What can rheumatologists learn from translational cancer therapy?
© BioMed Central Ltd 2013
Published: 1 May 2013
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 inflammation 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  and rheumatoid arthritis , and gastrointestinal inflammation in Crohn's disease and ulcerative colitis is likewise associated with increased risk of intestinal neoplasia . Inflammation induced by infectious organisms may also result in neoplasia, as exemplified by the association of Helicobacter pylori infection and gastric cancer, hepatitis C virus and hepatic cancer  and schistosomiasis and bladder cancer . It has been estimated that 15% of malignancies may be caused by an underlying infection .
One of the most fundamental biological similarities between inflammation and cancer is the presence of similar inflammatory 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  and macrophages promote invasive, metastatic behaviour in murine mammary cancer . The 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  and chronic myeloid leukaemia , but has also been reported to be effective in rheumatoid arthritis [11–13]. 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 inflammatory cytokines . As well as cells, inflammatory signalling molecules such as NF-kB are often shared between neoplastic and inflammatory conditions, and these molecules promote both processes. Thus, inactivation of this pathway in intestinal epithelial cells results in a direct reduction of tumour incidence, whereas its inactivation in myeloid cells, which cause inflammation, results in a reduction of pro-inflammatory cytokines and resultant decrease in tumour size . Similarly, both NF-κB and STAT-3 signalling pathways have been strongly implicated in hepatoma development . Further examples of the shared role of molecules in neoplasia and inflammatory arthritis include the Myc oncoprotein, which has also been shown to induce angiogenesis through the elaboration of IL-1β . As well as this role in tumour vascularisation, this cytokine contributes to inflammation in rheumatoid arthritis, as indicated by the effects of IL-1β neutralisation in this disease . 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 auto-immune and neoplastic pathologies [19, 20].
Suggestions of a causal role of inflammation in cancer emerge from the observation that the development of neoplasia in response to inflammation is strongly associated with the chronicity and intensity of the inflammatory stimulus. Patients with high disease activity in rheumatoid arthritis thus have the highest chance of developing lymphoma . Indeed, pro-inflammatory molecules produced within inflammatory lesions can themselves directly promote genomic instability, as exemplified by reactive oxygen and nitrogen species that result in DNA damage . Early experiments demonstrated that culture with neutrophils elaborating reactive oxygen species endows fibroblasts with an ability to induce tumour development when transferred into mice . Moreover, the rapid cell proliferation associated with inflammation results in further cellular susceptibility to DNA damage in an environment where, in addition, DNA repair processes are themselves compromised. 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 effect can be abrogated by inhibiting production of hypochlorous acid . Inflammatory cells, moreover, express tissue degradative enzymes and promote angiogenesis, processes that aid neoplastic cells to metastasise.
That inflammation itself can induce genetic mutation and thus predispose to neoplastic development is demonstrated by the spontaneous inflammatory bowel disease that develops in interleukin-10 deficient mice, since this is associated with a colonic mutation rate five times greater than wild-type mice, with a ten-fold increase in small deletions and insertions to DNA . Indeed, mutations of p53 are found in both human inflammatory bowel disease  and rheumatoid synovium . In addition to compromised p53 activity through mutation, this molecule can also be functionally inhibited by the pro-inflammatory molecule macrophage migration inhibitory factor , demonstrating another important means by which inflammation, if unchecked, can potentially induce dysregulated cellular proliferation.
The shared use of chemokine receptors in driving both tissue-specific inflammation and tissue-specific 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 . Differential expression of chemokine receptors on different tumours and their ligands in metastatic sites explains the differential patterns of metastases, just as these molecules co-ordinate immune cell trafficking.
The extremely potent pro-inflammatory cytokine IL-23 demonstrates a further central connection between autoimmune disease and cancer. This cytokine is central to autoimmune inflammation and has been shown to play a fundamental role in spondyloarthropathy, for which it is a promising therapeutic target . However, IL-23 is also expressed within the vast majority of human carcinomas, where it promotes inflammation and expression of degradative enzymes such as MMP9 . In neoplastic settings, IL-23 inhibits protective antitumour immunity. In addition to IL-23, other proinflammatory cytokines have been demonstrated to be important in promoting neoplasia, with TNF, IL-1 and IL-6 playing key roles in ovarian cancer , and these molecules are established therapeutic targets that are neutralised in routine clinical practice for rheumatoid arthritis [18, 32, 33].
The intimate connection between inflammation and cancer has encouraged the use of anti-inflammatory agents to halt neoplastic development. Indeed, aspirin has been shown to reduce the incidence of cancer  and mice with deficiency in the COX enzymes that this drug targets have reduced skin tumorigenesis . Indeed, the reduced incidence of gastrointestinal and gynaecological cancers in rheumatoid arthritis patients has been attributed to non-steroidal anti-inflammatory drug (NSAID) use . Many chemotherapeutic agents are in clinical use not only for treatment of cancer, but also for immune-mediated inflammation, prime examples being cyclophosphamide and methotrexate. Moreover, modern biological agents are also efficacious in both settings. Thus, rituximab is used to treat haematological malignancy, being effective in follicular and mantle cell lymphoma and diffuse large B cell lymphoma , but also significantly improves clinical outcomes in rheumatoid arthritis . 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 [39–42].
Both inflammatory conditions  and cancer  are associated with extensive modulation of local stromal tissue, with elaboration of pro-inflammatory molecules. Moreover, the aforementioned mutations in p53 in rheumatoid synovium occur in islands of the intimal lining, most likely in type B fibroblast-like synoviocytes, and this is associated with elevated production of IL-6, the latter itself driving inflammation. Indeed, inflammation itself is worse in mice deficient in p53, which develop more severe collagen-induced arthritis . Given the success of agents targeting cancer-associated stromal cells in general and the fibroblast markers FAP  and CD248  in particular, targeting similar pathogenic stromal cells in immune-mediated inflammation has already shown , and is likely to continue to show, considerable promise.
tumour necrosis factor.
- Kovács L, Szodoray P, Kiss E: Secondary tumours in Sjogren's syndrome. Autoimmun Rev. 2010, 9: 203-206. 10.1016/j.autrev.2009.07.002.View ArticlePubMedGoogle Scholar
- Franklin J, Lunt M, Bunn D, Symmons D, Silman A: Incidence of lymphoma in a large primary care derived cohort of cases of inflammatory polyarthritis. Ann Rheum Dis. 2006, 65: 617-622. 10.1136/ard.2005.044784.PubMed CentralView ArticlePubMedGoogle Scholar
- Fantini M-C, Pallone F: Cytokines: from gut inflammation to colorectal cancer. Curr Drug Targets. 2008, 9: 375-380. 10.2174/138945008784221206.View ArticlePubMedGoogle Scholar
- Chiba T, Marusawa H, Ushijima T: Inflammation-associated cancer development in digestive organs: mechanisms and roles for genetic and epigenetic modulation. Gastroenterology. 2012, 143: 550-563. 10.1053/j.gastro.2012.07.009.View ArticlePubMedGoogle Scholar
- Hirao Y, Kim W-J, Fujimoto K: Environmental factors promoting bladder cancer. Curr Opin Urol. 2009, 19: 494-499. 10.1097/MOU.0b013e32832eb4ef.View ArticlePubMedGoogle Scholar
- Kuper H, Adami HO, Trichopoulos D: Infections as a major preventable cause of human cancer. J Intern Med. 2000, 248: 171-183. 10.1046/j.1365-2796.2000.00742.x.View ArticlePubMedGoogle Scholar
- Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI: Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med. 2007, 13: 1211-1218. 10.1038/nm1649.View ArticlePubMedGoogle Scholar
- Lin EY, Nguyen AV, Russell RG, Pollard JW: Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med. 2001, 193: 727-740. 10.1084/jem.193.6.727.PubMed CentralView ArticlePubMedGoogle Scholar
- Pardanani A: Systemic mastocytosis in adults: 2012 Update on diagnosis, risk stratification, and management. Am J Hematol. 2012, 87: 401-411. 10.1002/ajh.23134.View ArticlePubMedGoogle Scholar
- Jabbour E, Kantarjian H: Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. Am J Hematol. 2012, 87: 1037-1045. 10.1002/ajh.23282.View ArticlePubMedGoogle Scholar
- Miyachi K, Ihara A, Hankins RW, Murai R, Maehiro S, Miyashita H: Efficacy of imatinib mesylate (STI571) treatment for a patient with rheumatoid arthritis developing chronic myelogenous leukemia. Clin Rheumatol. 2003, 22: 329-332. 10.1007/s10067-003-0716-3.View ArticlePubMedGoogle Scholar
- Pereira I, Fialho S, Castro G, Zimmermann A: Imatinib mesylate induces clinical remission in rheumatoid arthritis. Joint Bone Spine. 2010, 77: 372-373. 10.1016/j.jbspin.2010.03.014.View ArticlePubMedGoogle Scholar
- Ames PRJ, Aye WW, Beatty C, O'Reilly D: Imatinib treatment of seropositive arthritis in a young woman with chronic myeloid leukemia. J Rheumatol. 2008, 35: 1682-PubMedGoogle Scholar
- Marigo I, Dolcetti L, Serafini P, Zanovello P, Bronte V: Tumor-induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol Rev. 2008, 222: 162-179. 10.1111/j.1600-065X.2008.00602.x.View ArticlePubMedGoogle Scholar
- Greten FR, Eckmann L, Greten TF, Park JM, Li Z-W, Egan LJ, Kagnoff MF, Karin M: IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004, 118: 285-296. 10.1016/j.cell.2004.07.013.View ArticlePubMedGoogle Scholar
- He G, Karin M: NF-κB and STAT3 - key players in liver inflammation and cancer. Cell Res. 2011, 21: 159-168. 10.1038/cr.2010.183.PubMed CentralView ArticlePubMedGoogle Scholar
- Shchors K, Shchors E, Rostker F, Lawlor ER, Brown-Swigart L, Evan GI: The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1beta. Genes Dev. 2006, 20: 2527-2538. 10.1101/gad.1455706.PubMed CentralView ArticlePubMedGoogle Scholar
- Mertens M, Singh JA: Anakinra for rheumatoid arthritis: a systematic review. J Rheumatol. 2009, 36: 1118-1125. 10.3899/jrheum.090074.View ArticlePubMedGoogle Scholar
- Foster JG, Blunt MD, Carter E, Ward SG: Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies. Pharmacol Rev. 2012, 64: 1027-1054. 10.1124/pr.110.004051.View ArticlePubMedGoogle Scholar
- LoRusso PM: Mammalian target of rapamycin as a rational therapeutic target for breast cancer treatment. Oncology. 2013, 84: 43-56. 10.1159/000343063.View ArticlePubMedGoogle Scholar
- Jena NR: DNA damage by reactive species: Mechanisms, mutation and repair. J Biosci. 2012, 37: 503-517. 10.1007/s12038-012-9218-2.View ArticlePubMedGoogle Scholar
- Weitzman SA, Weitberg AB, Clark EP, Stossel TP: Phagocytes as carcinogens: malignant transformation produced by human neutrophils. Science. 1985, 227: 1231-1233. 10.1126/science.3975611.View ArticlePubMedGoogle Scholar
- Güngör N, Godschalk RWL, Pachen DM, Van Schooten FJ, Knaapen AM: Activated neutrophils inhibit nucleotide excision repair in human pulmonary epithelial cells: role of myeloperoxidase. FASEB J. 2007, 21: 2359-2367. 10.1096/fj.07-8163com.View ArticlePubMedGoogle Scholar
- Sato Y, Takahashi S, Kinouchi Y, Shiraki M, Endo K, Matsumura Y, Kakuta Y, Tosa M, Motida A, Abe H, Imai G, Yokoyama H, Nomura E, Negoro K, Takagi S, Aihara H, Masumura K-I, Nohmi T, Shimosegawa T: IL-10 deficiency leads to somatic mutations in a model of IBD. Carcinogenesis. 2006, 27: 1068-1073.View ArticlePubMedGoogle Scholar
- Brentnall TA, Crispin DA, Rabinovitch PS, Haggitt RC, Rubin CE, Stevens AC, Burmer GC: Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology. 1994, 107: 369-378.PubMedGoogle Scholar
- Yamanishi Y, Boyle DL, Rosengren S, Green DR, Zvaifler NJ, Firestein GS: Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc Natl Acad Sci USA. 2002, 99: 10025-10030. 10.1073/pnas.152333199.PubMed CentralView ArticlePubMedGoogle Scholar
- Hudson JD, Shoaibi MA, Maestro R, Carnero A, Hannon GJ, Beach DH: A proinflammatory cytokine inhibits p53 tumor suppressor activity. J Exp Med. 1999, 190: 1375-1382. 10.1084/jem.190.10.1375.PubMed CentralView ArticlePubMedGoogle Scholar
- Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A: Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001, 410: 50-56. 10.1038/35065016.View ArticlePubMedGoogle Scholar
- Sherlock JP, Joyce-Shaikh B, Turner SP, Chao C-C, Sathe M, Grein J, Gorman DM, Bowman EP, McClanahan TK, Yearley JH, Eberl G, Buckley CD, Kastelein RA, Pierce RH, LaFace DM, Cua DJ: IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4-CD8- entheseal resident T cells. Nat Med. 2012, 18: 1069-1076. 10.1038/nm.2817.View ArticlePubMedGoogle Scholar
- Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, Basham B, McClanahan T, Kastelein RA, Oft M: IL-23 promotes tumour incidence and growth. Nature. 2006, 442: 461-465. 10.1038/nature04808.View ArticlePubMedGoogle Scholar
- Macciò A, Madeddu C: Inflammation and ovarian cancer. Cytokine. 2012, 58: 133-147. 10.1016/j.cyto.2012.01.015.View ArticlePubMedGoogle Scholar
- Feldmann M, Maini RN: Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned?. Annu Rev Immunol. 2001, 19: 163-196. 10.1146/annurev.immunol.19.1.163.View ArticlePubMedGoogle Scholar
- Ash Z, Emery P: The role of tocilizumab in the management of rheumatoid arthritis. Expert Opin Biol Ther. 2012, 12: 1277-1289. 10.1517/14712598.2012.707178.View ArticlePubMedGoogle Scholar
- Rothwell PM, Price JF, Fowkes FGR, Zanchetti A, Roncaglioni MC, Tognoni G, Lee R, Belch JFF, Wilson M, Mehta Z, Meade TW: Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012, 379: 1602-1612. 10.1016/S0140-6736(11)61720-0.View ArticlePubMedGoogle Scholar
- Tiano HF, Loftin CD, Akunda J, Lee CA, Spalding J, Sessoms A, Dunson DB, Rogan EG, Morham SG, Smart RC, Langenbach R: Deficiency of either cyclooxygenase (COX)-1 or COX-2 alters epidermal differentiation and reduces mouse skin tumorigenesis. Cancer Res. 2002, 62: 3395-3401.PubMedGoogle Scholar
- Mercer LK, Davies R, Galloway JB, Low A, Lunt M, Dixon WG, Watson KD, Symmons DPM, Hyrich KL, British Society for Rheumatology Biologics Register (BSRBR) Control Centre Consortium: Risk of cancer in patients receiving non-biologic disease-modifying therapy for rheumatoid arthritis compared with the UK general population. Rheumatology. 2013, 52: 91-98. 10.1093/rheumatology/kes350.PubMed CentralView ArticlePubMedGoogle Scholar
- Coiffier B: Rituximab therapy in malignant lymphoma. Oncogene. 2007, 26: 3603-3613. 10.1038/sj.onc.1210376.View ArticlePubMedGoogle Scholar
- Emery P, Deodhar A, Rigby WF, Isaacs JD, Combe B, Racewicz AJ, Latinis K, Abud-Mendoza C, Szczepanski LJ, Roschmann RA, Chen A, Armstrong GK, Douglass W, Tyrrell H: Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)). Ann Rheum Dis. 2010, 69: 1629-1635. 10.1136/ard.2009.119933.PubMed CentralView ArticlePubMedGoogle Scholar
- Madhusudan S, Foster M, Muthuramalingam SR, Braybrooke JP, Wilner S, Kaur K, Han C, Hoare S, Balkwill F, Talbot DC, Ganesan TS, Harris AL: A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer. Clin Cancer Res. 2004, 10: 6528-6534. 10.1158/1078-0432.CCR-04-0730.View ArticlePubMedGoogle Scholar
- Madhusudan S, Muthuramalingam SR, Braybrooke JP, Wilner S, Kaur K, Han C, Hoare S, Balkwill F, Ganesan TS: Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer. J Clin Oncol. 2005, 23: 5950-5959. 10.1200/JCO.2005.04.127.View ArticlePubMedGoogle Scholar
- Brown ER, Charles KA, Hoare SA, Rye RL, Jodrell DI, Aird RE, Vora R, Prabhakar U, Nakada M, Corringham RE, DeWitte M, Sturgeon C, Propper D, Balkwill FR, Smyth JF: A clinical study assessing the tolerability and biological effects of infliximab, a TNF-alpha inhibitor, in patients with advanced cancer. Ann Oncol. 2008, 19: 1340-1346. 10.1093/annonc/mdn054.View ArticlePubMedGoogle Scholar
- Harrison ML, Obermueller E, Maisey NR, Hoare S, Edmonds K, Li NF, Chao D, Hall K, Lee C, Timotheadou E, Charles K, Ahern R, King DM, Eisen T, Corringham R, DeWitte M, Balkwill F, Gore M: Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose. J Clin Oncol. 2007, 25: 4542-4549. 10.1200/JCO.2007.11.2136.View ArticlePubMedGoogle Scholar
- Flavell SJ, Hou TZ, Lax S, Filer AD, Salmon M, Buckley CD: Fibroblasts as novel therapeutic targets in chronic inflammation. Br J Pharmacol. 2008, 153 (Suppl 1): S241-246.PubMed CentralPubMedGoogle Scholar
- Mueller MM, Fusenig NE: Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004, 4: 839-849.View ArticlePubMedGoogle Scholar
- Yamanishi Y, Boyle DL, Pinkoski MJ, Mahboubi A, Lin T, Han Z, Zvaifler NJ, Green DR, Firestein GS: Regulation of joint destruction and inflammation by p53 in collagen-induced arthritis. Am J Pathol. 2002, 160: 123-130. 10.1016/S0002-9440(10)64356-8.PubMed CentralView ArticlePubMedGoogle Scholar
- Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA, Fearon DT: Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 2010, 330: 827-830. 10.1126/science.1195300.View ArticlePubMedGoogle Scholar
- Maia M, DeVriese A, Janssens T, Moons M, Lories RJ, Tavernier J, Conway EM: CD248 facilitates tumor growth via its cytoplasmic domain. BMC Cancer. 2011, 11: 162-10.1186/1471-2407-11-162.PubMed CentralView ArticlePubMedGoogle Scholar
- Maia M, de Vriese A, Janssens T, Moons M, van Landuyt K, Tavernier J, Lories RJ, Conway EM: CD248 and its cytoplasmic domain: a therapeutic target for arthritis. Arthritis Rheum. 2010, 62: 3595-3606. 10.1002/art.27701.View ArticlePubMedGoogle Scholar