Disease Unit, Division of Gastroenterology, mutations mediated through the reactive oxygen species Milan 20089, Italy. E-mail: [email protected] released by innate immune cells (Kundu and Surh, 2008; Received 15 January 2010; revised 5 March 2010; accepted 9 March Colotta et al., 2009). Indeed, oxidative stress has been 2010; published online 19 April 2010 linked to several cancer-prone mutations in intestinal A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3314 epithelial cells including p53, Bcl-2, adenomatous ab polyposis coli (APC) and p16 (reviewed by Roessner et al., 2008). This disrupts key processes, resulting in the malignant transformation of cancer stem cells. Recently, the focus has been on the inflammatory cells and circuits that are active in the tumor microenviron- ment, as it is now becoming clear that they also have a crucial role in the development and progression of tumors (Balkwill and Mantovani, 2001; Coussens and Werb, 2002; Balkwill et al., 2005; Karin, 2006; Mantovani et al., 2008). cd

The pathophysiology of CAC

Several molecules have emerged as key players in the link between IBD and CAC. In particular, a variety of inflammatory mediators have a more specific role in the initiation and development of CAC. Until recently, very little data was available on the link between intestinal inflammation and colon cancer. However, the develop- ment of new animal models has opened up avenues on Figure 1 Colitis-associated cancer. Endoscopic view of murine healthy intestine (a) and after 7 days of 3% DSS treatment with key molecules involved in the progression from colonic colitis establishment (b). Treatment with three weekly cycles of 3% inflammation to cancer. DSS and AOM leads to colitis-associated cancer (c, d). Several experimental models of colonic cancer have been developed, including the APCmin and the azoxy- methane (AOM) model. The latter represents a very recently beginning to be unveiled. Recently, Garrett valuable rodent model for the study of CAC, because it et al. (2009) identified that DCs were the necessary is a variation on a standard UC model in which mice are cellular effectors for the proinflammatory carcinogenic administered dextran sulfate sodium (DSS) orally to program of their T-Bet(À/À) RAG2(À/À) UC model, induce colitis (Okayasu et al., 1990). Repeated oral elegantly showing that targeted restoration of T-bet in ingestion of DSS can cause colon carcinoma (Okayasu DC could reduce colonic inflammation and prevent the et al., 2002); however, the effect is enhanced by development of spontaneous neoplasia. In a novel administration of AOM before the first administration model of IBD and CAC using genetic inactivation of of DSS, which causes formation of O-6-methylguanine STAT3 in macrophages, Deng et al. (2010). showed that and consistently promotes the development of colon inflammation was associated with activation of the carcinoma (Okayasu et al., 1996) (Figures 1 and 2). mTOR-STAT3 pathway in epithelial and tumor cells, Although none of the models faithfully recapitulate the which was essential for both the excess proliferation of pathogenesis and diversity of human colon cancer, they these cells and the disruption of colonic homeostasis in have been invaluable in shedding fresh new light mutant mice. on CAC. Molecules that have been implicated in the develop- ment of colon carcinoma include positive regulators Toll-like receptors such as the proinflammatory cytokines tumor necrosis Toll-like receptors have a major role in sensing gut factor-a (TNFa), interleukin-1 (IL-1), IL-6 and proin- microbiota, and activation of these receptors is required flammatory CC-chemokines; negative regulators such as to maintain intestinal homeostasis that is often dis- transforming growth factor-b (TGFb), IL-10, TIR8 turbed in IBD. Polymorphisms in TLR4 have been (also known as single immunoglobulin IL-1R-related associated with UC and CD (Fukata and Abreu, 2008). molecule, SIGIRR), decoy receptor D6, cyclooxygen- TLR4 is upregulated in intestinal epithelial cells in active ase-2 (COX-2) as well as innate immunity receptors and CD and UC (Cario and Podolsky, 2000), and its signaling molecules such as toll-like receptor 4 (TLR4), signaling induces COX-2, prostaglandin E2 and reactive MyD88; and the master nuclear oxygen species (Fukata and Abreu, 2008). factor kB (NF-kB) (Figure 3). Evidence is mounting to support a role for TLRs in . It was shown that a deficiency in the Immune cells in CAC TLR adaptor, MyD88, significantly reduced tumor Colitis-associated cancer is characterized by a dense number and size in the Apcmin/ þ mouse model of infiltrate of immune cells, including macrophages, intestinal tumorigenesis (Rakoff-Nahoum and Medzhitov, dendritic cells and T cells, which include the subset of 2007). Furthermore, the absence of bacteria in several CD8 þ and CD4 þ (T-bet þ ) effector T cells and mouse models of inflammation-associated cancer has CD4 þ CD25 þ T cells (Waldner et al., 2006). How- resulted in abrogation of dysplasia or cancer (Fukata ever, the functional role of these immune cells is only and Abreu, 2008). Thus, the presence and recognition of

Oncogene A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3315

a b

10X 10X

c d

10X 40X

Figure 2 Colitis-associated cancer. Histological colonic sections of murine healthy intestine (a) and after 7 days of 3% DSS treatment with colitis induction (b). Treatment with three weekly cycles of 3% DSS and AOM leads to histological colitis-associated cancer (c, d). bacteria in the gut seems to be necessary for inflamma- expression. Indeed, it has been shown that patients tion-associated carcinogenesis. In the gut, mice inocu- carrying the TLR4 loss-of-function allele exhibited lated with colon cancer cells silenced for expression of reduced progression-free and overall survival, as com- TLR4 showed increased survival and a significant pared with patients carrying the normal TLR4 allele, reduction in tumor size compared with mice injected when treated with oxaliplatin. These data suggest that with cells expressing control short interfering RNA inflammation can act as a double-edged sword in clinical (Huang et al., 2005). Furthermore, using the AOM–DSS cancer and that further studies are needed to dissect mouse model of CRC, it was shown that TLR4-deficient the interplay between innate and adaptive immunity mice exhibited significantly reduced tumor number and (Tesniere et al., 2010). size compared with wild-type controls (Fukata et al., 2007). In general, a close link between innate and adaptive Cytokines immunity, inflammation and carcinogenesis is well TNFa. Tumor necrosis factor-a is a key regulator of established in many forms of cancer, including CAC. inflammation that binds to and activates its receptor Indeed, pattern recognition receptors such as TLR and (TNFR), inducing the recruitment of intracellular NLR are key components of the ‘danger model’ adaptor . The TNFR can trigger NF-kBand proposed by Rakoff-Nahoum and Medzhitov (2009). downstream cell survival pathways or it can trigger They have a critical role in the recognition of microbe- caspase 8 and associated apoptotic pathways (Balkwill, specific molecules (pathogen-associated molecular 2006). patterns, PAMPs) or endogenous stress signals (da- Mice deficient for TNFa or its receptor, TNFR, are mage-associated molecular pattern, DAMPs) and the resistant to skin carcinogenesis, which directly supports subsequent birth of a more or less effective or beneficial the concept that TNFa promotes tumorigenesis (Moore . One of the DAMPs, the nuclear et al., 1999; Arnott et al., 2004). Expression of TNFa HMGB1 , has been associated with the prolif- was also increased in gastric lesions and inflamed eration and metastasis of many tumor types. Very colonic mucosa of patients with IBD (Noach et al., recently, the clinical efficacy of some chemotherapeutic 1994; Noguchi et al., 1998). However, reports on the agents, such as oxaliplatin, has been related to TLR4 role of TNFa have been conflicting, potentially acting as

Oncogene A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3316

Negative regulators Colonic lumen Positive regulators TGF-β TNF-α IL-10 IL-6 TIR8 CCL2 D6 CC chemokines COX-2

D6 Innate immunity receptor and signaling molecules

Lymphatics TLR-4 MyD88 TLR-4 Ikkβ NFkB Tumor cell P IKKβ MyD88

T-cell NFκB

Macrophages

Figure 3 Overview of the molecules that have been implicated in the development of colitis-associated cancer that include positive and negative regulators, innate immunity receptors and signaling molecules.

either a tumor-promoting or tumor-destructive factor specific TNFa antagonist etanercept in the AOM (Szlosarek et al., 2006). At high doses, hemorrhagic challenge model. In these mice, neutrophil and macro- tumor necrosis occurs through selective destruction of phage infiltration into the mucosa was decreased, as was tumor blood vessels and activation of T cells that attack tumor number and size. Although etanercept is cur- and eliminate tumor cells. However, the levels of TNFa rently used for the treatment of rheumatoid arthritis, it required for this activity can be extremely toxic. showed insufficient efficacy compared with anti-TNFa However, at the low doses seen during chronic produc- monoclonal for the treatment of IBD. tion, expression of TNFa is observed in several tumor Nonetheless, these data point to the possibility that types and is important in the promotion of all stages of monoclonal antibodies directed against TNFa could cancer development, that is, from growth to invasion have a similar ability to inhibit tumor formation in these and metastasis. Indeed, several clinical studies provide patients (Burstein and Fearon, 2008). Patients who have evidence that TNFa contributes to the development of been exposed to anti-TNF antibodies were determined human cancers, including CRC. TNFa is found in the to be at increased risk of developing cancers, in a study microenvironment of many types of tumor, including that included patients who developed colon cancer breast, ovarian, colorectal, prostate, melanoma, lym- (Bongartz et al., 2006). However, no safety concerns phomas and leukemia (Szlosarek and Balkwill, 2003; regarding the incidence of IBD-associated colon carci- Balkwill, 2009) Specifically, in CRC, the mRNA and noma were identified in a recent study of patients who protein levels of TNFa are increased to abnormal levels were administered infliximab (Biancone et al., 2009). in the preneoplastic inflamed colonic mucosa (Noguchi et al., 1998). The role of the signaling pathways downstream of IL-6. Interleukin-6 is considered to be an important TNFa was explored in mice deficient in the type 1 TNF player in the transition between acute and chronic receptor, p55 (Popivanova et al., 2008). In the absence Inflammation, as well as between innate and acquired of TNFa signaling, there was decreased mucosal immunity, especially in intestinal inflammation (Hoebe damage, inflammatory cell infiltrates and et al., 2004; Jones, 2005). It modulates chemokine and expression in the mucosa, in response to the AOM adhesion molecule expression and apoptosis, suppres- challenge and DSS, as well as a significant reduction in sing neutrophil infiltration and promoting the accumu- tumor formation. Wild-type mice were administered the lation of mononuclear leukocytes, which directs the

Oncogene A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3317 resolution of acute inflammation and the activation of 1997; Luster, 1998; Mantovani, 1999). Their biological acquired immunity (Hurst et al., 2001; McLoughlin functions include diverse activities such as leukocyte et al., 2003; Mantovani et al., 2005). Evidence that IL-6 recruitment to sites of or inflammation, tumor has such a role came from the demonstration that metastasis, tissue patterning during development and inhibition of IL-6 signaling affected chemotaxis and human immunodeficiency virus-1 infection (Kelvin apoptosis of lamina propria mononuclear cells, improv- et al., 1993; Murphy, 1994; Murphy et al., 2000). Beside ing disease outcome in animal models of colitis (Atreya the conventional signaling receptors, ‘decoy’ chemokine- et al., 2000; McLoughlin et al., 2003). In clinical studies, binding proteins with structural similarity with conven- high levels of IL-6 and a soluble form of the IL-6 tional receptors but lacking signaling function, that is, receptor were shown in the peripheral blood of patients decoy receptors, have been described (D’Amico et al., with IBD, in which it promotes accumulation of T cells 2000; Mantovani et al., 2001). Essential attributes for in the lamina propria of the colon by upregulating the decoy receptors include loss of signaling function antiapoptotic factors, including Bcl-2 and Bcl-xl (Atreya and the desensitization response, while retaining high- et al., 2000; McLoughlin et al., 2003). IL-6 has also been affinity ligand binding. shown to have an important role in the generation of The atypical chemokine receptor D6, a decoy and TH17, the main pathogenic cells in CD (Mangan et al., scavenger receptor that is mainly expressed on non- 2006; Bettelli et al., 2006). hematopoietic cells, such as endothelial cells lining In human cancers, increased IL-6 levels have been afferent lymphatics in skin and (Nibbs et al., observed in both the serum of cancer patients and in 2001) and trophoblasts in the placenta (Nibbs et al., tumor biopsies (Chung and Chang, 2003; Kai et al., 1997) and in some leukocyte subsets (Nibbs et al., 1997, 2005). The role of IL-6 has subsequently been explored 2001; Bonecchi et al., 2004; Mantovani et al., 2006; in genetically manipulated loss-of-function and gain-of- Martinez de la Torre et al., 2007), selectively recognizes function mice (Bollrath et al., 2009; Grivennikov et al., and efficiently depletes most of the inflammatory 2009). Both loss-of-function and gain-of-function mice CC-chemokines from the extracellular milieu. Nibbs underwent the AOM challenge protocol. After induc- et al. (2007) investigated chemically induced de novo tion of colitis, it was shown that IL-6, which was mainly cutaneous tumor formation, and found that D6- produced by lamina propria myeloid cells, promoted deficient mice have increased susceptibility to disease proliferation and survival of premalignant intestinal development. epithelial cells, thus enhancing both initiation and D6 knock-out mice develop more severe colitis, which progression of CAC (Bollrath et al., 2009; Grivennikov is associated with an increased production of chemo- et al., 2009). The AOM experimental model was also kines and inflammatory cell recruitment (Vetrano et al., used to directly address whether IL-6 has a role in the 2009). When cancer is chemically induced in the D6 development of colon cancer. In the mouse AOM knock-out mice, D6 absence in the nonhematopoietic challenge model, tumor growth was dependent on the compartment leads to increased susceptibility of inflam- IL-6 from the inflamed tissues, whereas blockade of IL-6 mation and malignancy development. Finally, the signaling dramatically reduced the size and number of expression is increased in the lymphatic vascular bed tumors in these mice (Becker et al., 2004). On the other of colonic sections from humans with IBD compared hand, deletion of suppressor of cytokine signaling 3, with that in healthy humans, and this increase is even which limits the ability of IL-6 to activate transcription, more marked in patients who have developed colon results in mice with increased susceptibility to AOM/ cancer associated with IBD. These results point to a DSS-induced tumors (Rigby et al., 2007). novel and previously unknown role of D6 in the control Finally, Li et al. (2010) investigated the expression of of intestinal inflammation and inflammation-associated IL-6 and its epithelial targets in patients with UC who colon cancer through the . had progressed to CRC. They found that the expression Tumor necrosis factor-a induces expression of che- of both IL-6 and STAT3 was greater in both patients mokines from a variety of colonic cells such as epithelial with active UC and those who had progressed to CAC, cells, fibroblasts, endothelial cells and leukocytes (Wang compared with both patients with inactive disease and et al., 2003), thereby having an indirect chemotactic control patients. On the other hand, the expression of effect on macrophages and granulocytes. Indeed, the suppressor of cytokine signaling 3 was increased in mucosa of patients with IBD exhibited enhanced patients with either inactive or active UC, compared mRNA and protein expression of MCP-1/CCL2 with control individuals, but was decreased in patients (Reinecker et al., 1995; Mazzucchelli et al., 1996; with UC who had progressed to CRC. These data Uguccioni et al., 1999), a CC-chemokine with potent indicate that IL-6 and STAT3 have an important role in chemotactic and activating activities for / CAC, whereas loss of suppressor of cytokine signaling 3 macrophages (Matsushima et al., 1989). They observed is important to its progression (Li et al., 2010). that CCL2 mRNA expression was enhanced in the colon of the AOM challenged mouse model, and that blocking the TNFa/TNFR axis reduced colorectal Chemokines carcinogenesis, intracolonic macrophage infiltration Chemokines are a superfamily of small secretory and CCL2 mRNA expression (Popivanova et al., proteins that mediate the directional migration of both 2008). These observations prompted investigation of hematopoietic and nonhematopoietic cells (Rollins, the roles of CCL2 and its specific receptor, CCR2, in the

Oncogene A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3318 AOM challenged mouse model. In the presence of tumor formation, thus reinforcing the concept that CCL2-blocking agents, the expression of CCL2 was immunoregulatory molecules, such as IL-10 and TGFb, enhanced, together with intracolonic massive infiltration have a protective effect on intestinal inflammation and of macrophages, which were a major source of COX-2. in CAC formation (Becker et al., 2006). Mice deficient in CCR2 exhibited less macrophage Complementary data were obtained by Fantini et al. infiltration and lower tumor numbers with attenuated (2009), who generated mice transgenic for the TGFb COX-2 expression. Moreover, CCL2 antagonists de- inhibitor smad7, with overexpression specifically on T creased intracolonic macrophage infiltration and COX-2 cells. Although these mice developed a greater severity expression, attenuated neovascularization and even- of colitis in response to the AOM/DSS challenge, the tually reduced the numbers and size of colon tumors, mice only developed few, small tumors compared with even when given after multiple colon tumors had the many large tumors that developed in wild-type mice. developed. These observations identify CCL2 as a Interestingly, high expression of IFNg, IL-6 and IL-17 crucial mediator of the initiation and progression of were found in the tumor-free areas of the smad7 chronic colitis-associated colon carcinogenesis and transgenic mice, indicating a potential for IFNg in suggest that targeting CCL2 may be useful in treating antitumor responses in the gut. However, this is in colon cancers, particularly those associated with chronic contrast to work by Osawa et al. (2006). In a variation on inflammation (Popivanova et al., 2009). the standard AOM model, involving induction of colitis In addition to the mechanistic studies that have with trinitrobenzene sulfonic acid after the initial admin- addressed the direct role of chemokines in CAC, it is istration of AOM, Osawa and colleagues showed that also worth mentioning that chemokines are involved in mice genetically deficient for IFNg develop significantly a variety of functions, including angiogenesis. As fewer tumors compared with either wild-type mice angiogenesis is an essential step in the tissue damage or with IL-4-deficient mice. These conflicting reports and remodeling associated with IBD, and this is indicate the complexity of the underlying mechanisms. dependent on several chemokines, it is likely that chemokines could also have a role in CAC by promoting TIR8. Signaling by TLRs and IL-1 receptors is and maintaining the pathological angiogenesis present controlled by negative regulatory pathways (Brint in intestinal tumors. et al., 2004; Mantovani et al., 2004). A recently identified orphan member of the IL-1 receptor family, Negative regulators TIR8, inhibits signaling from IL-1R/TLR complexes, IL-10. Interleukin-10 is a key mediator in the patho- possibly by trapping interleukin-1 receptor-associated genesis of IBD. It has long been established that mice kinase-1 and TNF receptor-associated factor-6 (Tho- genetically deficient for IL-10 develop spontaneous massen et al., 1999; Polentarutti et al., 2003; Wald et al., enterocolitis (Kuhn et al., 1993). Very recently, Glocker 2003; Mantovani et al., 2004). TIR8 transfer et al. (2009) showed that patients with mutations in the experiments have revealed that it reduces activation of IL-10 receptors that abrogate IL-10 signaling develop NF-kB by the IL-1R complex (Polentarutti et al., 2003), early and aggressive disease. IL-10 knock-out mice go as well as by members of the TLR family (Wald et al., on to develop CAC through a mechanism that has been 2003; Garlanda et al., 2009). associated with aberrant Th1 cytokine production (Berg TIR8, also named SIGIRR, is expressed in several et al., 1996). In particular, the demonstration that IL-10 tissues, especially in the epithelial cells of the digestive suppresses IL-6 and controls CAC development in a tract (Polentarutti et al., 2003). Accordingly, there is model of microbial CRC indicates that control of CAC evidence for a nonredundant regulatory role of this development by IL-10 may be at least partially mediated molecule in inflammation involving the gastrointestinal through IL-6. Taken together, these data reinforce the mucosa (Garlanda et al., 2004, 2007; Xiao et al., 2007). notion that IL-10 is a key mediator for intestinal Tir8-deficient mice administered DSS exhibited dra- immune homeostasis, and suggest that IL-10-dependent matic weight loss, intestinal bleeding and mortality, inflammation influences IL-6-driven CAC development. whereas the susceptibility to CAC in the AOM challenge model was increased. An important end point of TLR signaling is NF-kB activation, and aberrant TLR Transforming growth factor-b signaling may contribute to the tumor-promoting Transforming growth factor-b has long been implicated activity of NF-kB. Interestingly, prostaglandin E2, in the pathogenesis of sporadic CAC. However, the proinflammatory cytokines (IL-1 and IL-6) and chemo- mechanism underlying its involvement has only recently kines (KC/CXC, JE/CCL2 and CCL3) are present been elucidated. In an elegant set of experiments, Becker downstream of NF-kB. The lack of a checkpoint et al. (2006) investigated the functional role of TGFb (TIR8) of NF-kB activation leads to increased carcino- using the AOM model with TGFb receptor-deficient genesis in the gastrointestinal tract. Thus, specific TLR and TGFb transgenic mice. The authors reported that pathways may provide new targets for therapies to the TGFb receptor-deficient mice developed a signifi- interrupt oncogenic pathways associated with IBD. cantly higher number of tumors than wild-type mice, whereas the opposite occurred in the TGFb transgenic mice. In mechanistic studies, the authors found that, COX-2. Cyclooxygenase-2 is a cytoplasmic protein similar to IL-10, TGFb also inhibited IL-6-dependent that catalyzes the synthesis of lipid inflammatory

Oncogene A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3319 mediators (prostaglandins and prostacyclins) from sensing molecules, or by TNFa and IL-1b (Mantovani arachidonic acid. Expression is increased at the sites of et al., 2008). Regulation of NF-kB involves sequestration inflammation (Herschman et al., 1995), as well as in of NF-kB in the cytoplasm by the inhibitor kB, which is in B80% of CRCs and 40% of colorectal adenomas turn regulated through phosphorylation by the inhibitor (Eberhart et al., 1994). Indeed, the COX-2 protein is kB kinase (IKK) complex, targeting it for ubiquitin- found in the cytoplasm of neoplastic colonic epithelial dependent degradation (Greten and Karin, 2004; Bollrath cells and to a lesser extent in stromal cells, whereas and Greten, 2009). Degradation of inhibitor kB releases normal is negative for COX-2 (Sinicrope and NF-kB, allowing it to translocate to the nucleus, wherein Gill, 2004). Finally, the expression of COX-2 is also it mediates transcription of downstream targets that can upregulated in neoplastic cells in mice with mutations in be separated into four functional categories: antiapoptotic the tumor suppressor Apc, after the AOM/DSS chal- genes, inflammatory and immunoregulatory genes, genes lenge (Sinicrope and Gill, 2004). that promote cell-cycle progression and genes that encode The fact that COX-2 is important in the development negative regulators of NF-kB. Many of these targets have of CAC is further supported by the demonstration that been associated with cancer initiation and progression nonsteroidal antiinflammatory drugs that specifically (Greten and Karin, 2004). target COX-2 (coxibs) can reduce both the incidence of Greten et al. (2004) showed that IKKb links inflamma- colon cancer and mortality rate in rodent models and tion and tumorigenesis in a mouse model of CAC, in humans (Jacoby et al., 2000; Oshima et al., 2001). COX- which IKKb was deleted either in intestinal epithelial cells 2 may contribute to tumor development by modulating or in the myeloid cells. CRC was induced in these two apoptosis, angiogenesis and tumor invasiveness, as different mouse models, with AOM and DSS. When NF- overexpression of COX-2 in rat intestinal epithelial cells kB activity was disrupted in colonic epithelial cells, there had increased adherence to the extracellular matrix, was a dramatic reduction in tumor number in these mice. resistance to apoptosis-inducing agents and upregula- This was associated with enhanced epithelial cell apopto- tion of the antiapoptotic protein B-cell lymphoma-2 sis during early tumor development, whereas there was no (Bcl-2) (Tsujii and DuBois, 1995). Similar results were reduction in inflammation. Thus, the authors concluded obtained when COX-2 was overexpressed in human that activation of NF-kB in epithelial cells contributes to colon cancer cells, with COX-2 providing resistance tumor initiation and promotion, primarily by suppressing to apoptosis after treatment with antineoplastic drugs apoptosis. In mice with IKKb deleted in the myeloid cells, (Sun et al., 2002). there was reduced expression of many genes involved in Cyclooxygenase-2 also has a role in the progression of inflammatory responses, including IL-1b, IL-6, macro- cancer, by activating metalloprotease, matrix metallo- phage inflammatory protein 2, TNFa, COX-2 and proteinase-2, and thereby increasing the invasiveness of intercellular adhesion molecule (Greten et al., 2004). colon cancer cells (Li et al., 2002). Furthermore, These mice exhibited a significant reduction in tumor size suppression of COX-2 in human prostate tumor cells and some reduction in tumor number. From these results, by a selective COX-2 inhibitor resulted in reduced levels the authors suggest that myeloid cells contribute to tumor of matrix metalloproteinase-2 and matrix metallo- development through production of paracrine signaling proteinase-9 (Attiga et al., 2000). As COX-2 has an molecules that promote tumor growth. NF-kB has also extensive role in inflammation and various aspects of been shown to induce vascular endothelial growth factor carcinogenesis, it is an attractive target for therapeutic and COX-2, which promote angiogenesis (Greten and intervention in inflammatory disorders and cancer. Karin, 2004). A search for COX-2-specific inhibitors resulted in The role of NFkB in the homeostasis of the epithelial promising candidates, such as valdecoxib, celecoxib barrier homeostasis and in the response to microbes and and rofecoxib. However, although the chemopreventive inflammatory signals is complex (Pasparakis, 2008). It action of these drugs is promising, the effects of therefore remains to be established whether it represents a COX-2 inhibitors in IBD is deleterious, as these drugs valuable target for the prevention and treatment of CAC. have negative effects on intestinal inflammation, by worsening the disease (Matuk et al., 2004). Conclusions and implications for therapy and prophylaxis

NF-kB. Activation of NF-kB is associated with Colon cancer has provided a paradigm for the connec- various types of cancers, including colon cancer, which tion between inflammation and cancer. However, key is not surprising given its key role in innate immunity, questions remain open. There is strong evidence show- inflammation and cell proliferation and survival (Naug- ing that T-cell infiltration, presumably a manifestation ler and Karin, 2008). It also controls the expression of of effective adaptive immunity, is a favorable prognostic inflammatory cytokines, adhesion molecules, enzymes in element in colon cancer (Laghi et al., 2009). Whether the prostaglandin synthesis pathway (including COX-2), and to what extent that applies to the tumors inducible nitric oxide synthase and a number of anti- epidemiologically related to colitis remains to be apoptotic genes, including Bcl-2, thus providing a survival defined. At a more fundamental level, activation and advantage to tumor cells (Mantovani et al., 2008). orientation of adaptive responses depends on innate Nuclear factor kB is activated by signaling pathways immunity. In other clinical settings, chemotherapy- mediated through TLRs and other microorganism- induced cell death can activate protective innate

Oncogene A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3320 responses (Apetoh et al., 2007). Thus, the Yin–Yang is an important step toward identifying new targets for balance of innate immunity and inflammation in colon therapeutic intervention. cancer and in CAC remains to be dissected. Beside TNFa, a number of other inflammatory Both association and mechanistic studies provide a cytokines and adhesion molecules are being targeted as clear link between the chronic inflammation found in potential therapies for IBD (Nakamura et al., 2006), and patients with IBD and the development of CAC. these may also be efficacious for the prevention and However, our knowledge of the molecules involved in treatment of CAC. Therapies in clinical trials include the initiation of CAC in IBD is very much in its infancy. antibodies against the p40 subunit of IL-12/IL-23 and Interestingly, some drugs routinely used for the treat- the IL-6 receptor. In addition, adhesion molecules that ment of patients have been shown to reduce the risk promote trafficking of leukocytes into the inflamed gut of CAC. wall, such as a4-integrins, vascular cellular adhesion For instance, in recent years a large amount of molecule 1 and intercellular adhesion molecule-1 are molecular data has accumulated supporting the notion being targeted with antibodies and oligodeoxynucleo- that the biological effects of 5-aminosalicylic acid (5- tides. The challenge of these strategies is to identify ASA) interfere with the development of CRC. 5-ASA therapies that can reduce aberrant inflammatory re- reduces oxidative stress, inhibits cell proliferation and sponses while retaining proper defenses against infection promotes apoptosis (Gasche, 2004; Stolfi et al., 2008b). and functional tumor surveillance mechanisms. At the molecular level, 5-ASA inhibits COX-2 (Peskar et al., 1987; Stolfi et al., 2008a), decreases transcriptional activity of NF-kB by modulating phosphorylation of Conflict of interest RelA/p65 and interferes with Wnt pathway through protein phosphatase 2A (Egan et al., 1999; Bos et al., The authors declare no conflict of interest. 2006). In addition to the therapeutic utility of 5-ASA for the prevention of CAC, the ongoing clarification of the molecular targets of 5-ASA will therefore likely provide Acknowledgements novel targets for the development of chemopreventive compounds. This study was supported by grants from the Broad Medical In addition, azathioprine was very recently reported Research Program, the Italian Ministery of Health (Ricerca to significantly decrease the risk of colon cancer in Finalizzata 2006, n.72 and Bando Giovani Ricercatori), patients with IBD (Beaugerie et al., 2009). Even though Fondazione Cariplo and the Italian Association for Cancer the mechanism is unclear, a possible explanation could Research (My first AIRC Grant) to SD, and the European be the simple reduction of mucosal inflammation and Community (INNOCHEM project 518167), the Ministero dell’Istruzione dell’Universita` e della Ricerca (Rome, Italy; the induction of mucosal healing. Overall, although PRIN project 2002061255; FIRB project RBIN04EKCX) and there is some utility of the therapeutics already used for Fondazione Cariplo (Milan, Italy; NOBEL project). This work the treatment of IBD, the ongoing elucidation of the was conducted in the context and with the support of the molecules that are involved in the development of CAC Fondazione Humanitas per la Ricerca (Rozzano, Italy).

References

Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A Balkwill F, Mantovani A. (2001). Inflammation and cancer: back to et al. (2007). Toll-like receptor 4-dependent contribution of the Virchow? Lancet 357: 539–545. immune system to anticancer chemotherapy and radiotherapy. Nat Beaugerie L, Brousse N, Bouvier AM, Colombel JF, Lemann M, Med 13: 1050–1059. Cosnes J et al. (2009). Lymphoproliferative disorders in patients Arnott CH, Scott KA, Moore RJ, Robinson SC, Thompson RG, receiving thiopurines for inflammatory bowel disease: a prospective Balkwill FR. (2004). Expression of both TNF-alpha receptor observational cohort study. Lancet 374: 1617–1625. subtypes is essential for optimal skin tumour development. Becker C, Fantini MC, Neurath MF. (2006). TGF-beta as a Oncogene 23: 1902–1910. regulator in colitis and colon cancer. Cytokine Growth Factor Rev Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S et al. (2000). 17: 97–106. Blockade of interleukin 6 trans signaling suppresses T-cell resistance Becker C, Fantini MC, Schramm C, Lehr HA, Wirtz S, Nikolaev A against apoptosis in chronic intestinal inflammation: evidence in crohn et al. (2004). TGF-beta suppresses tumor progression in colon disease and experimental colitis in vivo. Nat Med 6: 583–588. cancer by inhibition of IL-6 trans-signaling. Immunity 21: 491–501. Attiga FA, Fernandez PM, Weeraratna AT, Manyak MJ, Berg DJ, Davidson N, Kuhn R, Muller W, Menon S, Holland G et al. Patierno SR. (2000). Inhibitors of prostaglandin synthesis inhibit (1996). Enterocolitis and colon cancer in interleukin-10-deficient human prostate tumor cell invasiveness and reduce the release of mice are associated with aberrant cytokine production and CD4(+) matrix metalloproteinases. Cancer Res 60: 4629–4637. TH1-like responses. J Clin Invest 98: 1010–1020. Balkwill F. (2006). TNF-alpha in promotion and progression of Bernstein CN, Blanchard JF, Kliewer E, Wajda A. (2001). Cancer risk cancer. Cancer Metastasis Rev 25: 409–416. in patients with inflammatory bowel disease: a population-based Balkwill F. (2009). Tumour necrosis factor and cancer. Nat Rev Cancer study. Cancer 91: 854–862. 9: 361–371. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M et al. Balkwill F, Charles KA, Mantovani A. (2005). Smoldering and (2006). Reciprocal developmental pathways for the generation polarized inflammation in the initiation and promotion of of pathogenic effector TH17 and regulatory T cells. Nature 441: malignant disease. Cancer Cell 7: 211–217. 235–238.

Oncogene A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3321 Biancone L, Petruzziello C, Calabrese E, Zorzi F, Naccarato P, Onali development of colitis-associated colorectal tumors. Gastroentero- S et al. (2009). Long-term safety of Infliximab for the treatment of logy 133: 1869–1881. inflammatory bowel disease: does blocking TNFalpha reduce Garlanda C, Anders HJ, Mantovani A. (2009). TIR8/SIGIRR: an colitis-associated colorectal carcinogenesis? Gut 58: 1703. IL-1R/TLR family member with regulatory functions in inflamma- Bollrath J, Greten FR. (2009). IKK/NF-kappaB and STAT3 path- tion and T cell polarization. Trends Immunol 30: 439–446. ways: central signalling hubs in inflammation-mediated tumour Garlanda C, Riva F, Polentarutti N, Buracchi C, Sironi M, De BM promotion and metastasis. EMBO Rep 10: 1314–1319. et al. (2004). Intestinal inflammation in mice deficient in Tir8, an Bollrath J, Phesse TJ, von BV, Putoczki T, Bennecke M, Bateman T inhibitory member of the IL-1 receptor family. Proc Natl Acad Sci et al. (2009). gp130-mediated Stat3 activation in enterocytes USA 101: 3522–3526. regulates cell survival and cell-cycle progression during colitis- Garlanda C, Riva F, Veliz T, Polentarutti N, Pasqualini F, Radaelli E associated tumorigenesis. Cancer Cell 15: 91–102. et al. (2007). Increased susceptibility to colitis-associated cancer of Bonecchi R, Locati M, Galliera E, Vulcano M, Sironi M, Fra AM mice lacking TIR8, an inhibitory member of the interleukin-1 et al. (2004). Differential recognition and scavenging of native and receptor family. Cancer Res 67: 6017–6021. truncated macrophage-derived chemokine (macrophage-derived Garrett WS, Punit S, Gallini CA, Michaud M, Zhang D, Sigrist KS chemokine/CC chemokine ligand 22) by the D6 decoy receptor. et al. (2009). Colitis-associated colorectal cancer driven by T-bet J Immunol 172: 4972–4976. deficiency in dendritic cells. Cancer Cell 16: 208–219. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Gasche C. (2004). Review article: the chemoprevention of colorectal Montori V. (2006). Anti-TNF therapy in rheumatoid carcinoma. Aliment Pharmacol Ther 20(Suppl 4): 31–35. arthritis and the risk of serious and malignancies: Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F systematic review and meta-analysis of rare harmful effects in et al. (2009). Inflammatory bowel disease and mutations affecting randomized controlled trials. JAMA 295: 2275–2285. the interleukin-10 receptor. N Engl J Med 361: 2033–2045. Bos CL, Diks SH, Hardwick JC, Walburg KV, Peppelenbosch MP, Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ et al. Richel DJ. (2006). Protein phosphatase 2A is required for (2004). IKKbeta links inflammation and tumorigenesis in a mouse mesalazine-dependent inhibition of Wnt/beta-catenin pathway model of colitis-associated cancer. Cell 118: 285–296. activity. Carcinogenesis 27: 2371–2382. Greten FR, Karin M. (2004). The IKK/NF-kappaB activation Brint EK, Xu D, Liu H, Dunne A, McKenzie AN, O0Neill LA et al. pathway-a target for prevention and treatment of cancer. Cancer (2004). ST2 is an inhibitor of interleukin 1 receptor and Toll-like Lett 206: 193–199. receptor 4 signaling and maintains endotoxin tolerance. Nat Grivennikov S, Karin E, Terzic J, Mucida D, Yu GY, Vallabhapurapu Immunol 5: 373–379. S et al. (2009). IL-6 and Stat3 are required for survival of intestinal Burstein E, Fearon ER. (2008). Colitis and cancer: a tale of epithelial cells and development of colitis-associated cancer. Cancer inflammatory cells and their cytokines. J Clin Invest 118: 464–467. Cell 15: 103–113. Cario E, Podolsky DK. (2000). Differential alteration in intestinal Gyde S, Prior P, Dew MJ, Saunders V, Waterhouse JA, Allan RN. epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in (1982). Mortality in ulcerative colitis. Gastroenterology 83: 36–43. inflammatory bowel disease. Infect Immun 68: 7010–7017. Herschman HR, Xie W, Reddy S. (1995). Inflammation, reproduction, Choi PM, Zelig MP. (1994). Similarity of colorectal cancer in Crohn0s cancer and all that. The regulation and role of the inducible disease and ulcerative colitis: implications for carcinogenesis and prostaglandin synthase. Bioessays 17: 1031–1037. prevention. Gut 35: 950–954. Hoebe K, Janssen E, Beutler B. (2004). The interface between innate Chung YC, Chang YF. (2003). Serum interleukin-6 levels reflect the and adaptive immunity. Nat Immunol 5: 971–974. disease status of colorectal cancer. J Surg Oncol 83: 222–226. Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH et al. (2005). Toll- Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. (2009). like receptors on tumor cells facilitate evasion of immune Cancer-related inflammation, the seventh hallmark of cancer: links surveillance. Cancer Res 65: 5009–5014. to genetic instability. Carcinogenesis 30: 1073–1081. Hurst SM, Wilkinson TS, McLoughlin RM, Jones S, Horiuchi S, Coussens LM, Werb Z. (2002). Inflammation and cancer. Nature 420: Yamamoto N et al. (2001). Il-6 and its soluble receptor orchestrate a 860–867. temporal switch in the pattern of leukocyte recruitment seen during D’Amico G, Frascaroli G, Bianchi G, Transidico P, Doni A, Vecchi A acute inflammation. Immunity 14: 705–714. et al. (2000). Uncoupling of inflammatory chemokine receptors by Jacoby RF, Seibert K, Cole CE, Kelloff G, Lubet RA. (2000). The IL-10: generation of functional decoys. Nat Immunol 1: 387–391. cyclooxygenase-2 inhibitor celecoxib is a potent preventive and Deng L, Zhou JF, Sellers RS, Li JF, Nguyen AV, Wang Y et al. (2010). therapeutic agent in the min mouse model of adenomatous A novel mouse model of inflammatory bowel disease links polyposis. Cancer Res 60: 5040–5044. mammalian target of rapamycin-dependent hyperproliferation Jones SA. (2005). Directing transition from innate to acquired of colonic epithelium to inflammation-associated tumorigenesis. immunity: defining a role for IL-6. J Immunol 175: 3463–3468. Am J Pathol 176: 952–967. Kai H, Kitadai Y, Kodama M, Cho S, Kuroda T, Ito M et al. (2005). Eaden JA, Abrams KR, Mayberry JF. (2001). The risk of colorectal Involvement of proinflammatory cytokines IL-1beta and IL-6 in cancer in ulcerative colitis: a meta-analysis. Gut 48: 526–535. progression of human gastric carcinoma. Anticancer Res 25: Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, 709–713. DuBois RN. (1994). Up-regulation of cyclooxygenase 2 gene Karin M. (2006). Nuclear factor-kappaB in cancer development and expression in human colorectal adenomas and adenocarcinomas. progression. Nature 441: 431–436. Gastroenterology 107: 1183–1188. Kelvin DJ, Michiel DF, Johnston JA, Lloyd AR, Sprenger H, Egan LJ, Mays DC, Huntoon CJ, Bell MP, Pike MG, Sandborn WJ Oppenheim JJ et al. (1993). Chemokines and serpentines: the et al. (1999). Inhibition of interleukin-1-stimulated NF-kappaB molecular biology of chemokine receptors. J Leukoc Biol 54: RelA/p65 phosphorylation by mesalamine is accompanied 604–612. by decreased transcriptional activity. J Biol Chem 274: Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. (1993). 26448–26453. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75: Fantini MC, Rizzo A, Fina D, Caruso R, Sarra M, Stolfi C et al. 263–274. (2009). Smad7 controls resistance of colitogenic T cells to regulatory Kundu JK, Surh YJ. (2008). Inflammation: gearing the journey to T cell-mediated suppression. Gastroenterology 136: 1308–1303. cancer. Mutat Res 659: 15–30. Fukata M, Abreu MT. (2008). Role of Toll-like receptors in Laghi L, Bianchi P, Miranda E, Balladore E, Pacetti V, Grizzi F et al. gastrointestinal malignancies. Oncogene 27: 234–243. (2009). CD3+ cells at the invasive margin of deeply invading Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, (pT3-T4) colorectal cancer and risk of post-surgical metastasis: a Krishnareddy S et al. (2007). Toll-like receptor-4 promotes the longitudinal study. Lancet Oncol 10: 877–884.

Oncogene A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3322 Li G, Yang T, Yan J. (2002). Cyclooxygenase-2 increased the Nibbs RJ, Kriehuber E, Ponath PD, Parent D, Qin S, Campbell JD angiogenic and metastatic potential of tumor cells. Biochem Biophys et al. (2001). The beta-chemokine receptor D6 is expressed by Res Commun 299: 886–890. lymphatic endothelium and a subset of vascular tumors. Am J Li Y, de HC, Chen M, Deuring J, Gerrits MM, Smits R et al. (2010). Pathol 158: 867–877. Disease-related expression of the IL-6/STAT3/SOCS3 signaling Nibbs RJ, Wylie SM, Yang J, Landau NR, Graham GJ. (1997). pathway in ulcerative colitis and ulcerative colitis-related carcino- Cloning and characterization of a novel promiscuous human beta- genesis. Gut 59: 227–235. chemokine receptor D6. J Biol Chem 272: 32078–32083. Luster AD. (1998). Chemokines—chemotactic cytokines that mediate Noach LA, Bosma NB, Jansen J, Hoek FJ, van Deventer SJ, Tytgat inflammation. N Engl J Med 338: 436–445. GN. (1994). Mucosal tumor necrosis factor-alpha, interleukin-1 Mangan PR, Harrington LE, O0Quinn DB, Helms WS, Bullard DC, beta, and interleukin-8 production in patients with Helicobacter Elson CO et al. (2006). Transforming growth factor-beta induces pylori infection. Scand J Gastroenterol 29: 425–429. development of the T(H)17 lineage. Nature 441: 231–234. Noguchi M, Hiwatashi N, Liu Z, Toyota T. (1998). Secretion Mantovani A. (1999). The chemokine system: redundancy for robust imbalance between tumour necrosis factor and its inhibitor in outputs. Immunol Today 20: 254–257. inflammatory bowel disease. Gut 43: 203–209. Mantovani A. (2009). Cancer: inflaming metastasis. Nature 457: Okayasu I, Hatakeyama S, Yamada M, Ohkusa T, Inagaki Y, Nakaya 36–37. R. (1990). A novel method in the induction of reliable experimental Mantovani A, Allavena P, Sica A, Balkwill F. (2008). Cancer-related acute and chronic ulcerative colitis in mice. Gastroenterology 98: inflammation. Nature 454: 436–444. 694–702. Mantovani A, Bonecchi R, Locati M. (2006). Tuning inflammation Okayasu I, Ohkusa T, Kajiura K, Kanno J, Sakamoto S. (1996). and immunity by chemokine sequestration: decoys and more. Nat Promotion of colorectal neoplasia in experimental murine ulcerative Rev Immunol 6: 907–918. colitis. Gut 39: 87–92. Mantovani A, Locati M, Polentarutti N, Vecchi A, Garlanda C. Okayasu I, Yamada M, Mikami T, Yoshida T, Kanno J, Ohkusa T. (2004). Extracellular and intracellular decoys in the tuning of (2002). Dysplasia and carcinoma development in a repeated dextran inflammatory cytokines and Toll-like receptors: the new entry sulfate sodium-induced colitis model. J Gastroenterol Hepatol 17: TIR8/SIGIRR. J Leukoc Biol 75: 738–742. 1078–1083. Mantovani A, Locati M, Vecchi A, Sozzani S, Allavena P. (2001). Osawa E, Nakajima A, Fujisawa T, Kawamura YI, Toyama- Decoy receptors: a strategy to regulate inflammatory cytokines and Sorimachi N, Nakagama H et al. (2006). Predominant T helper chemokines. Trends Immunol 22: 328–336. type 2-inflammatory responses promote murine colon cancers. Int J Mantovani A, Sica A, Locati M. (2005). Macrophage polarization Cancer 118: 2232–2236. comes of age. Immunity 23: 344–346. Oshima M, Murai N, Kargman S, Arguello M, Luk P, Kwong E et al. Martinez de la Torre Y, Buracchi C, Borroni EM, Dupor J, Bonecchi (2001). Chemoprevention of intestinal polyposis in the Apcdelta716 R, Nebuloni M et al. (2007). Protection against inflammation- and mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. Cancer autoantibody-caused fetal loss by the chemokine decoy receptor D6. Res 61: 1733–1740. Proc Natl Acad Sci USA 104: 2319–2324. Pasparakis M. (2008). IKK/NF-kappaB signaling in intestinal Matsushima K, Larsen CG, DuBois GC, Oppenheim JJ. (1989). epithelial cells controls immune homeostasis in the gut. Mucosal Purification and characterization of a novel chemotactic Immunol 1(Suppl 1): S54–S57. and activating factor produced by a human myelomonocytic cell Peskar BM, Dreyling KW, May B, Schaarschmidt K, Goebell H. line. J Exp Med 169: 1485–1490. (1987). Possible mode of action of 5-aminosalicylic acid. Dig Dis Sci Matuk R, Crawford J, Abreu MT, Targan SR, Vasiliauskas EA, 32: 51S–56S. Papadakis KA. (2004). The spectrum of gastrointestinal toxicity and Polentarutti N, Rol GP, Muzio M, Bosisio D, Camnasio M, Riva F effect on disease activity of selective cyclooxygenase-2 inhibitors in et al. (2003). Unique pattern of expression and inhibition of IL-1 patients with inflammatory bowel disease. Inflamm Bowel Dis 10: signaling by the IL-1 receptor family member TIR8/SIGIRR. Eur 352–356. Cytokine Netw 14: 211–218. Mazzucchelli L, Hauser C, Zgraggen K, Wagner HE, Hess MW, Popivanova BK, Kitamura K, Wu Y, Kondo T, Kagaya T, Kaneko S Laissue JA et al. (1996). Differential in situ expression of the genes et al. (2008). Blocking TNF-alpha in mice reduces colorectal encoding the chemokines MCP-1 and RANTES in human carcinogenesis associated with chronic colitis. JClinInvest118: inflammatory bowel disease. J Pathol 178: 201–206. 560–570. McLoughlin RM, Witowski J, Robson RL, Wilkinson TS, Hurst SM, Popivanova BK, Kostadinova FI, Furuichi K, Shamekh MM, Kondo Williams AS et al. (2003). Interplay between IFN-gamma and IL-6 T, Wada T et al. (2009). Blockade of a chemokine, CCL2, reduces signaling governs neutrophil trafficking and apoptosis during acute chronic colitis-associated carcinogenesis in mice. Cancer Res 69: inflammation. J Clin Invest 112: 598–607. 7884–7892. Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N et al. Rakoff-Nahoum S, Medzhitov R. (2007). Regulation of spontaneous (1999). Mice deficient in tumor necrosis factor-alpha are resistant to intestinal tumorigenesis through the adaptor protein MyD88. skin carcinogenesis. Nat Med 5: 828–831. Science 317: 124–127. Murphy PM. (1994). The molecular biology of leukocyte chemoat- Rakoff-Nahoum S, Medzhitov R. (2009). Toll-like receptors and tractant receptors. Annu Rev Immunol 12: 593–633. cancer. Nat Rev Cancer 9: 57–63. Murphy PM, Baggiolini M, Charo IF, Hebert CA, Horuk R, Reinecker HC, Loh EY, Ringler DJ, Mehta A, Rombeau JL, Matsushima K et al. (2000). International union of pharmacology. MacDermott RP. (1995). Monocyte-chemoattractant protein 1 gene XXII. Nomenclature for chemokine receptors. Pharmacol Rev 52: expression in intestinal epithelial cells and inflammatory bowel 145–176. disease mucosa. Gastroenterology 108: 40–50. Nakamura K, Honda K, Mizutani T, Akiho H, Harada N. (2006). Rigby RJ, Simmons JG, Greenhalgh CJ, Alexander WS, Lund PK. Novel strategies for the treatment of inflammatory bowel disease: (2007). Suppressor of cytokine signaling 3 (SOCS3) limits damage- Selective inhibition of cytokines and adhesion molecules. World J induced crypt hyper-proliferation and inflammation-associated Gastroenterol 12: 4628–4635. tumorigenesis in the colon. Oncogene 26: 4833–4841. Naugler WE, Karin M. (2008). NF-kappaB and cancer-identifying Roessner A, Kuester D, Malfertheiner P, Schneider-Stock R. (2008). targets and mechanisms. Curr Opin Genet Dev 18: 19–26. Oxidative stress in ulcerative colitis-associated carcinogenesis. Nibbs RJ, Gilchrist DS, King V, Ferra A, Forrow S, Hunter KD et al. Pathol Res Pract 204: 511–524. (2007). The atypical chemokine receptor D6 suppresses the Rollins BJ. (1997). Chemokines. Blood 90: 909–928. development of chemically induced skin tumors. J Clin Invest 117: Sinicrope FA, Gill S. (2004). Role of cyclooxygenase-2 in colorectal 1884–1892. cancer. Cancer Metastasis Rev 23: 63–75.

Oncogene A paradigm of the Yin–Yang interplay between inflammation and cancer S Danese and A Mantovani 3323 Stolfi C, Fina D, Caruso R, Caprioli F, Sarra M, Fantini MC et al. Tsujii M, DuBois RN. (1995). Alterations in cellular adhesion and (2008a). Cyclooxygenase-2-dependent and -independent inhibition apoptosis in epithelial cells overexpressing prostaglandin endopero- of proliferation of colon cancer cells by 5-aminosalicylic acid. xide synthase 2. Cell 83: 493–501. Biochem Pharmacol 75: 668–676. Uguccioni M, Gionchetti P, Robbiani DF, Rizzello F, Peruzzo S, Stolfi C, Pellegrini R, Franze E, Pallone F, Monteleone G. (2008b). Campieri M et al. (1999). Increased expression of IP-10, IL-8, MCP- Molecular basis of the potential of mesalazine to prevent colorectal 1, and MCP-3 in ulcerative colitis. Am J Pathol 155: 331–336. cancer. World J Gastroenterol 14: 4434–4439. Vetrano S, Borroni EM, Sarukhan A, Savino B, Bonecchi R, Correale Sun Y, Tang XM, Half E, Kuo MT, Sinicrope FA. (2002). C et al. (2009). The lymphatic system controls intestinal inflamma- Cyclooxygenase-2 overexpression reduces apoptotic susceptibility tion and inflammation-associated colon cancer through the chemo- by inhibiting the cytochrome c-dependent apoptotic pathway in kine decoy receptor D6. Gut. 59: 197–206. human colon cancer cells. Cancer Res 62: 6323–6328. Wald D, Qin J, Zhao Z, Qian Y, Naramura M, Tian L et al. (2003). Szlosarek P, Charles KA, Balkwill FR. (2006). Tumour necrosis SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 factor-alpha as a tumour . Eur J Cancer 42: 745–750. receptor signaling. Nat Immunol 4: 920–927. Szlosarek PW, Balkwill FR. (2003). Tumour necrosis factor alpha: Waldner M, Schimanski CC, Neurath MF. (2006). Colon cancer and a potential target for the therapy of solid tumours. Lancet Oncol 4: the immune system: the role of tumor invading T cells. World J 565–573. Gastroenterol 12: 7233–7238. Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F Wang H, Czura C, Tracey K. (2003). The Cytokine Handbook In: et al. (2010). Immunogenic death of colon cancer cells treated with Thomson A. and Lotze M. (eds). Elsevier Science: London, pp 837–860. oxaliplatin. Oncogene 29: 482–491. Xiao H, Gulen MF, Qin J, Yao J, Bulek K, Kish D et al. (2007). The Thomassen E, Renshaw BR, Sims JE. (1999). Identification and Toll-interleukin-1 receptor member SIGIRR regulates colonic characterization of SIGIRR, a molecule representing a novel epithelial homeostasis, inflammation, and tumorigenesis. Immunity subtype of the IL-1R superfamily. Cytokine 11: 389–399. 26: 461–475.

Oncogene