What can rheumatologists learn from translational cancer therapy?

It is well established that an intimate connection exists between inflammation and neoplasia. Indeed, particular chronic infections and autoimmune processes giving rise to prolonged site-specific inflammation are known to increase the probability of the development of specific cancers. Molecular characterisation of these processes has revealed profound similarities in the specific molecules involved in persistence of inflammation and in both the primary induction of neoplastic processes and in specification of the preferred anatomic sites of metastatic spread. The therapeutic importance of these findings is underscored by the remarkable success in the treatment of autoimmune pathology using medications initially developed for use in oncology and this arena is one of considerable therapeutic promise for rheumatologists.

An intimate connection between infl ammation and cancer has been proposed for decades based upon both biological similarities and clinical observation. Numerous autoimmune diseases are associated with neoplasia, with an elevated risk of lymphoma in Sjögren's syndrome [1] and rheumatoid arthritis [2], and gastrointestinal infl ammation in Crohn's disease and ulcerative colitis is likewise associated with increased risk of intestinal neoplasia [3]. Infl ammation induced by infectious organisms may also result in neoplasia, as exemplifi ed by the association of Helicobacter pylori infection and gastric cancer, hepatitis C virus and hepatic cancer [4] and schistosomiasis and bladder cancer [5]. It has been estimated that 15% of malignancies may be caused by an underlying infection [6].
One of the most fundamental biological similarities between infl ammation and cancer is the presence of similar infl ammatory cells in these processes, and on occasions these immune cells have been demonstrated to be essential for tumour progression. Mast cells, for example, are required for tumour growth in a model of pancreatic cancer [7] and macrophages promote invasive, metastatic behaviour in murine mammary cancer [8]. Th e importance of these cellular similarities is underscored by the observation that inhibition of tyrosine kinase activity with imatinib is an established therapeutic strategy in systemic mastocytosis [9] and chronic myeloid leukaemia [10], but has also been reported to be eff ective in rheumatoid arthritis [11][12][13]. Tumours frequently manipulate the host immune response -for example, by secreting chemokines to induce a tolerogenic cellular microenvironment -and may stimulate angiogenesis through elaboration of infl ammatory cytokines [14]. As well as cells, infl ammatory signalling molecules such as NF-kB are often shared between neoplastic and infl ammatory conditions, and these molecules promote both processes. Th us, inactivation of this pathway in intestinal epithelial cells results in a direct reduction of tumour incidence, whereas its inactivation in myeloid cells, which cause infl ammation, results in a reduction of proinfl ammatory cytokines and resultant decrease in tumour size [15]. Similarly, both NF-κB and STAT-3 signalling pathways have been strongly implicated in hepatoma development [16]. Further examples of the shared role of molecules in neoplasia and infl ammatory arthritis include the Myc oncoprotein, which has also been shown to induce angiogenesis through the elaboration of IL-1β [17]. As well as this role in tumour vascularisation, this cytokine contributes to infl ammation in rheumatoid arthritis, as indicated by the eff ects of IL-1β neutralisation in this disease [18]. Given the importance of the signalling pathway that operates through the mammalian target of rapamycin (mTOR) in both immune and neoplastic cells, attention is currently focussed on therapeutic approaches centred on this molecule for both autoimmune and neoplastic pathologies [19,20].
Suggestions of a causal role of infl ammation in cancer emerge from the observation that the development of

Abstract
It is well established that an intimate connection exists between infl ammation and neoplasia. Indeed, particular chronic infections and autoimmune processes giving rise to prolonged site-specifi c infl ammation are known to increase the probability of the development of specifi c cancers. Molecular characterisation of these processes has revealed profound similarities in the specifi c molecules involved in persistence of infl ammation and in both the primary induction of neoplastic processes and in specifi cation of the preferred anatomic sites of metastatic spread. The therapeutic importance of these fi ndings is underscored by the remarkable success in the treatment of autoimmune pathology using medications initially developed for use in oncology and this arena is one of considerable therapeutic promise for rheumatologists. neoplasia in response to infl ammation is strongly associated with the chronicity and intensity of the infl ammatory stimulus. Patients with high disease activity in rheumatoid arthritis thus have the highest chance of developing lymphoma [2]. Indeed, pro-infl ammatory molecules produced within infl ammatory lesions can themselves directly promote genomic instability, as exemplifi ed by reactive oxygen and nitrogen species that result in DNA damage [21]. Early experiments demonstrated that culture with neutrophils elaborating reactive oxygen species endows fi broblasts with an ability to induce tumour development when transferred into mice [22]. Moreover, the rapid cell proliferation asso ciated with infl ammation results in further cellular susceptibility to DNA damage in an environment where, in addition, DNA repair processes are themselves com promised. Coculture of activated neutrophils with human alveolar epithelial cells reveals that neutrophils and the hypochlorous acid that they produce can strongly inhibit nucleotide excision repair (NER) of damaged DNA and this eff ect can be abrogated by inhibiting production of hypochlorous acid [23]. Infl ammatory cells, moreover, express tissue degradative enzymes and promote angiogenesis, processes that aid neoplastic cells to metastasise.
Th at infl ammation itself can induce genetic mutation and thus predispose to neoplastic development is demonstrated by the spontaneous infl ammatory bowel disease that develops in interleukin-10 defi cient mice, since this is associated with a colonic mutation rate fi ve times greater than wild-type mice, with a ten-fold increase in small deletions and insertions to DNA [24]. Indeed, mutations of p53 are found in both human infl ammatory bowel disease [25] and rheumatoid synovium [26]. In addition to compromised p53 activity through mutation, this molecule can also be functionally inhibited by the pro-infl ammatory molecule macrophage migration inhibitory factor [27], demonstrating another important means by which infl ammation, if unchecked, can potentially induce dysregulated cellular proliferation.
Th e shared use of chemokine receptors in driving both tissue-specifi c infl ammation and tissue-specifi c metastases of neoplastic cells has received increasing attention. Indeed, the chemokine receptors CXCR4 and CCR7 are expressed on breast cancer tumours and metastases, and their ligands highly expressed in the preferential metastatic sites [28]. Diff erential expression of chemokine receptors on diff erent tumours and their ligands in metastatic sites explains the diff erential patterns of metastases, just as these molecules co-ordinate immune cell traffi cking.
Th e extremely potent pro-infl ammatory cytokine IL-23 demonstrates a further central connection between autoimmune disease and cancer. Th is cytokine is central to autoimmune infl ammation and has been shown to play a fundamental role in spondyloarthropathy, for which it is a promising therapeutic target [29]. However, IL-23 is also expressed within the vast majority of human carcinomas, where it promotes infl ammation and expression of degradative enzymes such as MMP9 [30]. In neoplastic settings, IL-23 inhibits protective antitumour immunity. In addition to IL-23, other proinfl ammatory cytokines have been demonstrated to be important in promoting neoplasia, with TNF, IL-1 and IL-6 playing key roles in ovarian cancer [31], and these molecules are established therapeutic targets that are neutralised in routine clinical practice for rheumatoid arthritis [18,32,33].
Th e intimate connection between infl ammation and cancer has encouraged the use of anti-infl ammatory agents to halt neoplastic development. Indeed, aspirin has been shown to reduce the incidence of cancer [34] and mice with defi ciency in the COX enzymes that this drug targets have reduced skin tumorigenesis [35]. Indeed, the reduced incidence of gastrointestinal and gynaecological cancers in rheumatoid arthritis patients has been attributed to non-steroidal anti-infl ammatory drug (NSAID) use [36]. Many chemotherapeutic agents are in clinical use not only for treatment of cancer, but also for immune-mediated infl ammation, prime examples being cyclophosphamide and methotrexate. Moreover, modern biological agents are also effi cacious in both settings. Th us, rituximab is used to treat haematological malignancy, being eff ective in follicular and mantle cell lymphoma and diff use large B cell lymphoma [37], but also signifi cantly improves clinical outcomes in rheu matoid arthritis [38]. Even TNF blockade, which some view as potentially facilitating oncogenesis, may also be viewed as protective against cancer development with recent studies conducted in renal cell and ovarian carcinoma [39][40][41][42].
Both infl ammatory conditions [43] and cancer [44] are associated with extensive modulation of local stromal tissue, with elaboration of pro-infl ammatory molecules. Moreover, the aforementioned mutations in p53 in rheumatoid synovium occur in islands of the intimal lining, most likely in type B fi broblast-like synoviocytes, and this is associated with elevated production of IL-6, the latter itself driving infl ammation. Indeed, infl am mation itself is worse in mice defi cient in p53, which develop more severe collagen-induced arthritis [45]. Given the success of agents targeting cancer-associated stromal cells in general and the fi broblast markers FAP [46] and CD248 [47] in particular, targeting similar pathogenic stromal cells in immune-mediated infl ammation has already shown [48], and is likely to continue to show, considerable promise.