- Email: [email protected]
Inflammation in the context of oral cancer
Oral Oncology 49 (2013) 887–892
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Review
Inflammation in the context of oral cancer L. Feller a,⇑, M. Altini b, J. Lemmer a a b
Department of Periodontology and Oral Medicine, University of Limpopo, Medunsa Campus, South Africa Division of Anatomical Pathology, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
a r t i c l e
i n f o
Article history: Received 22 May 2013 Received in revised form 4 July 2013 Accepted 6 July 2013 Available online 30 July 2013 Keywords: Oral squamous cell carcinoma Cancer-associated inflammation COX-2 STAT-3 AP-1 NF-jB Oral submucous fibrosis Oral lichen planus
s u m m a r y The link between cancer and inflammation is specific transcription factors that once activated have the capacity to enhance expression of genes that are common to both the regulation and the production of mediators of inflammation, and also to the regulation of the survival and proliferation of cancer cells. Cellular pathways activated by chronic inflammation brought about by chronic infections, by immune-mediated diseases, or by dysregulated wound healing at sites of repetitive tissue injury, constitute risk factors for initial cell transformation and for cancer progression. In established cancers, the cancer cells induce development of an exaggerated inflammatory state in the stroma, which in turn promotes cancer growth, invasion and metastasis. Inflammatory cells of myeloid origin in the tumour-associated stroma, mediate suppression of immune responses against cancer cells, which suppression favours tumour growth. Oral submucous fibrosis, and to a lesser extent oral lichen planus are precancerous conditions in which immuno-inflammatory processes are implicated in their pathogenesis, and in their cancerous transformation, if it occurs. Although there is some evidence for an association between oral squamous cell carcinoma on the one hand and dento-gingival bacterial plaques and chronic periodontitis on the other hand, the role of inflammation as the sole cause of cancerous transformation in such cases is not proven. The purpose of this article is to elaborate on some of the more important relationships between oral cancer and inflammation, and to comment on the role of inflammation in the pathogenesis of oral squamous cell carcinoma. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction There is evidence that chronic inflammation brought about by persistent chemical, bacterial or viral agents is a risk factor for cancer [1–7]. For example, chronic infection with Helicobacter pylori is associated with gastric cancer, chronic viral hepatitis B or C is associated with hepatocellular cancer, and chronic pancreatitis or chronic prostatitis of non-specific origin are associated with cancers of the pancreas or of the prostate, respectively [3,5,6]. Dysregulated inflammatory processes brought about by certain autoimmune reactions, or by minor, persistent repetitive soft tissue trauma, also impose a risk of cancer [8]. Cytokines, chemokines, prostaglandins and reactive oxygen and nitrogen radicals accumulate in the microenvironment of tissues affected by chronic inflammation. If persistent, these inflammatory factors have the capacity to induce cell proliferation and to promote prolonged cell survival through activation of oncogenes and inactivation of tumour-suppressor genes. This may result in genetic instability with an increased risk of cancer [3,9].
⇑ Corresponding author. Tel.: +27 12 521 4834; fax: +27 12 521 4833. E-mail address: [email protected] (L. Feller). 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.07.003
In genetically altered cells at different stages of transformation, the intrinsic cellular circuits that bring about increased cell proliferation and cell survival may also bring about the production and secretion of inflammatory mediators. These biological mediators generate an inflammatory microenvironment that further increase cell survival and proliferation of the transformed cells, as well as promoting angiogenesis and evasion of protective immune responses [3,5,6]. Once an inflammatory microenvironment has been established, reciprocal interactions between the evolving tumour cells and their stromal cells sustain cancer cell proliferation and promote the progression of the tumour [4,10]. Thus, common transcription factors that normally regulate genes producing inflammatory mediators, and genes controlling cell survival and proliferation are the link between cancer and inflammation [9]. However, as chronic inflammatory processes of the oral mucosa are common and as cancers of the oral mucosa are relatively uncommon, it is evident that inflammatory processes on their own only rarely induce cancer development [6,11]. The aim of this short review is to outline the association between inflammation and cancer and to shed light on the role of inflammation in the pathogenesis of oral squamous cell carcinoma.
888
L. Feller et al. / Oral Oncology 49 (2013) 887–892
Figure. 1. The interaction between cancer and inflammation. In the intrinsic pathway, activated transcription factors that regulate both oncogenic circuits and inflammation related programs, drive the process of tumour development. In the extrinsic pathway, pre-existing inflammatory conditions may favour the onset of cancer and promote tumour progression (adapted from Mantovani, 2010).
Inflammation-driven carcinogenesis and cancer-induced inflammation Tobacco, alcohol, certain environmental and infectious agents and inflammatory mediators have the capacity to activate the nuclear signal transducers and activators of transcription-3 (STAT-3), the activator protein-1 (AP-1) and the nuclear factor-kB (NF-kB). In turn, these transcription factors activate oncogenes regulating apoptosis, cell proliferation and angiogenesis; and genes regulating the production of inflammatory mediators including growth factors, cytokines, prostaglandins and proteinases [1–3,5,12]. Thus, through these common transcription factors, cancer cells, concurrently induce both inflammation and uncontrolled selfproliferation (intrinsic pathway) (Fig. 1). The inflammatory microenvironment in turn, is conducive to tumour progression. This intrinsic pathway explains why inflammatory cells and inflammatory mediators are almost invariably present in the microenvironment of all cancer types [3,5]. In addition, there is cross talk between cancer cells and noncancer cells within the tumour-associated stroma. The cancer cells induce the secretion of inflammatory mediators by immunoinflammatory cells within the stroma; the inflammatory mediators in turn induce cancer cell proliferation and survival, and the angiogenesis essential to tumour progression [4]. This might explain why cancers that are rapidly progressing, microscopically show an intense inflammatory infiltrate [8]. In inflamed non-cancerous tissues the transcription factors mentioned above may bring about an increase in cell proliferation and prolonged cell survival that may favour initial cancerous transformation (extrinsic pathway) (Fig. 1) [2,3,5]. Inflammatory cells may secrete reactive oxygen species and reactive nitrogen species that have the capacity to cause direct DNA damage, and to
dysregulate mechanisms of DNA repair, of cell-cycle checkpoint control and of apoptosis. This brings about a genomic instability favouring the evolution of random mutations and development of cancer [3,4,8]. Reactive nitrogen species may also act as mediators of intracellular signalling circuits including the mitogenactivated protein kinase (MAPK) signallingpathway that plays a part in inducing cell proliferation and differentiation [1]. Thus, inflammatory pathways activated by the chronic inflammation of chronic infections, autoimmune diseases, or by repetitive and habit-related chemical trauma may not only promote cancer progression but may also constitute the risk factors of initial cell transformation [7,8,10]. Molecular patterns of microorganisms associated with pathogenesis, specific moieties which are the by-product of tissue damage, and inflammatory cytokines including TNF-a and IL-1b, have the capacity to trigger Toll-like receptor (TLR)-MyD88 intracellular signalling pathways in epithelial cells and in immuno-inflammatory cells of the innate arm of the immune system. These activated signalling pathways mediate the production of inflammatory factors that in turn activate NF-jB, STAT-3 and AP-1 transcription factors. These promote cell survival by upregulating expression of anti-apoptotic genes and of genes regulating cell cycle checkpoints, including c-Myc, Mc-1, cyclin-D, Bcl-2, c-Flip and survivin, thus bringing about a state of cellular genomic instability [3,5,12]. Out of all the proinflammatory members of the prostaglandin (PG) family, PGE-2 is the one most frequently implicated in cancerization [13]. While cyclo-oxygenase-1 (COX-1) is expressed constitutively in most tissues producing prostaglandins that mediate physiological activities, COX-2 is expressed mainly in response to inflammatory and mitogenic stimuli [13–15]. COX-2 is an important enzyme in PGE-2 biosynthesis [13,16]; it is expressed at high levels in different types of epithelial malignancies and its expression is
L. Feller et al. / Oral Oncology 49 (2013) 887–892
associated with poor prognosis [14,15,17]. By direct interaction with the transmembrane G protein-coupled receptors EP(1-4) [13,18], and by transactivation of epithelial growth factor receptor (EGFR) [14,19], COX-2-derived PGE-2 activates intracellular oncogenic pathways resulting in prolonged cell survival, increased cell proliferation and migration, and in the associated neoangiogenesis [14,18]. Thus, a positive feedback loop is created whereby COX-2 ultimately upregulates its own expression resulting in increased production of PGE-2, perpetuating a malignant cycle [15].
Cancer in relation to wound healing Normal wound healing is a complex, multifactorial and regulated process. It is driven by cytokines, chemokines, growth factors, proteinases and prostaglandins that are secreted by immuneinflammatory cells recruited to the site of injury. If the process of wound healing is dysregulated in such a way that activated immuno-inflammatory cells persist at the site of injury/incomplete wound healing, aberrant healing processes such as hypertrophic scars and keloids may develop. Hypertrophic scars, keloids and non-healing ulcers are associated with an increased risk of cancer [4,8]. This increased risk of cancer may stem from the fact that certain genes and cellular pathways are common to wound healing and to cancerization. However, whereas in normal wound healing these mechanisms are orderly bringing about self-limiting repair that restores the integrity and homeostasis of the affected tissues, at sites of chronic inflammation the mechanisms may be dysregulated [8,10,20]. Growth factors, cytokines, prostaglandins and proteinases that are essential for normal tissue repair, can also play malicious roles in the development of cancers at sites of repetitive tissue injury [8,10]. The mechanisms that mediate resolution of inflammatory responses are not well understood, but they are essential for re-establishing post-inflammatory tissue homeostasis; their dysregulation with the persistence of chronic inflammatory processes may be a factor in carcinogenesis [21]. COX-2 is a mediator of inflammation and of epithelial repair. Studies on intestinal mucosa have shown that both epithelial cells, and macrophages in the lamina propria express COX-2 in response to epithelial injury. The expression of COX-2 is mediated by stimulation of TLR-MyD88. In turn, COX-2-derived PGE-2 has the capacity to mediate epithelial repair through signalling pathways activated by epidermal growth factor receptor [22]. TLR4-MyD88 signalling pathways that mediate the expression of COX-2 have been shown to be essential for the repair of, to be linked to inflammatory signalling in, and to be required for homeostasis of the intestinal epithelium [23]. However, constitutive upregulation of the TLR-MyD88 signalling in epithelial and in innate immune cells at sites of mucosal injury may cause hyperproliferation of epithelial cells. These hyperproliferating cells, if exposed to mutagenic initiating and promoting agents, are predisposed to undergo cancerous transformation [22]. In advanced cancers, stromal macrophages express COX-2-derived PGE-2 that has the capacity to upregulate anti-apoptotic and tumour growth pathways [24–26]. COX-2 and PGE-2 are upregulated during skin wound healing, particularly in the first days after injury (1–7 days). They are expressed in the progenitor basal cell layer of the epidermis at the wound margins, and also in proliferating endothelial cells and fibroblast like cells within the granulation tissue of the wound. Simply stated, COX-2-derived PGE-2 most probably takes part in mediating migration and proliferation of progenitor keratinocytes, and of endothelial cells which drive the process of re-epithelialisation and angiogenesis. Corollary to this is that drug-induced suppression of COX-2 activity brings about a delay in wound healing. [16].
889
It is possible therefore, that in the presence of persistent COX-2derived PGE-2, there will be continuous stimulation of epithelial and endothelial cell proliferation which may contribute to the creation of a field of precancerization, since the progenitor cells, in the presence of PGE-2 will have a growth advantage over the neighbouring epithelial cells that have not been subject to repeated trauma and that therefore do not express COX-2. In inflamed non-cancer tissues, the macrophages that are engaged in wound healing are of the M1 phenotype. M1 macrophages secrete inflammatory agents which have antimicrobial, and immunostimulatory functions as well as having the capacity to induce angiogenesis. These inflammatory agents mediate normal wound healing and tissue homeostasis. M1 macrophages can also be found in cancer-associated stroma of early-stage cancers, supposedly mediating anticancer protective immune responses [5,8]. On the other hand, in advanced cancers, cancer cell-derived bioactive factors mediate the recruitment, differentiation and activation of macrophages of the M2 phenotype. These M2 cells express high-levels of pro-angiogenic factors such as matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF) and COX-2. These mediators generate a pronounced ‘inflammatory regenerative response’ with exaggerated tissue remodelling, angiogenesis and lymphogenesis promoting cell motility, cancer cell invasion and metastasis [5,8,27–30]. Thus, it appears that there are at least two subclasses of immunostimulatory cells within the stroma of the tumour. The ‘conventional ones’ that are engaged in normal immuno-inflammatory activities (wound healing, innate and adaptive immune responses), and the ‘tumour-associated’ macrophages, neutrophils and myeloid progenitor cells that bring about exaggerated wound healing and angiogenic responses that promote cancer growth and suppress anti-tumour protective immuno-inflammatory responses [4].
Tumour-associated stroma There is a reciprocal signalling interaction between cancer cells and stromal cells within the tumour microenvironment. The tumour-associated stromal cell population comprises distinctive cancer-associated cell types including fibroblasts, endothelial cells, pericytes, tissue-specific stem cells, bone marrow derived stem and progenitor cells and immuno-inflammatory cells. In established cancers, these distinctive stromal cells support cancer progression [4]. Tumour-associated inflammatory cells include myeloid dendritic cells, macrophage subtypes (M1 and M2), a TIE2-expressing monocyte subset, mast cells, neutrophils, and T and B lymphocytes. These cells secrete chemokines, prostaglandins, proteinases, and complement components that collectively bring about an exaggerated inflammatory state, and that promote cancer growth, tissue invasion and metastasis [3,5,6,28,31,32]. In addition to the above mentioned immuno-inflammatory cells, tumour-associated stroma contains partially differentiated myeloid (progenitor) cells which have the capacity to support tumour progression [4]. The myeloid-derived suppressor cells are an important subclass of these partially differentiated myeloid cells, and are the immature myeloid precursors of dendritic cells, macrophages and granulocytes [33] and express both the macrophage marker CD11b and the neutrophil marker Gr1. However, whether these highly variable markers play a role in the context of human myeloid-derived suppressor cells is controversial. Myeloid-derived suppressor cells are induced by tumour-secreted inflammatory factors including vascular endothelial growth factor, granulocyte-monocyte colony stimulating factors, IL-1b, IL-6, COX2-derived PGE-2, and S100A8/A9 proteins [33] and have the capacity to suppress the activities of natural killer cells and cytotoxic T
890
L. Feller et al. / Oral Oncology 49 (2013) 887–892
lymphocytes, thus enabling cancer cells to escape immunity-mediated killing [3]. Myeloid-derived suppressor cells, through the secretion of high-levels of reactive oxidative species and of reactive nitrogen species, mediate immune tolerance of cancer cells in the local microenvironment. They mediate T-cell anergy to tumour-specific antigens by inducing non-specific suppression of T-cell function and apoptosis of T-cells [34]. Myeloid-derived suppressor cells also downregulate effective antitumour cell-mediated immunity through induction of regulatory T cells, and promote IL-10-driven suppression of anti-tumour immune responses [33]. Ineffective or suppressed immune reactions against cancer cells are also caused by downregulation of expression of critical tumour antigens, and of MHC class 1 molecules on tumour cells, resulting in immune escape [35]; and by M2 macrophage-induced Th2 and regulatory T cell responses [29,36,37]. PGE2 in the tumour microenvironment has the capacity to suppress antitumour immune responses, firstly by altering the functions of dendritic cells, resulting in suboptimal generation of antitumour-specific cytotoxic T cell activation; and secondly by promoting differentiation of immunosuppressive regulatory T cells that downregulate antitumour immune responses [38] through TGF-b and IL-10 [39]. On the other hand, some immuno-inflammatory responses, particularly Th1 and possibly Th17 responses within the tumour-associated stroma represent anti-tumour protective reactions aimed at eradicating tumour cells by cytotoxic T lymphocytes (CTL) and natural killer cells [2]. Thus, the cancer-associated inflammatory infiltrate has the capacity either to promote or to inhibit cancer growth, and it appears that the transcription factor NFjB in macrophages plays a key role in determining whether promotion or inhibition of cancer growth will predominate [5].
Chronic inflammation and oral squamous cell carcinoma There are a number of oral inflammatory conditions that have been proposed as being implicated in the pathogenesis of oral squamous cell carcinoma: oral submucous fibrosis, oral lichen planus, discoid lupus erythematosus, oral ulcers related to repetitive tissue injury and chronic periodontal disease. To deal with each one of these individually is beyond the scope of this paper, but three conditions will serve to illustrate the broad principles of the link between oral inflammation and oral squamous cell carcinoma. Oral submucous fibrosis is a potentially malignant condition that is causally associated with the habitual use of areca nut/betel quid. It is characterised histopathologically by dense fibrosis of the lamina propria at the affected site, by a juxta-epithelial inflammatory reaction, and by atrophy or hyperplasia of the overlying epithelium. The inflammatory infiltrate comprises predominantly lymphocytes, but also plasma cells and macrophages [40–43]. Chemical agents of areca nut/betel quid induce the production of inflammatory mediators and growth factors including prostaglandins, reactive oxygen species, TNF-a, IL-8, IL-6, TGF-b, platelet derived growth factor, and basic fibroblast growth factor, by oral keratinocytes, and by inflammatory cells within the lamina propria. These biological mediators drive the process of fibrosis [43–48]. Some of the chemical components of areca nut/betel quid are also mutagenic, having the capacity to bring about DNA breaks or DNA–protein cross-links in oral keratinocytes, creating an epithelial field of genetically altered precancerised keratinocytes that may or may not show atypia but are fitter in relation to their neighbouring normal keratinocytes in terms of metabolic activity and proliferation rate. TNF-a, IL-6 and PGE-2 within the inflamed microenvironment of the submucous fibrosis may favour malignant transformation of the precancerised keratinocytes by driving
their clonal expansion [46]. Subsequent to the acquisition of additional genetic alterations some of these proliferating precancerous keratinocytes may undergo clonal divergence and acquire a malignant phenotype. Oral lichen planus has been associated, although debatably, with an increased risk of oral squamous cell carcinoma [49–52]. It has been suggested that the unique profile of the cytokines and chemokines that initiate oral lichen planus may also on occasion be a factor in the transformation of oral lichen planus to oral squamous cell carcinoma [53]. Oral lichen planus is characterised by a T cell-mediated chronic immuno-inflammatory reaction against an as yet undefined antigen within the basal cell layer of the oral epithelium, and by upregulated expression of several inflammatory mediators including TGF-b, TNF-a, IL-6, COX-2 and MMP-7 [54–56]. It is probable that in those rare cases of oral lichen planus that evolve to OSCC, the local inflammatory microenvironment provides the signals that activate transcription factors that not only promote proliferation and longevity of the epithelial cells affected by the lichen planus but also promote angiogenesis, invasion and metastasis [54,55,57]. In established oral squamous cell carcinoma, TNF-a and IL-6 are produced by malignant keratinocytes, and by stromal fibroblasts and macrophages [58]. These cytokines not only increase tumour cell proliferation and survival, but also promote tumour growth through modifying the expression of cell-adhesion molecules and extracellular matrix proteins, and by stimulation of angiogenesis [58,59]. There is high-level COX-2 expression in the cells of the stroma, and in cancerous cells at the invasive front of oral squamous cell carcinoma. It has been suggested that COX-2 plays a role in the process of local invasion and metastasis. Increased expression of COX-2 in oral squamous cell carcinoma is associated with a high rate of recurrence after treatment, with a poor response to radiotherapy and with a poor prognosis [17,25,26,60]. Epidemiological studies suggest that there is an association between dento-gingival bacterial plaques and chronic periodontal disease on the one hand, and oral squamous cell carcinoma on the other hand. This risk appears to be independent of other high-risk habits such as smoking cigarettes and drinking alcoholic beverages [61–63]. The bacteria of dento-gingival plaques and their products, through local inflammatory responses that they generate, through the production of nitrosamines by nitrate-reducing bacteria, and through mutagenic agents formed consequent to the interaction between some bacterial species and the saliva, have the capacity to trigger mitogenic and anti-apoptotic pathways in oral keratinocytes. Thus, oral bacteria and inflammatory mediators associated with periodontal disease may be co-factors in the initiation and in the promotion of oral squamous cell carcinoma [61,63–66]. Although the reported statistical association between dentogingival plaques and chronic periodontitis on the one hand, and increased risk of oral squamous cell carcinoma on the other hand cannot be ignored, clinical experience is not supportive of any such significant causal association, because considering the great number of people with periodontal disease, the incidence of gingival carcinoma is very low compared to what might be expected if the association were real.
Summary The link between cancer and inflammation is specific transcription factors that once activated, have the capacity to enhance the expression of genes regulating the production of inflammatory mediators and to enhance the expression of genes regulating cell survival and proliferation, as well as mediating angiogenesis, immune evasion and metastasis.
L. Feller et al. / Oral Oncology 49 (2013) 887–892
There is clear evidence that persistent inflammation promotes cell proliferation and may induce DNA damage; and that at initial stages of tumorigenesis, inflammatory factors mediate the development of a tumour associated stroma. In turn, activated cells in this stroma promote angiogenesis, cancer growth and metastasis, and mediate immune evasion.
Conflict of interest statement None declared. References [1] Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer 2007;121(11):2373–80. [2] Aivaliotis IL, Pateras IS, Papaioannou M, Glytsou C, Kontzoglou K, Johnson EO, et al. How do cytokines trigger genomic instability? J Biomed Biotechnol 2012;2012:536761. [3] Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009;30(7):1073–81. [4] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. [5] Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454(7203):436–44. [6] Mantovani A. Molecular pathways linking inflammation and cancer. Curr Mol Med 2010;10(4):369–73. [7] Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 2007;117(5):1175–83. [8] Schafer M, Werner S. Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 2008;9(8):628–38. [9] Moore MM, Chua W, Charles KA, Clarke SJ. Inflammation and cancer: causes and consequences. Clin Pharmacol Ther 2010;87(4):504–8. [10] Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420(6917):860–7. [11] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140(6):883–99. [12] Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 2009;9(4):351–69. [13] Kim JI, Lakshmikanthan V, Frilot N, Daaka Y. Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome. Mol Cancer Res 2010;8(4):569–77. [14] Chen Z, Zhang X, Li M, Wang Z, Wieand HS, Grandis JR, et al. Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck. Clin Cancer Res 2004;10(17):5930–9. [15] Dannenberg AJ, Lippman SM, Mann JR, Subbaramaiah K, DuBois RN. Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 2005;23(2):254–66. [16] Futagami A, Ishizaki M, Fukuda Y, Kawana S, Yamanaka N. Wound healing involves induction of cyclooxygenase-2 expression in rat skin. Lab Invest 2002;82(11):1503–13. [17] Wirth LJ, Haddad RI, Lindeman NI, Zhao X, Lee JC, Joshi VA, et al. Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23(28):6976–81. [18] Lalier L, Pedelaborde F, Braud C, Menanteau J, Vallette FM, Olivier C. Increase in intracellular PGE2 induces apoptosis in Bax-expressing colon cancer cell. BMC Cancer 2011;11:153. [19] Buchanan FG, Wang D, Bargiacchi F, DuBois RN. Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003;278(37):35451–7. [20] Vacchelli E, Galluzzi L, Eggermont A, Galon J, Tartour E, Zitvogel L, et al. Trial Watch: Immunostimulatory cytokines. Oncoimmunology 2012;1(4):493–506. [21] Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 2006;124(4):823–35. [22] Fukata M, Chen A, Klepper A, Krishnareddy S, Vamadevan AS, Thomas LS, et al. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine. Gastroenterology 2006;131(3):862–77. [23] Xiao H, Gulen MF, Qin J, Yao J, Bulek K, Kish D, et al. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 2007;26(4):461–75. [24] Kojima M, Morisaki T, Izuhara K, Uchiyama A, Matsunari Y, Katano M, et al. Lipopolysaccharide increases cyclo-oxygenase-2 expression in a colon carcinoma cell line through nuclear factor-kappa B activation. Oncogene 2000;19(9):1225–31. [25] Choi S, Myers JN. Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res 2008;87(1):14–32. [26] Goulart Filho JA, Nonaka CF, da Costa Miguel MC, de Almeida Freitas R, Galvao HC. Immunoexpression of cyclooxygenase-2 and p53 in oral squamous cell carcinoma. Am J Otolaryngol 2009;30(2):89–94.
891
[27] Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002;23(11):549–55. [28] Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 2010;18(6):884–901. [29] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell 2010;141(1):39–51. [30] Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 2006;42(6):717–27. [31] Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, et al. Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 2010;70(13):5270–80. [32] Lewis CE, De Palma M, Naldini L. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 2007;67(18):8429–32. [33] Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 2009;182(8):4499–506. [34] Nagaraj S, Gabrilovich DI. Tumor escape mechanism governed by myeloidderived suppressor cells. Cancer Res 2008;68(8):2561–3. [35] Manjili MH, Payne KK. Cancer immunotherapy: re-programming cells of the innate and adaptive immune systems. Oncoimmunology 2012;1(2):201–4. [36] Johansson M, Denardo DG, Coussens LM. Polarized immune responses differentially regulate cancer development. Immunol Rev 2008;222:145–54. [37] Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357(9255):539–45. [38] Legler DF, Bruckner M, Uetz-von Allmen E, Krause P. . Prostaglandin E2 at new glance: novel insights in functional diversity offer therapeutic chances. Int J Biochem Cell Biol 2010;42(2):198–201. [39] Finn OJ. Cancer immunology. N Engl J Med 2008;358(25):2704–15. [40] Lemmer J, Shear M. Oral submucous fibrosis. A possible case in a person of Caucasian descent. Br Dent J 1967;122(8):343–6. [41] Rajendran R. Oral submucous fibrosis: etiology, pathogenesis, and future research. Bull World Health Organ 1994;72(6):985–96. [42] Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis–a collagen metabolic disorder. J Oral Pathol Med 2005;34(6):321–8. [43] Chiang CP, Wu HY, Liu BY, Wang JT, Kuo MY. Quantitative analysis of immunocompetent cells in oral submucous fibrosis in Taiwan. Oral Oncol 2002;38(1):56–63. [44] Haque MF, Harris M, Meghji S, Barrett AW. Immunolocalization of cytokines and growth factors in oral submucous fibrosis. Cytokine 1998;10(9):713–9. [45] Chiu CJ, Chiang CP, Chang ML, Chen HM, Hahn LJ, Hsieh LL, et al. Association between genetic polymorphism of tumor necrosis factor-alpha and risk of oral submucous fibrosis, a pre-cancerous condition of oral cancer. J Dent Res 2001;80(12):2055–9. [46] Jeng JH, Wang YJ, Chiang BL, Lee PH, Chan CP, Ho YS, et al. Roles of keratinocyte inflammation in oral cancer: regulating the prostaglandin E2, interleukin-6 and TNF-alpha production of oral epithelial cells by areca nut extract and arecoline. Carcinogenesis 2003;24(8):1301–15. [47] Khan S, Chatra L, Prashanth SK, Veena KM, Rao PK. Pathogenesis of oral submucous fibrosis. J Cancer Res Ther 2012;8(2):199–203. [48] Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994;331(19):1286–92. [49] Feller L, Lemmer J. Oral Squamous cell carcinoma: epidemiology, clinical presentation and treatment. J Cancer Ther 2012;3(4):263–8. [50] Mattsson U, Jontell M, Holmstrup P. Oral lichen planus and malignant transformation: is a recall of patients justified? Crit Rev Oral Biol Med 2002;13(5):390–6. [51] Gonzalez-Moles MA, Scully C, Gil-Montoya JA. Oral lichen planus: controversies surrounding malignant transformation. Oral Dis 2008;14(3):229–43. [52] Sousa FA, Paradella TC, Brandao AA, Rosa LE. Oral lichen planus versus epithelial dysplasia: difficulties in diagnosis. Braz J Otorhinolaryngol 2009;75(5):716–20. [53] Liu Y, Messadi DV, Wu H, Hu S. Oral lichen planus is a unique disease model for studying chronic inflammation and oral cancer. Med Hypotheses 2010;75(6):492–4. [54] Scully C, Beyli M, Ferreiro MC, Ficarra G, Gill Y, Griffiths M, et al. Update on oral lichen planus: etiopathogenesis and management. Crit Rev Oral Biol Med 1998;9(1):86–122. [55] Mignogna MD, Fedele S, Lo Russo L, Lo Muzio L, Bucci E. Immune activation and chronic inflammation as the cause of malignancy in oral lichen planus: is there any evidence ? Oral Oncol 2004;40(2):120–30. [56] Li TJ, Cui J. COX-2, MMP-7 expression in oral lichen planus and oral squamous cell carcinoma. Asian Pac J Trop Med 2013;6(8):640–3. [57] Georgakopoulou EA, Achtari MD, Achtaris M, Foukas PG, Kotsinas A. Oral lichen planus as a preneoplastic inflammatory model. J Biomed Biotechnol 2012;2012:759626. [58] Nakano Y, Kobayashi W, Sugai S, Kimura H, Yagihashi S. Expression of tumor necrosis factor-alpha and interleukin-6 in oral squamous cell carcinoma. Jpn J Cancer Res 1999;90(8):858–66. [59] Oyama N, Iwatsuki K, Homma Y, Kaneko F. Induction of transcription factor AP-2 by inflammatory cytokines in human keratinocytes. J Invest Dermatol 1999;113(4):600–6. [60] Massano J, Regateiro FS, Januario G, Ferreira A. Oral squamous cell carcinoma: review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102(1):67–76.
892
L. Feller et al. / Oral Oncology 49 (2013) 887–892
[61] Meyer MS, Joshipura K, Giovannucci E, Michaud DS. A review of the relationship between tooth loss, periodontal disease, and cancer. Cancer Causes Control 2008;19(9):895–907. [62] Tezal M, Sullivan MA, Hyland A, Marshall JR, Stoler D, Reid ME, et al. Chronic periodontitis and the incidence of head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prevent 2009;18(9):2406–12. [63] Tezal M, Sullivan Nasca M, Stoler DL, Melendy T, Hyland A, Smaldino PJ, et al. Chronic periodontitis-human papillomavirus synergy in base of tongue cancers. Arch Otolaryngol Head Neck Surg 2009;135(4):391–6.
[64] Hooper SJ, Wilson MJ, Crean SJ. Exploring the link between microorganisms and oral cancer: a systematic review of the literature. Head Neck 2009;31(9):1228–39. [65] Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol 2009;45(4–5):301–8. [66] Bloching M, Reich W, Schubert J, Grummt T, Sandner A. The influence of oral hygiene on salivary quality in the Ames test, as a marker for genotoxic effects. Oral Oncol 2007;43(9):933–9.
Contents lists available at SciVerse ScienceDirect
Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology
Review
Inflammation in the context of oral cancer L. Feller a,⇑, M. Altini b, J. Lemmer a a b
Department of Periodontology and Oral Medicine, University of Limpopo, Medunsa Campus, South Africa Division of Anatomical Pathology, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
a r t i c l e
i n f o
Article history: Received 22 May 2013 Received in revised form 4 July 2013 Accepted 6 July 2013 Available online 30 July 2013 Keywords: Oral squamous cell carcinoma Cancer-associated inflammation COX-2 STAT-3 AP-1 NF-jB Oral submucous fibrosis Oral lichen planus
s u m m a r y The link between cancer and inflammation is specific transcription factors that once activated have the capacity to enhance expression of genes that are common to both the regulation and the production of mediators of inflammation, and also to the regulation of the survival and proliferation of cancer cells. Cellular pathways activated by chronic inflammation brought about by chronic infections, by immune-mediated diseases, or by dysregulated wound healing at sites of repetitive tissue injury, constitute risk factors for initial cell transformation and for cancer progression. In established cancers, the cancer cells induce development of an exaggerated inflammatory state in the stroma, which in turn promotes cancer growth, invasion and metastasis. Inflammatory cells of myeloid origin in the tumour-associated stroma, mediate suppression of immune responses against cancer cells, which suppression favours tumour growth. Oral submucous fibrosis, and to a lesser extent oral lichen planus are precancerous conditions in which immuno-inflammatory processes are implicated in their pathogenesis, and in their cancerous transformation, if it occurs. Although there is some evidence for an association between oral squamous cell carcinoma on the one hand and dento-gingival bacterial plaques and chronic periodontitis on the other hand, the role of inflammation as the sole cause of cancerous transformation in such cases is not proven. The purpose of this article is to elaborate on some of the more important relationships between oral cancer and inflammation, and to comment on the role of inflammation in the pathogenesis of oral squamous cell carcinoma. Ó 2013 Elsevier Ltd. All rights reserved.
Introduction There is evidence that chronic inflammation brought about by persistent chemical, bacterial or viral agents is a risk factor for cancer [1–7]. For example, chronic infection with Helicobacter pylori is associated with gastric cancer, chronic viral hepatitis B or C is associated with hepatocellular cancer, and chronic pancreatitis or chronic prostatitis of non-specific origin are associated with cancers of the pancreas or of the prostate, respectively [3,5,6]. Dysregulated inflammatory processes brought about by certain autoimmune reactions, or by minor, persistent repetitive soft tissue trauma, also impose a risk of cancer [8]. Cytokines, chemokines, prostaglandins and reactive oxygen and nitrogen radicals accumulate in the microenvironment of tissues affected by chronic inflammation. If persistent, these inflammatory factors have the capacity to induce cell proliferation and to promote prolonged cell survival through activation of oncogenes and inactivation of tumour-suppressor genes. This may result in genetic instability with an increased risk of cancer [3,9].
⇑ Corresponding author. Tel.: +27 12 521 4834; fax: +27 12 521 4833. E-mail address: [email protected] (L. Feller). 1368-8375/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.oraloncology.2013.07.003
In genetically altered cells at different stages of transformation, the intrinsic cellular circuits that bring about increased cell proliferation and cell survival may also bring about the production and secretion of inflammatory mediators. These biological mediators generate an inflammatory microenvironment that further increase cell survival and proliferation of the transformed cells, as well as promoting angiogenesis and evasion of protective immune responses [3,5,6]. Once an inflammatory microenvironment has been established, reciprocal interactions between the evolving tumour cells and their stromal cells sustain cancer cell proliferation and promote the progression of the tumour [4,10]. Thus, common transcription factors that normally regulate genes producing inflammatory mediators, and genes controlling cell survival and proliferation are the link between cancer and inflammation [9]. However, as chronic inflammatory processes of the oral mucosa are common and as cancers of the oral mucosa are relatively uncommon, it is evident that inflammatory processes on their own only rarely induce cancer development [6,11]. The aim of this short review is to outline the association between inflammation and cancer and to shed light on the role of inflammation in the pathogenesis of oral squamous cell carcinoma.
888
L. Feller et al. / Oral Oncology 49 (2013) 887–892
Figure. 1. The interaction between cancer and inflammation. In the intrinsic pathway, activated transcription factors that regulate both oncogenic circuits and inflammation related programs, drive the process of tumour development. In the extrinsic pathway, pre-existing inflammatory conditions may favour the onset of cancer and promote tumour progression (adapted from Mantovani, 2010).
Inflammation-driven carcinogenesis and cancer-induced inflammation Tobacco, alcohol, certain environmental and infectious agents and inflammatory mediators have the capacity to activate the nuclear signal transducers and activators of transcription-3 (STAT-3), the activator protein-1 (AP-1) and the nuclear factor-kB (NF-kB). In turn, these transcription factors activate oncogenes regulating apoptosis, cell proliferation and angiogenesis; and genes regulating the production of inflammatory mediators including growth factors, cytokines, prostaglandins and proteinases [1–3,5,12]. Thus, through these common transcription factors, cancer cells, concurrently induce both inflammation and uncontrolled selfproliferation (intrinsic pathway) (Fig. 1). The inflammatory microenvironment in turn, is conducive to tumour progression. This intrinsic pathway explains why inflammatory cells and inflammatory mediators are almost invariably present in the microenvironment of all cancer types [3,5]. In addition, there is cross talk between cancer cells and noncancer cells within the tumour-associated stroma. The cancer cells induce the secretion of inflammatory mediators by immunoinflammatory cells within the stroma; the inflammatory mediators in turn induce cancer cell proliferation and survival, and the angiogenesis essential to tumour progression [4]. This might explain why cancers that are rapidly progressing, microscopically show an intense inflammatory infiltrate [8]. In inflamed non-cancerous tissues the transcription factors mentioned above may bring about an increase in cell proliferation and prolonged cell survival that may favour initial cancerous transformation (extrinsic pathway) (Fig. 1) [2,3,5]. Inflammatory cells may secrete reactive oxygen species and reactive nitrogen species that have the capacity to cause direct DNA damage, and to
dysregulate mechanisms of DNA repair, of cell-cycle checkpoint control and of apoptosis. This brings about a genomic instability favouring the evolution of random mutations and development of cancer [3,4,8]. Reactive nitrogen species may also act as mediators of intracellular signalling circuits including the mitogenactivated protein kinase (MAPK) signallingpathway that plays a part in inducing cell proliferation and differentiation [1]. Thus, inflammatory pathways activated by the chronic inflammation of chronic infections, autoimmune diseases, or by repetitive and habit-related chemical trauma may not only promote cancer progression but may also constitute the risk factors of initial cell transformation [7,8,10]. Molecular patterns of microorganisms associated with pathogenesis, specific moieties which are the by-product of tissue damage, and inflammatory cytokines including TNF-a and IL-1b, have the capacity to trigger Toll-like receptor (TLR)-MyD88 intracellular signalling pathways in epithelial cells and in immuno-inflammatory cells of the innate arm of the immune system. These activated signalling pathways mediate the production of inflammatory factors that in turn activate NF-jB, STAT-3 and AP-1 transcription factors. These promote cell survival by upregulating expression of anti-apoptotic genes and of genes regulating cell cycle checkpoints, including c-Myc, Mc-1, cyclin-D, Bcl-2, c-Flip and survivin, thus bringing about a state of cellular genomic instability [3,5,12]. Out of all the proinflammatory members of the prostaglandin (PG) family, PGE-2 is the one most frequently implicated in cancerization [13]. While cyclo-oxygenase-1 (COX-1) is expressed constitutively in most tissues producing prostaglandins that mediate physiological activities, COX-2 is expressed mainly in response to inflammatory and mitogenic stimuli [13–15]. COX-2 is an important enzyme in PGE-2 biosynthesis [13,16]; it is expressed at high levels in different types of epithelial malignancies and its expression is
L. Feller et al. / Oral Oncology 49 (2013) 887–892
associated with poor prognosis [14,15,17]. By direct interaction with the transmembrane G protein-coupled receptors EP(1-4) [13,18], and by transactivation of epithelial growth factor receptor (EGFR) [14,19], COX-2-derived PGE-2 activates intracellular oncogenic pathways resulting in prolonged cell survival, increased cell proliferation and migration, and in the associated neoangiogenesis [14,18]. Thus, a positive feedback loop is created whereby COX-2 ultimately upregulates its own expression resulting in increased production of PGE-2, perpetuating a malignant cycle [15].
Cancer in relation to wound healing Normal wound healing is a complex, multifactorial and regulated process. It is driven by cytokines, chemokines, growth factors, proteinases and prostaglandins that are secreted by immuneinflammatory cells recruited to the site of injury. If the process of wound healing is dysregulated in such a way that activated immuno-inflammatory cells persist at the site of injury/incomplete wound healing, aberrant healing processes such as hypertrophic scars and keloids may develop. Hypertrophic scars, keloids and non-healing ulcers are associated with an increased risk of cancer [4,8]. This increased risk of cancer may stem from the fact that certain genes and cellular pathways are common to wound healing and to cancerization. However, whereas in normal wound healing these mechanisms are orderly bringing about self-limiting repair that restores the integrity and homeostasis of the affected tissues, at sites of chronic inflammation the mechanisms may be dysregulated [8,10,20]. Growth factors, cytokines, prostaglandins and proteinases that are essential for normal tissue repair, can also play malicious roles in the development of cancers at sites of repetitive tissue injury [8,10]. The mechanisms that mediate resolution of inflammatory responses are not well understood, but they are essential for re-establishing post-inflammatory tissue homeostasis; their dysregulation with the persistence of chronic inflammatory processes may be a factor in carcinogenesis [21]. COX-2 is a mediator of inflammation and of epithelial repair. Studies on intestinal mucosa have shown that both epithelial cells, and macrophages in the lamina propria express COX-2 in response to epithelial injury. The expression of COX-2 is mediated by stimulation of TLR-MyD88. In turn, COX-2-derived PGE-2 has the capacity to mediate epithelial repair through signalling pathways activated by epidermal growth factor receptor [22]. TLR4-MyD88 signalling pathways that mediate the expression of COX-2 have been shown to be essential for the repair of, to be linked to inflammatory signalling in, and to be required for homeostasis of the intestinal epithelium [23]. However, constitutive upregulation of the TLR-MyD88 signalling in epithelial and in innate immune cells at sites of mucosal injury may cause hyperproliferation of epithelial cells. These hyperproliferating cells, if exposed to mutagenic initiating and promoting agents, are predisposed to undergo cancerous transformation [22]. In advanced cancers, stromal macrophages express COX-2-derived PGE-2 that has the capacity to upregulate anti-apoptotic and tumour growth pathways [24–26]. COX-2 and PGE-2 are upregulated during skin wound healing, particularly in the first days after injury (1–7 days). They are expressed in the progenitor basal cell layer of the epidermis at the wound margins, and also in proliferating endothelial cells and fibroblast like cells within the granulation tissue of the wound. Simply stated, COX-2-derived PGE-2 most probably takes part in mediating migration and proliferation of progenitor keratinocytes, and of endothelial cells which drive the process of re-epithelialisation and angiogenesis. Corollary to this is that drug-induced suppression of COX-2 activity brings about a delay in wound healing. [16].
889
It is possible therefore, that in the presence of persistent COX-2derived PGE-2, there will be continuous stimulation of epithelial and endothelial cell proliferation which may contribute to the creation of a field of precancerization, since the progenitor cells, in the presence of PGE-2 will have a growth advantage over the neighbouring epithelial cells that have not been subject to repeated trauma and that therefore do not express COX-2. In inflamed non-cancer tissues, the macrophages that are engaged in wound healing are of the M1 phenotype. M1 macrophages secrete inflammatory agents which have antimicrobial, and immunostimulatory functions as well as having the capacity to induce angiogenesis. These inflammatory agents mediate normal wound healing and tissue homeostasis. M1 macrophages can also be found in cancer-associated stroma of early-stage cancers, supposedly mediating anticancer protective immune responses [5,8]. On the other hand, in advanced cancers, cancer cell-derived bioactive factors mediate the recruitment, differentiation and activation of macrophages of the M2 phenotype. These M2 cells express high-levels of pro-angiogenic factors such as matrix metalloproteinase (MMP)-9, vascular endothelial growth factor (VEGF) and COX-2. These mediators generate a pronounced ‘inflammatory regenerative response’ with exaggerated tissue remodelling, angiogenesis and lymphogenesis promoting cell motility, cancer cell invasion and metastasis [5,8,27–30]. Thus, it appears that there are at least two subclasses of immunostimulatory cells within the stroma of the tumour. The ‘conventional ones’ that are engaged in normal immuno-inflammatory activities (wound healing, innate and adaptive immune responses), and the ‘tumour-associated’ macrophages, neutrophils and myeloid progenitor cells that bring about exaggerated wound healing and angiogenic responses that promote cancer growth and suppress anti-tumour protective immuno-inflammatory responses [4].
Tumour-associated stroma There is a reciprocal signalling interaction between cancer cells and stromal cells within the tumour microenvironment. The tumour-associated stromal cell population comprises distinctive cancer-associated cell types including fibroblasts, endothelial cells, pericytes, tissue-specific stem cells, bone marrow derived stem and progenitor cells and immuno-inflammatory cells. In established cancers, these distinctive stromal cells support cancer progression [4]. Tumour-associated inflammatory cells include myeloid dendritic cells, macrophage subtypes (M1 and M2), a TIE2-expressing monocyte subset, mast cells, neutrophils, and T and B lymphocytes. These cells secrete chemokines, prostaglandins, proteinases, and complement components that collectively bring about an exaggerated inflammatory state, and that promote cancer growth, tissue invasion and metastasis [3,5,6,28,31,32]. In addition to the above mentioned immuno-inflammatory cells, tumour-associated stroma contains partially differentiated myeloid (progenitor) cells which have the capacity to support tumour progression [4]. The myeloid-derived suppressor cells are an important subclass of these partially differentiated myeloid cells, and are the immature myeloid precursors of dendritic cells, macrophages and granulocytes [33] and express both the macrophage marker CD11b and the neutrophil marker Gr1. However, whether these highly variable markers play a role in the context of human myeloid-derived suppressor cells is controversial. Myeloid-derived suppressor cells are induced by tumour-secreted inflammatory factors including vascular endothelial growth factor, granulocyte-monocyte colony stimulating factors, IL-1b, IL-6, COX2-derived PGE-2, and S100A8/A9 proteins [33] and have the capacity to suppress the activities of natural killer cells and cytotoxic T
890
L. Feller et al. / Oral Oncology 49 (2013) 887–892
lymphocytes, thus enabling cancer cells to escape immunity-mediated killing [3]. Myeloid-derived suppressor cells, through the secretion of high-levels of reactive oxidative species and of reactive nitrogen species, mediate immune tolerance of cancer cells in the local microenvironment. They mediate T-cell anergy to tumour-specific antigens by inducing non-specific suppression of T-cell function and apoptosis of T-cells [34]. Myeloid-derived suppressor cells also downregulate effective antitumour cell-mediated immunity through induction of regulatory T cells, and promote IL-10-driven suppression of anti-tumour immune responses [33]. Ineffective or suppressed immune reactions against cancer cells are also caused by downregulation of expression of critical tumour antigens, and of MHC class 1 molecules on tumour cells, resulting in immune escape [35]; and by M2 macrophage-induced Th2 and regulatory T cell responses [29,36,37]. PGE2 in the tumour microenvironment has the capacity to suppress antitumour immune responses, firstly by altering the functions of dendritic cells, resulting in suboptimal generation of antitumour-specific cytotoxic T cell activation; and secondly by promoting differentiation of immunosuppressive regulatory T cells that downregulate antitumour immune responses [38] through TGF-b and IL-10 [39]. On the other hand, some immuno-inflammatory responses, particularly Th1 and possibly Th17 responses within the tumour-associated stroma represent anti-tumour protective reactions aimed at eradicating tumour cells by cytotoxic T lymphocytes (CTL) and natural killer cells [2]. Thus, the cancer-associated inflammatory infiltrate has the capacity either to promote or to inhibit cancer growth, and it appears that the transcription factor NFjB in macrophages plays a key role in determining whether promotion or inhibition of cancer growth will predominate [5].
Chronic inflammation and oral squamous cell carcinoma There are a number of oral inflammatory conditions that have been proposed as being implicated in the pathogenesis of oral squamous cell carcinoma: oral submucous fibrosis, oral lichen planus, discoid lupus erythematosus, oral ulcers related to repetitive tissue injury and chronic periodontal disease. To deal with each one of these individually is beyond the scope of this paper, but three conditions will serve to illustrate the broad principles of the link between oral inflammation and oral squamous cell carcinoma. Oral submucous fibrosis is a potentially malignant condition that is causally associated with the habitual use of areca nut/betel quid. It is characterised histopathologically by dense fibrosis of the lamina propria at the affected site, by a juxta-epithelial inflammatory reaction, and by atrophy or hyperplasia of the overlying epithelium. The inflammatory infiltrate comprises predominantly lymphocytes, but also plasma cells and macrophages [40–43]. Chemical agents of areca nut/betel quid induce the production of inflammatory mediators and growth factors including prostaglandins, reactive oxygen species, TNF-a, IL-8, IL-6, TGF-b, platelet derived growth factor, and basic fibroblast growth factor, by oral keratinocytes, and by inflammatory cells within the lamina propria. These biological mediators drive the process of fibrosis [43–48]. Some of the chemical components of areca nut/betel quid are also mutagenic, having the capacity to bring about DNA breaks or DNA–protein cross-links in oral keratinocytes, creating an epithelial field of genetically altered precancerised keratinocytes that may or may not show atypia but are fitter in relation to their neighbouring normal keratinocytes in terms of metabolic activity and proliferation rate. TNF-a, IL-6 and PGE-2 within the inflamed microenvironment of the submucous fibrosis may favour malignant transformation of the precancerised keratinocytes by driving
their clonal expansion [46]. Subsequent to the acquisition of additional genetic alterations some of these proliferating precancerous keratinocytes may undergo clonal divergence and acquire a malignant phenotype. Oral lichen planus has been associated, although debatably, with an increased risk of oral squamous cell carcinoma [49–52]. It has been suggested that the unique profile of the cytokines and chemokines that initiate oral lichen planus may also on occasion be a factor in the transformation of oral lichen planus to oral squamous cell carcinoma [53]. Oral lichen planus is characterised by a T cell-mediated chronic immuno-inflammatory reaction against an as yet undefined antigen within the basal cell layer of the oral epithelium, and by upregulated expression of several inflammatory mediators including TGF-b, TNF-a, IL-6, COX-2 and MMP-7 [54–56]. It is probable that in those rare cases of oral lichen planus that evolve to OSCC, the local inflammatory microenvironment provides the signals that activate transcription factors that not only promote proliferation and longevity of the epithelial cells affected by the lichen planus but also promote angiogenesis, invasion and metastasis [54,55,57]. In established oral squamous cell carcinoma, TNF-a and IL-6 are produced by malignant keratinocytes, and by stromal fibroblasts and macrophages [58]. These cytokines not only increase tumour cell proliferation and survival, but also promote tumour growth through modifying the expression of cell-adhesion molecules and extracellular matrix proteins, and by stimulation of angiogenesis [58,59]. There is high-level COX-2 expression in the cells of the stroma, and in cancerous cells at the invasive front of oral squamous cell carcinoma. It has been suggested that COX-2 plays a role in the process of local invasion and metastasis. Increased expression of COX-2 in oral squamous cell carcinoma is associated with a high rate of recurrence after treatment, with a poor response to radiotherapy and with a poor prognosis [17,25,26,60]. Epidemiological studies suggest that there is an association between dento-gingival bacterial plaques and chronic periodontal disease on the one hand, and oral squamous cell carcinoma on the other hand. This risk appears to be independent of other high-risk habits such as smoking cigarettes and drinking alcoholic beverages [61–63]. The bacteria of dento-gingival plaques and their products, through local inflammatory responses that they generate, through the production of nitrosamines by nitrate-reducing bacteria, and through mutagenic agents formed consequent to the interaction between some bacterial species and the saliva, have the capacity to trigger mitogenic and anti-apoptotic pathways in oral keratinocytes. Thus, oral bacteria and inflammatory mediators associated with periodontal disease may be co-factors in the initiation and in the promotion of oral squamous cell carcinoma [61,63–66]. Although the reported statistical association between dentogingival plaques and chronic periodontitis on the one hand, and increased risk of oral squamous cell carcinoma on the other hand cannot be ignored, clinical experience is not supportive of any such significant causal association, because considering the great number of people with periodontal disease, the incidence of gingival carcinoma is very low compared to what might be expected if the association were real.
Summary The link between cancer and inflammation is specific transcription factors that once activated, have the capacity to enhance the expression of genes regulating the production of inflammatory mediators and to enhance the expression of genes regulating cell survival and proliferation, as well as mediating angiogenesis, immune evasion and metastasis.
L. Feller et al. / Oral Oncology 49 (2013) 887–892
There is clear evidence that persistent inflammation promotes cell proliferation and may induce DNA damage; and that at initial stages of tumorigenesis, inflammatory factors mediate the development of a tumour associated stroma. In turn, activated cells in this stroma promote angiogenesis, cancer growth and metastasis, and mediate immune evasion.
Conflict of interest statement None declared. References [1] Hussain SP, Harris CC. Inflammation and cancer: an ancient link with novel potentials. Int J Cancer 2007;121(11):2373–80. [2] Aivaliotis IL, Pateras IS, Papaioannou M, Glytsou C, Kontzoglou K, Johnson EO, et al. How do cytokines trigger genomic instability? J Biomed Biotechnol 2012;2012:536761. [3] Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 2009;30(7):1073–81. [4] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. [5] Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature 2008;454(7203):436–44. [6] Mantovani A. Molecular pathways linking inflammation and cancer. Curr Mol Med 2010;10(4):369–73. [7] Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 2007;117(5):1175–83. [8] Schafer M, Werner S. Cancer as an overhealing wound: an old hypothesis revisited. Nat Rev Mol Cell Biol 2008;9(8):628–38. [9] Moore MM, Chua W, Charles KA, Clarke SJ. Inflammation and cancer: causes and consequences. Clin Pharmacol Ther 2010;87(4):504–8. [10] Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420(6917):860–7. [11] Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010;140(6):883–99. [12] Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 2009;9(4):351–69. [13] Kim JI, Lakshmikanthan V, Frilot N, Daaka Y. Prostaglandin E2 promotes lung cancer cell migration via EP4-betaArrestin1-c-Src signalsome. Mol Cancer Res 2010;8(4):569–77. [14] Chen Z, Zhang X, Li M, Wang Z, Wieand HS, Grandis JR, et al. Simultaneously targeting epidermal growth factor receptor tyrosine kinase and cyclooxygenase-2, an efficient approach to inhibition of squamous cell carcinoma of the head and neck. Clin Cancer Res 2004;10(17):5930–9. [15] Dannenberg AJ, Lippman SM, Mann JR, Subbaramaiah K, DuBois RN. Cyclooxygenase-2 and epidermal growth factor receptor: pharmacologic targets for chemoprevention. J Clin Oncol 2005;23(2):254–66. [16] Futagami A, Ishizaki M, Fukuda Y, Kawana S, Yamanaka N. Wound healing involves induction of cyclooxygenase-2 expression in rat skin. Lab Invest 2002;82(11):1503–13. [17] Wirth LJ, Haddad RI, Lindeman NI, Zhao X, Lee JC, Joshi VA, et al. Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23(28):6976–81. [18] Lalier L, Pedelaborde F, Braud C, Menanteau J, Vallette FM, Olivier C. Increase in intracellular PGE2 induces apoptosis in Bax-expressing colon cancer cell. BMC Cancer 2011;11:153. [19] Buchanan FG, Wang D, Bargiacchi F, DuBois RN. Prostaglandin E2 regulates cell migration via the intracellular activation of the epidermal growth factor receptor. J Biol Chem 2003;278(37):35451–7. [20] Vacchelli E, Galluzzi L, Eggermont A, Galon J, Tartour E, Zitvogel L, et al. Trial Watch: Immunostimulatory cytokines. Oncoimmunology 2012;1(4):493–506. [21] Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 2006;124(4):823–35. [22] Fukata M, Chen A, Klepper A, Krishnareddy S, Vamadevan AS, Thomas LS, et al. Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine. Gastroenterology 2006;131(3):862–77. [23] Xiao H, Gulen MF, Qin J, Yao J, Bulek K, Kish D, et al. The Toll-interleukin-1 receptor member SIGIRR regulates colonic epithelial homeostasis, inflammation, and tumorigenesis. Immunity 2007;26(4):461–75. [24] Kojima M, Morisaki T, Izuhara K, Uchiyama A, Matsunari Y, Katano M, et al. Lipopolysaccharide increases cyclo-oxygenase-2 expression in a colon carcinoma cell line through nuclear factor-kappa B activation. Oncogene 2000;19(9):1225–31. [25] Choi S, Myers JN. Molecular pathogenesis of oral squamous cell carcinoma: implications for therapy. J Dent Res 2008;87(1):14–32. [26] Goulart Filho JA, Nonaka CF, da Costa Miguel MC, de Almeida Freitas R, Galvao HC. Immunoexpression of cyclooxygenase-2 and p53 in oral squamous cell carcinoma. Am J Otolaryngol 2009;30(2):89–94.
891
[27] Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002;23(11):549–55. [28] Egeblad M, Nakasone ES, Werb Z. Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 2010;18(6):884–901. [29] Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell 2010;141(1):39–51. [30] Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 2006;42(6):717–27. [31] Coffelt SB, Tal AO, Scholz A, De Palma M, Patel S, Urbich C, et al. Angiopoietin-2 regulates gene expression in TIE2-expressing monocytes and augments their inherent proangiogenic functions. Cancer Res 2010;70(13):5270–80. [32] Lewis CE, De Palma M, Naldini L. Tie2-expressing monocytes and tumor angiogenesis: regulation by hypoxia and angiopoietin-2. Cancer Res 2007;67(18):8429–32. [33] Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol 2009;182(8):4499–506. [34] Nagaraj S, Gabrilovich DI. Tumor escape mechanism governed by myeloidderived suppressor cells. Cancer Res 2008;68(8):2561–3. [35] Manjili MH, Payne KK. Cancer immunotherapy: re-programming cells of the innate and adaptive immune systems. Oncoimmunology 2012;1(2):201–4. [36] Johansson M, Denardo DG, Coussens LM. Polarized immune responses differentially regulate cancer development. Immunol Rev 2008;222:145–54. [37] Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet 2001;357(9255):539–45. [38] Legler DF, Bruckner M, Uetz-von Allmen E, Krause P. . Prostaglandin E2 at new glance: novel insights in functional diversity offer therapeutic chances. Int J Biochem Cell Biol 2010;42(2):198–201. [39] Finn OJ. Cancer immunology. N Engl J Med 2008;358(25):2704–15. [40] Lemmer J, Shear M. Oral submucous fibrosis. A possible case in a person of Caucasian descent. Br Dent J 1967;122(8):343–6. [41] Rajendran R. Oral submucous fibrosis: etiology, pathogenesis, and future research. Bull World Health Organ 1994;72(6):985–96. [42] Rajalalitha P, Vali S. Molecular pathogenesis of oral submucous fibrosis–a collagen metabolic disorder. J Oral Pathol Med 2005;34(6):321–8. [43] Chiang CP, Wu HY, Liu BY, Wang JT, Kuo MY. Quantitative analysis of immunocompetent cells in oral submucous fibrosis in Taiwan. Oral Oncol 2002;38(1):56–63. [44] Haque MF, Harris M, Meghji S, Barrett AW. Immunolocalization of cytokines and growth factors in oral submucous fibrosis. Cytokine 1998;10(9):713–9. [45] Chiu CJ, Chiang CP, Chang ML, Chen HM, Hahn LJ, Hsieh LL, et al. Association between genetic polymorphism of tumor necrosis factor-alpha and risk of oral submucous fibrosis, a pre-cancerous condition of oral cancer. J Dent Res 2001;80(12):2055–9. [46] Jeng JH, Wang YJ, Chiang BL, Lee PH, Chan CP, Ho YS, et al. Roles of keratinocyte inflammation in oral cancer: regulating the prostaglandin E2, interleukin-6 and TNF-alpha production of oral epithelial cells by areca nut extract and arecoline. Carcinogenesis 2003;24(8):1301–15. [47] Khan S, Chatra L, Prashanth SK, Veena KM, Rao PK. Pathogenesis of oral submucous fibrosis. J Cancer Res Ther 2012;8(2):199–203. [48] Border WA, Noble NA. Transforming growth factor beta in tissue fibrosis. N Engl J Med 1994;331(19):1286–92. [49] Feller L, Lemmer J. Oral Squamous cell carcinoma: epidemiology, clinical presentation and treatment. J Cancer Ther 2012;3(4):263–8. [50] Mattsson U, Jontell M, Holmstrup P. Oral lichen planus and malignant transformation: is a recall of patients justified? Crit Rev Oral Biol Med 2002;13(5):390–6. [51] Gonzalez-Moles MA, Scully C, Gil-Montoya JA. Oral lichen planus: controversies surrounding malignant transformation. Oral Dis 2008;14(3):229–43. [52] Sousa FA, Paradella TC, Brandao AA, Rosa LE. Oral lichen planus versus epithelial dysplasia: difficulties in diagnosis. Braz J Otorhinolaryngol 2009;75(5):716–20. [53] Liu Y, Messadi DV, Wu H, Hu S. Oral lichen planus is a unique disease model for studying chronic inflammation and oral cancer. Med Hypotheses 2010;75(6):492–4. [54] Scully C, Beyli M, Ferreiro MC, Ficarra G, Gill Y, Griffiths M, et al. Update on oral lichen planus: etiopathogenesis and management. Crit Rev Oral Biol Med 1998;9(1):86–122. [55] Mignogna MD, Fedele S, Lo Russo L, Lo Muzio L, Bucci E. Immune activation and chronic inflammation as the cause of malignancy in oral lichen planus: is there any evidence ? Oral Oncol 2004;40(2):120–30. [56] Li TJ, Cui J. COX-2, MMP-7 expression in oral lichen planus and oral squamous cell carcinoma. Asian Pac J Trop Med 2013;6(8):640–3. [57] Georgakopoulou EA, Achtari MD, Achtaris M, Foukas PG, Kotsinas A. Oral lichen planus as a preneoplastic inflammatory model. J Biomed Biotechnol 2012;2012:759626. [58] Nakano Y, Kobayashi W, Sugai S, Kimura H, Yagihashi S. Expression of tumor necrosis factor-alpha and interleukin-6 in oral squamous cell carcinoma. Jpn J Cancer Res 1999;90(8):858–66. [59] Oyama N, Iwatsuki K, Homma Y, Kaneko F. Induction of transcription factor AP-2 by inflammatory cytokines in human keratinocytes. J Invest Dermatol 1999;113(4):600–6. [60] Massano J, Regateiro FS, Januario G, Ferreira A. Oral squamous cell carcinoma: review of prognostic and predictive factors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2006;102(1):67–76.
892
L. Feller et al. / Oral Oncology 49 (2013) 887–892
[61] Meyer MS, Joshipura K, Giovannucci E, Michaud DS. A review of the relationship between tooth loss, periodontal disease, and cancer. Cancer Causes Control 2008;19(9):895–907. [62] Tezal M, Sullivan MA, Hyland A, Marshall JR, Stoler D, Reid ME, et al. Chronic periodontitis and the incidence of head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prevent 2009;18(9):2406–12. [63] Tezal M, Sullivan Nasca M, Stoler DL, Melendy T, Hyland A, Smaldino PJ, et al. Chronic periodontitis-human papillomavirus synergy in base of tongue cancers. Arch Otolaryngol Head Neck Surg 2009;135(4):391–6.
[64] Hooper SJ, Wilson MJ, Crean SJ. Exploring the link between microorganisms and oral cancer: a systematic review of the literature. Head Neck 2009;31(9):1228–39. [65] Scully C, Bagan J. Oral squamous cell carcinoma overview. Oral Oncol 2009;45(4–5):301–8. [66] Bloching M, Reich W, Schubert J, Grummt T, Sandner A. The influence of oral hygiene on salivary quality in the Ames test, as a marker for genotoxic effects. Oral Oncol 2007;43(9):933–9.