Mechanisms linking pathogens-associated inflammation and cancer

Cancer Letters 305 (2011) 250–262

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Cancer Letters journal homepage: www.elsevier.com/locate/canlet

Mini-review

Mechanisms linking pathogens-associated inflammation and cancer Chiara Porta a, Elena Riboldi a, Antonio Sica a,b,⇑ a b

DISCAFF, University of Piemonte Orientale A. Avogadro, via Bovio 6, 28100 Novara, Italy Istituto Clinico Humanitas, IRCCS, via Manzoni 56, 20089 Rozzano, Milan, Italy

a r t i c l e

i n f o

Keywords: Inflammation Cancer Pathogens

a b s t r a c t It has been estimated that chronic infections with viruses, bacteria and parasites are the causative agents of 8–17% of global cancers burden. Carcinogenesis associated with infections is a complex process, often mediated by chronic inflammatory conditions and accumulating evidence indicate that a smouldering inflammation is a component of the tumor microenvironment and represents the 7th hallmark of cancer. Selected infectious agents promote a cascade of events culminating in chronic inflammatory responses, thus predisposing target tissues to increased cancer susceptibility. A causal link also exists between an inflammatory microenvironment, consisting of inflammatory cells and mediators, and tumor progression. Tumor-Associated Macrophages (TAM) represent the major inflammatory population present in tumors, orchestrating various aspects of cancer, including: diversion and skewing of adaptive responses; cell growth; angiogenesis; matrix deposition and remodelling; construction of a metastatic niche and actual metastasis; response to hormones and chemotherapeutic agents. Recent studies on human and murine tumors indicate that TAM show a remarkable degree of plasticity and functional heterogeneity, during tumour development. In established tumors, TAM acquire an M2 polarized phenotype are engaged in immunosuppression and the promotion of tumor angiogenesis and metastasis. Being a first line of the innate defence mechanisms, macrophages are also equipped with pathogen-recognition receptors, to sense the presence of danger signals, including onco-pathogens. Here we discuss the evidence suggesting a causal relationship between selected infectious agents and the pro-tumoral reprogramming of inflammatory cells, as well as its significance in tumor development. Finally, we discuss the implications of this phenomenon for both cancer prevention and therapy. Ó 2010 Elsevier Ireland Ltd. All rights reserved.

1. Chronic infections and cancers In developing countries infective diseases are still the main cause of death, with an estimation of 44% of annual deaths, whereas in developed countries, effective public sanitation along with health-care programmes have allowed to eradicate or control many of such infections. However, the ‘‘war’’ against pathogens is far from being ⇑ Corresponding author at: DISCAFF, University of Piemonte Orientale A. Avogadro, via Bovio 6, 28100 Novara, Italy. Tel.: +39 02 8224 5111; fax: +39 02 8224 5101. E-mail addresses: [email protected], [email protected] (A. Sica). 0304-3835/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.canlet.2010.10.012

successfully completed. Among diseases with infective etiology, it has been estimated that almost 8–17% of global cancers burden is related to chronic infections with virus, bacteria and parasites (Table 1). 1.1. Viruses Since the late 1960s to date, six different human virus, namely Epstein–Barr virus (EBV), human papilloma virus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV), human T-cell lymphotrophic virus (HTLV) and Kaposi’s associated sarcoma virus (KSHV) were found to be associated with 10–15% of cancers worldwide [1].

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C. Porta et al. / Cancer Letters 305 (2011) 250–262 Table 1 Pathogens associated with human cancers. Pathogen

Name

Cancer site

Annual cases worldwide

Virus

Epstein–Barr virus (EBV)

113,000a

Virus Virus

Human T-cell lymphotrophic virus (HTLV) Human papilloma virus (HPV)

Virus Virus Virus Bacteria Helminth Helminth Helminth

Hepatitis B virus (HBV) Hepatitis C virus (HCV) Kaposi’s associated sarcoma virus (KSHV) Helicobacter pylori Schistosoma haematobium Clonorchis sinensis Opisthorchis viverrini

Burkitt’s lymphoma, Hodgkin’s B cell lymphoma, gastric and nasopharyngeal carcinoma T cell lymphoma Cervix, anus, vulva, penis, oropharynx, head and neck area cancers Liver (hepatocellular carcinoma) Liver (hepatocellular carcinoma) Kaposi’s sarcoma Gastric adenocarcinoma Bladder carcinoma Liver (cholangiocarcinoma) Liver (cholangiocarcinoma)

3300a 561,180a 340,000a 195,000a 102,300a 690,400–728,000b 200,000,000c,* 15,000,000c,* 8,000,000c,*

a

Source [1]. Source [20]. Source [26]. Incidence of people infected worldwide.

b

c

*

In 1958 Dennis Burkitt, describing a new childhood B-cell malignancy, suggested a viral etiology [2]. Three years later, Anthony Epstein and Yvonne Barr identified in Burkitt’s lymphoma cells, a new type of herpesvirus that was called Human Herpes Virus-4 (HHV-4) or Epstein–Barr virus (EBV) [3]. Like other members of the herpes virus family, following primary infection (lytic phase) EBV persists within memory B cells in a latent (non replicative) state, for the life of the host. EBV infection is related with different human malignancies, including African Burkitt’s lymphoma, almost half of the cases of Hodgkin’s lymphoma and B cell lymphoma in immunocompromised patients, gastric carcinoma and nasopharyngeal carcinoma, a highly aggressive cancer type greatly diffuse in Southeast Asia [1]. Although more than 90% of world population is infected by EBV, fortunately the majority of patients develops only a benign disease (infectious mononucleosis) at the time of primary infection. The reason why in some people infection progresses towards malignancy seems to be related with genetic (e.g. translocation of myc gene) and environmental factors (e.g. malaria, malnutrition, alteration in the immune system) [1]. Human T cell lymphotropic virus-1 (HTLV-1) was the first human oncogenic retrovirus identified by Robert Gallo in human T cell lymphoma cells in 1980 [4]. HTLV-1 is the causative agent of adult T cell leukemia, a malignancy often associated with poor prognosis. Currently 10–20 millions of people worldwide are infected by this virus, and neither vaccines nor specific antiviral therapies are available for HTLV-1 [1]. The infective etiology of cervical cancer was suggested as early as 1842, but the proof of this hypothesis was provided only in 1907, when it was demonstrated that warts could be transmitted by cell free extracts [5]. At present, human papilloma virus (HPV) is recognized as the causative agent for cervix, anus, vulva, penis, oropharynx, head and neck cancers [5]. HPV is considered the most common sexually transmitted disease. While 90% of infections is asymptomatic and resolves within 1–2 years, more than 500,000 of new annual cases of human cancers worldwide are related to HPV, in particular to the highly aggressive HPV types 16 and 18 [1]. The recent development of

vaccines against these high risk HPV strains is expected to reduce more than 450,000 of new annual cases of cervical cancer [5] and to counteract the emerging spread of oral cancers [6]. Hepatitis B and C virus, discovered in 1969 [7] and 1989 [8,9], respectively, are recognized as the major risk factors for hepatocellular carcinoma (HCC), the third leading cause of cancer death worldwide [10]. In most of adults, HBV infection is asymptomatic or causes an acute hepatitis that is resolved within 6 months [11]. On the contrary, in the majority of newborns or young children HBV gives rise to chronic infection, with high risk of progression to HCC [12]. This scenario is even worst for HCV infections, which exhibit a higher frequency of chronic infection (10% of HBV cases versus 60–80% of HCV) and have a greater propensity to promote liver cirrhosis (10–20-fold higher than HBV) [13]. When hepatitis is not resolved, the prolonged inflammation and liver damage lead to cirrhosis and this ultimately results in HCC. It has been estimated that 350 and 270 millions of people worldwide are chronically infected with HBV and HCV, respectively [1]. The development of an HBV vaccine along with the global vaccination program lead to a significant decrease in the rate of new annual cases of infections and will likely results in a remarkable reduction of HBV-related HCC in the next decades [14]. Unfortunately, although many efforts have been invested, the research for an HCV vaccine is still in progress [14]. A comprehensive elucidation of molecular pathways linking HCV infection and HCC is required for the development of new therapeutics drugs able to prevent disease progression towards cancer. Human herpes virus 8 (HHV-8) or Kaposi’s sarcoma associated herpesvirus (KSHV) is the last human oncogenic virus discovered in the 1990s [15], when, in association with HIV infection burden, the incidence of Kaposi’s sarcoma dramatically increased. As HIV-infection started to be controlled by highly-active antiretroviral therapy (HAART), the incidence of Kaposi’s sarcoma lowered again. In developed countries this type of tumor is found in minority groups (e.g. transplanted patients undergoing immunosuppressive therapy), while in developing countries, such as Africa, is the most prevalent cancer in children [1].

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1.2. Bacteria Following the isolation of Helicobacter pylori by Robin Warren and Barry Marshall [16] and the demonstration that this pathogen is responsible for peptic ulcer disease, researchers began to hypothesize a casual relationship between this bacterium and gastric cancer. Based on different observational studies, in 1994, H. pylori was the first bacterium classified by the International Agency for Research on Cancer and World Health Organization (WHO) as human carcinogen (group I) (IARC Working group, 1994). Later, large scale prospective clinical studies clearly supported the casual relationship between H. pylori and gastric cancer [17–20]. Presently, it has been estimated that H. pylori is the major cause of stomach inflammation that results in peptic ulcer disease (10–20%), distal gastric adenocarcinoma (1–2%) and gastric mucosal-associated lymphoid tissue (MALT) lymphoma (<1%) [21]. Since the risk of gastric cancer development in the general population is estimated as high as 75%, H. pylori infections would be responsible for 5.5% of all cancers worldwide [22]. Nevertheless, large scale screening and treatment programmes for H. pylori remain controversial. Indeed, H. pylori has developed complex relationship with humans, behaving both as pathogen and as commensal bacterium. Furthermore, recent evidence indicates that H. pylori plays a protective role in different diseases including esophageal adenocarcinoma, asthma, gastroenteritis and tuberculoses [22]. Hence, eradication of H. pylori is widely accepted only in specific groups of people, including patients with peptic ulcer disease, gastric MALT lymphoma, early gastric cancer, first degree relatives of gastric cancer patients and uninvestigated dyspepsia patients in high prevalence population [21]. 1.3. Parasites Helminth infections are largely diffused among poor populations of developing countries and their association with cancer was mainly suggested by epidemiological studies showing a significant correlation between the

occurrence of certain types of cancer in geographic areas where a specific parasite is endemic. For example cholangiocarcinoma (CCA) is generally less common than HCC, but in Thailand, where the prevalence of Opisthorchis viverrini is the highest in the world, CCA is the predominant type of liver cancer [23]. Similarly, in Korea, the endemism of Clonorchis sinensis infection correlates with the morbidity and the mortality associated with CCA [24]. Moreover, a high prevalence of squamous cell carcinoma of bladder was observed in geographic areas where Schistosoma haematobium is endemic (e.g. Egypt, Iraq, Zambia, Malawi, Kuwait) [25]. The carcinogenic role of S. haematobium was also supported by several case-control studies [26] and by experimental studies in animals (monkeys and opossum) where infection with this trematode triggered superficial transition cell carcinomas. Based on these evidences, S. haematobium, C. sinensis, and O. viverrini have been recently classified as human carcinogens (group I) (International Agency for research on cancer, IARC, Working group, 2009), while the role of other trematodes (e.g. Schistosoma mansoni, Schistosoma, japonicum, Fascicola hepatica), cestodes (e.g. Taenia solium), and nematodes (e.g. Trichostrongylus colubriformis) is still under investigation [26]. Schistosomiasis is endemic in 74 tropical and sub-tropical countries with about 700 million of people at risk of infection, whereas C. sinensis and O. viverrini are highly diffused in east Asia and Eastern Europe with more than 600 million people at risk of infection [26]. Considering that the development of helminth-related cancer often requires the exposure to the infection for many years, whether a sustainable control of helminth infections in the endemic areas will be adopted, a large number of cancers could be prevented. As a consequence of the increase of the human lifespan, diseases of aging represent the major public health problem in developed countries. Since neoplastic transformation is usually a long process, cancer’s incidence increases with age and, indeed, tumors represent the main health challenge for modern society. It is widely accepted that fighting

Table 2 Mechanisms linking pathogens-associated inflammation and cancer. Pathogen

Pathogen molecules

Epstein–Barr virus (EBV) Human T-cell lymphotrophic virus (HTLV) Human papilloma virus (HPV) Hepatitis B virus (HBV) Hepatitis C virus (HCV)

LMP1

Kaposi’s associated sarcoma virus (KSHV) Helicobacter pylori Schistosoma haematobium, Clonorchis sinensis, Opisthorchis viverrini

Host molecules

Cancer-related inflammatory pathways

Cellular immune response

Proliferation and survival of infected cells (IL-6, STAT3, PGE2)

Ref. [1,46]

Tax

E6

NF-jB,

Oxidative stress (ROS, RNS)

Th2, Treg

[48,50,60,67]

HBx Core protein protein 5A vFLIP, vlL-6 vCCL1,2, 3

HIF-1a

Promotion of angiogenesis (VEGF) Inhibition of adaptive immune response (IL-10)

M2 macroph.

[71–73,13,83]

CagA, VacA

NF-jB NF-jB

IL-6, IL-8, TNFa, IL-1b, PGE2, ROS, RNS ROS, RNS, Arginase I, Fizz1, Ym1, MGL2, IL-4, IL-5, IL-9, IL-10, IL-13

Th1,Treg Th2, M2 macroph.

[51,87] [26]

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against cancer requires a multitasks approach based on prevention, diagnosis, and therapy. In this scenario, eradication of pathogens associated with cancers by vaccination/therapy represents an important strategy to prevent a significant percentage of tumors. In addition, the analysis of molecular mechanisms underlying pathogen oncogenic activities could provide valuable molecular targets for new therapeutic approaches. Overall, carcinogenesis associated with infections is a complex process. However, along with pathogen-specific mechanisms, chronic inflammation is a common and crucial feature of infection-induced cancers (Table 2). This review will focus on the inflammatory pathways linking infections with cancers. 2. Molecular mechanisms linking pathogen-associated inflammation and cancer development Although inflammation acts as a host defence mechanism against infection or injury and is primarily a self limiting process, it is generally accepted that inadequate resolution of inflammatory responses represents a major pathological basis for tumour development. Accordingly, about 25% of all cancer cases worldwide are linked to chronic inflammation caused by chronic infections, autoimmune diseases (e.g. Inflammatory Bowel Disease) or inflammatory conditions of uncertain origin (e.g. prostatitis) [27]. Furthermore, smouldering inflammation is a hallmark of the microenvironment of most neoplastic tissues, including those not etiologically related to infections [28]. Inflammation and cancer are connected by two pathways: the extrinsic pathway, driven by exogenous factors able to trigger a persistent inflammatory response and the intrinsic pathway, induced by alterations in cancer-associated genetic factors (e.g. mutation of either oncogenes or tumor-suppressor genes), which promote cancer-related inflammation (CRI) [28]. The two pathways converge in the activation of transcription factors (NF-jB, HIFs, STAT-3) which are key orchestrators of the inflammatory response (e.g. production of cytokines, chemokines, prostaglandins and nitric oxide) [28]. CRI contributes to tumour development through different mechanisms, including induction of genomic instability, alteration in epigenetic events and subsequent inappropriate gene expression, enhanced proliferation and resistance to apoptosis of initiated cells, immune suppression, induction of tumour angiogenesis and tissue remodelling with consequent promotion of tumour cells invasion and metastasis [28]. Crucial inflammatory pathways activated by pathogens and promoting cancer development and progression are herein discussed (Fig. 1). Extrinsic signals are mainly sensed by families of pathogen-recognition receptors (PRR). 2.1. Pattern-recognition receptors (PRR) Toll-like receptors (TLR) is the major family of patternrecognition receptors (PRRs) that play a central role in host defence by recognizing pathogen-associated molecular patterns (PAMPs). In epithelial cells, which are the first line of defence at mucosal sites, TLR activation triggers the

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release of potent anti-microbial factors such as defensins, lysozyme and phospholipase A2 [29]. In phagocytes, TLR engagement enhances microbial killing through the promotion of microorganisms uptake along with the activation of neutrophils oxidative burst [30,31]. In addition, TLR activation in macrophages and dendritic cells leads to the expression of pro-inflammatory cytokines, chemokines and co-stimulatory molecules which are crucial for the activation of the adaptive immune response. TLRs also play a key role in B and T cells responses. Indeed, they directly promote B cell proliferation, immunoglobulin class switching and somatic hypermutation [32] and, through the induction of cytokines such as IL-12, IL-23, and IL-27, can trigger TH1 and TH17 cell differentiation and maintenance [33]. Up today, eleven human TLR members have been described. They are localized on the plasma membrane or in endosomal compartment and, recognize microbial macromolecules of lipid and protein origin (TLR1, TLR2, TLR4, TLR5, TLR6) as well as nucleic acid (TLR3, TLR7, TLR9). Upon TLR engagement, one or more of four adaptor proteins (MyD88, MAL, TRIF, and TRAM) promote activation of intracellular signal transduction cascades that lead to activation of transcription factors (e.g. NF-jB, IRFs, AP-1) which in turns induce the inflammatory program [34,35]. Thus, TLR-induced inflammatory mediators orchestrate innate and adaptive immune responses which often result in the eradication of the invading pathogens. TLR activation also plays a key role in modulation of cell survival and proliferation [36]. TLRs also recognize different endogenous ligands (e.g. heat shock proteins-60 and -70, high mobility group box 1, uric acid crystals, surfactant protein A) and extracellular matrix components (e.g. fibronectin, heparin sulphate, biglycan, fibrinogen, oligosaccharide of hyaluronan and hyaluronan breakdown fragments), suggesting that TLRs play a key role also in inflammation associated with tissue injury and repair [36]. In this context, both infections and injury induce TLR-dependent inflammation that can promote tumorigenesis, due to chronic tissue damage and the subsequent induction of tissue repair. Since solid tumors growth can mimic tissue damage, TLR activation can play also a prominent role in the induction of inflammation in tumors that are unrelated to a preexisting inflammatory process. The importance of TLR activation in tumorigenesis is supported by several studies showing the association of polymorphisms in TLRs with human cancer, in a variety of organs such as nasopharynx, stomach, prostate, breast, blood and colon [36]. Further, different studies performed in murine models of spontaneous carcinogenesis demonstrated the importance of TLRdependent pathways in tumor development. In line with the importance of TLRs signalling in tissue repair after injury, in a chemical model of colitis-associated cancer, mice deficient in TLR4 were protected against the development of neoplasia induced by the carcinogen azoxymethane and dextran sulphate. [37]. Intestinal TLRs play also a crucial role in the development of sporadic colon cancers. The effect of decreased TLR signalling on colorectal carcinogenesis has been studied by crossing APCMin mice with MYD88-deficient mice. A lower incidence and size of intestinal tumours in double mutant (APCMin-MYD88–/–)

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Fig. 1. Molecular mechanisms linking pathogen-associated inflammation and cancer development. Chronic infections lead to cancer-related inflammation by the construction of an inflammatory microenvironment. Host recognizes pathogens (viruses, bacteria, parasites) through a class of receptors which bind conserved microbial structures named ‘‘pathogen-associated molecular pattern’’ (PAMPs). Toll-like receptors (TLR) are the major class of pathogens recognition receptors (PRR) expressed by cells belonging to either the innate (macrophages, neutrophils, eosinophils, mast cells, dendritic cells) or adaptive (B and T lymphocytes) immunity, as well as by other cell types. TLR engagement leads to the activation of transcription factors (e.g. NF-jB, HIF-1a) which are key orchestrators of the inflammatory response. Inflammation promotes cancer development rough various mechanisms. Inflammatory mediators (e.g. cytokines and prostaglandins) promote survival and proliferation of cancer cells, reactive oxygen and nitric oxide species (ROS and RNS) induce genetic instability. Further, NF-jB activation in response to both microbial compounds and inflammatory cytokines, drives the transcription of genes promoting proliferation and survival.

mice as compared to APCMin mice [38] was found. Interestingly, Cycloxygenase-2 (COX-2) expression is lower in the tumour tissue of MYD88–/– mice. COX-2 promotes tumour growth through the induction of PGE2 and other mediators to stabilize b-catenin [39]. The importance of

TLR-MyD88-dependent pathways in tumor promotion was also demonstrated in other preclinical models of chemically induced carcinogenesis in liver, skin and connective tissue [40,41]. Despite this, new evidence also suggest that functional TLR4 in dendritic cells is necessary

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to promote an efficient adaptive immune response, in breast cancer patients undergoing chemo- and radio-therapy [42]. 2.2. Cytokines Several studies with genetically modified mice, along with the analysis of human tumours, have highlighted that altered expression of selected pro-inflammatory (e.g. TNFa, IL-1b, IL-6) and/or anti-inflammatory cytokines (e.g. IL-10, TGFb) has a crucial role in the promotion of different type of tumors, including gastric, colorectal, liver, breast, skin [43]. Different pathogens with oncogenic properties promote up-regulation of pro-inflammatory cytokines. For example, KSHV encodes for a homolog of the human IL-6 cytokines (vIL-6) that is able to signal through the gp-130-coreceptor subunit alone [44]. To study the biological activities of vIL-6 in the contest of KSHV-associated diseases, notably Kaposi’s sarcoma, primary effusion lymphoma (PEL) and multicentric Castelman’s disease (MCD), athymic mice were injected with vIL-6 overexpressing NIH3T3 cells [45]. v-IL-6 positive mice showed an increased tumor growth and vascularisation along with enhanced hematopoiesis and plasmacytosis in lymphoid organs [45]. Further, mice bearing vIL-6 producing tumors selectively express vascular endothelial growth factor (VEGF) in tumors as well as in spleen and lymph nodes [45]. Since vIL-6 is expressed only in few cells of Kaposi’s sarcoma, while it is abundant in both PEL cells and MCD lesions, is likely to play a major role in KSHV-associated lymphoproliferative disorders [46]. Accordingly, in vitro studies of PEL cell proliferation in presence of anti-vIL-6 neutralizing antibodies demonstrated vIL-6 as a crucial autocrine growth factor for PEL cells [46]. Engagement of gp130 by vIL-6 leads to STAT3 activation which is a crucial transcription factor for genes controlling cell survival and proliferation. Further STAT3 is a key modulator of VEGF expression which in turn promotes vascular permeability resulting in the accumulation of body cavity effusion [46]. In MCD patients, the serum levels of vIL-6, but not human-IL-6, increase during the acute symptoms of the disease and decline at undetectable levels with clinical remission. This selective correlation between KSHV replication, vIL-6 expression and disease activity suggests the importance of viral cytokines in the pathogenesis of MCD [46]. IL-6 is a key player in the pathogenesis of HCC. IL-6deficient mice develop less tumors in the diethylnitrosamine (DEN)-induced HCC model [41]. In this model, the DNA damage contributes to necrotic cell death, resulting in an inflammatory reaction that promotes tumor development [47]. IL-1a released by damaged hepatocytes triggers MyD88-NFjB signaling and IL-6 synthesis by Kupffer cells. In turn, IL-6 favours compensatory proliferation of surviving hepatocytes, some of which may harbor oncogenic mutations. IL-6 production is gender-biased and males, who produce higher levels of this cytokine, have a higher HCC load [41]. Accordingly, high serum IL-6 was demonstrated to be predictive of HCC development in patients with chronic hepatitis B [48]. Strikingly, IL-6 expression is directly mod-

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ulated by HBV, through the HBV X protein (HBx), a small viral protein interacting with several virus and host factors. In particular, it was shown that HBx interacts with NF-jB enhancing its binding activity on the IL-6 promoter and increasing its transcriptional activity [49]. Like the HBx protein, HCV core protein may modulate multiple cellular processes leading to the development of progressive hepatic steatosis and hepatocarcinogenesis. Recently, to gain insights into the molecular mechanisms of HCV core protein-mediated hepatocyte growth regulation, DNA microarray analysis was performed with HCV core-transfected primary human hepatocytes, at different stages of immortalization and transformation [50]. Remarkably, introduction of the HCV core protein resulted in a significant up-regulation of genes associated with the IL-6-signalling pathway (e.g. IL-6, gp130, leptin receptor, STAT3) [50]. The tumor-promoting effect of IL-6 is mainly exerted via STAT3 that activates multiple target genes involved in cell survival and proliferation [28]. As results, STAT3 activation and downstream molecules (e.g. c-myc, cyclin D1) were greatly increased in immortalized human hepatocytes transfected with HCV core protein [50], thus supporting it’s oncogenic activity in hepatocytes [50]. H. pylori bacterial strains containing the cag pathogenic island (PAI), induce the highest inflammation and are the most closely linked to malignancy. PAI is a 40 kb segment of DNA containing genes that encode for different virulence factors such as the Cytotoxic Associated Antigen (CagA) along with type IV secretory system (TASS), the vacuolating toxin (VacA), the blood group antigen binding adhesion (BabA) and the outer membrane proteins Oip and IceA [51]. Accordingly with epidemiological association of CagA positive strains with gastric cancer, the studies of Ohnishi and co-workers assessed that CagA protein has oncogenic activities. These authors showed that mice carrying the transgenic expression of CagA spontaneously developed gastric epithelia hyperplasia and adenocarcinoma [52]. It has been demonstrated that upon injection of CagA in epithelial cells, the bacterial protein interacts with multiple cellular pathways which in turn result in the promotion of proliferation, apoptosis, motility and in the induction inflammatory gene expression [51]. CagAinduced epithelial cell death provides additional signals guiding increased compensatory proliferation and tumor load. The importance of cytokines levels in H. pylori-associated gastric cancer is confirmed by different studies showing that polymorphisms associated with enhanced expression of cytokines (e.g. IL-1b, IL-8, TNFa) or other pro-inflammatory molecules (e.g. MPO, MMP7, TIMP, PPARc) are associated with high risk of gastric cancer [19]. It is now recognized that the interplay between strain-specific pathogenic factors, host genetic and microenvironmental factors (e.g. smoke and dietary factors) concur to the development of gastric cancer. 2.3. Cycloxygenase-2 (COX-2) Cycloxygenase-1 (COX-1) and -2 (COX-2) enzymes play a key role in the synthesis of lipid inflammatory mediators (prostaglandins and prostacyclines) from arachidonic acid. Several studies have indicated that aberrant induction of

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COX-2 and prostaglandins are implicated in the pathogenesis of various type of malignancies. In line, epidemiological studies have highlighted that the treatment with COX-2 inhibitors reduce the risk of developing certain cancers (such as colon and breast cancer) and the mortality caused by these cancers [53]. Moreover, mice genetically engineered to overexpress COX-2 in mammary glands, skin or stomach are more susceptible to develop tumours in these organs, while COX-2-deficient mice are more resistant to intestinal, skin and mammary tumourigenesis [53]. Noticeably, in gastric epithelial cells COX-2-dependent pathway is activated by gastrin, a factor greatly up-regulated and associated to the progression of gastritis towards cancer. Mice over-expressing gastrin spontaneously develop gastric cancer. Importantly, in these mice cancerogenesis is consistently accelerated by H. pylori infections [54]. Indeed, H. pylori enhances gastrin secretion and synergizes with gastrin in the induction of inflammation. H. pylori engagement of the intracellular PRR Nod1 leads to the activation of NF-jB, which results in the up-regulation of COX2 and several pro-inflammatory cytokines (e.g. IL-8, TNF, IL-1) [54]. 2.4. NF-jB The transcription factor NF-jB has a pivotal role in innate immunity and inflammation and recent evidence suggests that this factor represents a potential molecular bridge between inflammation and cancer [55]. NF-jB drives the expression of inflammatory cytokines, adhesion molecules, angiogenic factors and enzymes, like COX-2 and iNOS, which are important for the synthesis of inflammatory mediators (PGE2 and NO, respectively). In cancer and epithelial cells exposed to carcinogens, NFjB promotes cell survival and proliferation through the activation of genes encoding for proteins regulating cell cycle progression (e.g. cyclin D1, c-Myc) and apoptosis (e.g. cIAPs, A1/BFL1, BCL-2, c-FLIP). Hepatocarcinogenesis greatly depends on NF-jB activation in both parenchymal (hepatocytes) and non parenchymal cells of the liver. The MDR2-KO mouse strain lacks a biliary phospholipid transporter and develops cholestatic hepatitis followed by HCC. Hepatocyte-specific inhibition of NF-jB in transgenic animals during the later stages of tumor progression results in failure to progress to HCC [56]. The scenario is quite different in a model of chemically-induced liver carcinogenesis. Hepatocyte-specific NF-jB inactivation results in a higher incidence of liver tumors upon treatment with the carcinogen DEN [57]. These divergent effects of NF-jB may be likely ascribed to two distinct pathogenic processes. In the chronic inflammation-induced HCC model (MDR2-KO mice), NF-jB is chronically activated. Blocking this transcription factor in the promotion phase would favor apoptotic death of hepatocytes. On the contrary, DEN administration provokes an acute injury and NF-jB activation is likely restricted to this acute phase. Early NF-jB inactivation leads to accelerated apoptosis and compensatory hyperproliferation of cancer-prone hepatocytes, thus increasing tumor load [57]. It was reported that mice lacking the NFjB activator IKKb in their hepatocytes spontaneously de-

velop chronic hepatitis and HCC [58]. As opposed to IKKb ablation in hepatocytes only, IKKb inactivation in both hepatocytes and Kuppfer cells, results in a reduction in the number and size of tumors elicited by DEN treatment [57]. Several factor can be imputable for discrepancies in different studies, including the use of different transgenic mice, the influence of different animal facilities, the fact that mice lacking an intact NF-jB pathway are more prone to infections, and the involvement of IKKb targets outside the NF-jB [59]. In innate immune cells and in cancer cells NF-jB activation can be promoted by pro-inflammatory cytokines, such as TNF-a and IL-1, as well as by recognition of pathogenassociated molecular patterns. Oncogenic viruses encode proteins able to activate NF-jB with consequent reinforcement of TLR-dependent pathways. HBV X is a small protein of 154 amino acids encoded by the X open reading frame (one of the four HBV ORF). HBx play a key role the development of HCC, by interacting with the p53 tumor suppressor, as well as with several crucial transcription factors involved in proliferation and inflammation, such as NF-jB, MAPK, PKC and PI3 K pathways [1]. Similarly, NF-jB is activated by both the HCV core protein and the protein 5A, which are among the most important viral factors for HCV-associated pathogenesis [48]. EBV Latent membrane protein 1 (LMP-1) is a six-span transmembrane protein that mimics CD40, a member of tumor necrosis factor family. LMP1 is constitutively active and triggers the activation of NF-jB and other key transcriptional factors (e.g. AP1, STATs), all of which have a crucial role in driving the expansion of B cell populations [59]. Consequently, LMP1–transgenic mice develop B cells lymphoma with high frequency and their survival is significantly decreased by inhibition of NF-jB, Akt, STAT3 [60]. LMP1-dependent activation of NF-jB promotes oncogenesis through several mechanisms, including induction of miR-155, an endogenous microRNA implicated in the pathogenesis of lymphoproliferative disorders, upregulation of the catalytic subunit of human telomerase, a crucial factor driving cell immortalization, and increased expression of Bcl-3, a key inducer of cell proliferation and survival [60]. In the same way, the HTLV-1 Tax protein promotes lymphocytes proliferation through the activation of NFjB, AP-1 and CRE; it also interacts with several factors modulating chromatin remodelling and inhibiting DNA repair, which in turn lead to genomic instability and cellular transformation [61]. NF-jB is constitutively active also in KSHV–associated cancers and the latent protein vFLIP is recognized as both an essential viral oncogenic factor and as a major activator of NF-jB in infected cells [60]. In vitro studies have shown that ectopic expression of vFLIP in primary endothelial cells is sufficient to promote the spindle-cell morphology, a feature of Kaposi’s sarcoma mainly controlled by constitutive NF-jB activation [60]. Accordingly, in vivo studies with transgenic mice selectively expressing vFLIP in B or endothelial cells showed constitutive NF-jB activation and increased tumor incidence [60]. Of note, in in vivo models of KSHV-associated cancer the malignant transformation appears to require the synergistic effects of vFLIP-driven NF-jB activation and other viral (e.g.

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vGPCR, K1) or cellular products promoting VEGF expression [60].

2.5. Oxidative stress It is well known that an impaired ‘‘oxidant-anti-oxidant’’ balance causes DNA damage and may result in cell death and/or in the generation of mutations leading to increased expression of oncogenes and inactivation of tumor-suppressor genes. An important mechanism underlying carcinogenesis induced by H. pylori infections is the oxidative stress generated by the bacterium itself, as well as by the activation of gastric epithelial [62] and mucosal inflammatory cells [63]. In response to H. pylori infection, mucosal leukocytes up-regulate enzyme such as iNOS, myeloperoxidases, NADPH oxidases and peroxidases which generate a great amount of reactive oxygen (ROS) and nitrogen species (RNS). Even if, to inhibit the bactericidal effects of nitric oxide (NO), H. pylori itself produces a great amount of superoxide anions [64] and release anti-oxidant enzymes (e.g. catalase, superoxide dismutase), it is in amounts likely insufficient to clear excess of extracellular oxidants [65]. Oxidative stress, mainly produced by inflammatory cells, is as well the major mechanism underlying parasite-related cancerogenesis. Chronic inflammation, parasites, their eggs or secreted products cause repeated tissue damage associated with restorative hyperplasia. In this context cells carrying genotoxic insults may be easily propagated and accumulate additional mutations which ultimately lead to malignancy [26]. As a result, cancers often arise close to the site of parasite or eggs deposition, which is bladder for S. haematobium and liver for C. sinensis and O. viverrini. Moreover, inflammatory cells may contribute to the activation of pro-carcinogens such as aflatoxins, which are a common environmental factor present in the areas where S. haematobium infections are endemic [66]. Although C. sinensis and O. viverrini secrete proteins that induce cell proliferation, CAC is likely a slow indirect process mainly dependent on chronic inflammation [26]. Oxidative stress is associated with chronic HBV and HCV infections and with the development of HCC. Chronic HBV hepatitis is characterized by periodic down-regulations of viral titers accompanied by immune mediated liver injures known as ‘‘flares’’. The recurrence of this damage results in repeating cycles of death and proliferation of hepatocytes [67]. High hepatocyte proliferation rate represents a major risk factor for HCC development in the cirrhotic liver. During chronic inflammation high levels of reactive oxygen species and reactive nitrogen species are released by activated inflammatory cells. Reactive species can cause DNA damage and lead to gene mutations. Moreover, ROS can activate several transduction pathways (e.g. MAPK, NF-jB) involved in the regulation of proliferation, differentiation and apoptosis. The oxidative stress and the influx of liver mononuclear phagocytes, the Kuppfer cells, can promote the fibrotic action of stellate cells, representing the main producers of extracellular matrix in the liver. Their persistent activation eventually results in cirrhosis, characterized by the co-existence of regenerative nodules, irreversible fibrosis and severe liver injury.

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2.6. Hypoxia-inducible factors (HIFs) Hypoxia-inducible factors (HIF) are key mediators of the cellular oxygen-signaling pathway [68]. HIF activation has been found to promote key steps in tumorigenesis, including angiogenesis, metabolism, proliferation, metastasis and differentiation. Acute viral infections is generally found to induce HIF proteins activation in target cells, leading to the expression of type I IFN and other antiviral genes (e.g. vesicular stomatitis virus and respiratory syncytial virus infections) [69]. However, in the case of some persistent viral infections the induction of HIFs fails to result in the eradication of the virus. The consequence is the activation of pathways contributing to oncogenic transformation. This seems to be the case of HBV and HCV. HIFs levels were reported to be augmented in liver cells transfected with the oncogenic X protein of HBV and in the livers of HBX-transgenic mice [70]. HBx interferes with HIF1a binding to the Von Hippel–Lindau factor (VHL), thus blocking its ubiquitin–proteasome-mediated degradation [71]. Recently, HCV infection has also been found to stabilize HIF-1a protein, with the involvement of the NF-jB and MAPK signaling pathways, promoting VEGF release and angiogenesis [72]. Experimental studies showed that also HPV induces VEGF expression and capillary formation in a HIF-dependent manner, and HPV16 and HIF-1a synergize in the promotion of cervical cancer lesions in a mouse model [69]. In agreement, increased HIF levels correlates with poor prognosis of patients with advanced cervical lesions [73]. HIF is also activated during chronic infection with other oncogenic viruses, namely HTLV-1, EBV, and HHV8. [69].

3. Cellular basis linking pathogens-associated inflammation and cancer development Several studies have highlighted that a leukocytes infiltrate, varying in size composition and distribution, is present in the majority of tumours and is involved in carcinogenesis, tumour growth, invasion and metastasis [28]. However, genetic studies of mouse models have also demonstrated that the inflammatory response supported by innate immune cells is crucial for the activation of an adaptive immune response capable to eliminate nascent tumours [74]. It is speculated that immune cells continuously recognize and destroy nascent tumour cells but, due to their genetic instability, the arising new cancer cell variants evade the immune surveillance [74]. In this regard, several studies aimed to elucidate the mechanisms driving immune escape have emphasized that a ‘‘smouldering’’ inflammation associated with established tumours is mainly oriented to tune the adaptive immune response. In agreement, tumour associated dendritic cells show an immature phenotype and infiltrating myelomonocytic cells express an alternative M2 functional phenotype, primarily oriented towards the suppression of the adaptive immune response [75,76]. Most helminths induce the expression of an inflammatory program that is M2 (Arginase I, Fizz1, Ym1, MGL2) and

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Th2 (IL-4, IL-5, IL-9, IL-10, IL-13) related, which persists for the duration of the infection [77]. It has been speculated that long-lived helminths may affect host immune surveillance and thereby contribute to clonal expansion of malignant transformed cells [78]. This is achieved by shifting the Th1–Th2 balance resulting in a downregulation of the Th1 immune responses [79,80]. A Th1 versus Th2 switch is also reported for KSHV infection. During replication, KSHV release virally encoded chemokines (vCCL1, vCCL2, vCCL3) that act as non signalling ligands for multiple CC and CX receptors expressed by Th1 cells. On the contrary, the viral chemokines appear to be involved in the recruitment of Th2 lymphocytes [81]. The importance of type 2 immune response is also evident in HCC progression. In fact, a dominant Th2-like cytokines profile (IL-4High, IL-8High, IL-10High, IL-5High and IL-1aLow, IL-1bLow, IL-2Low, IL-12p35Low, IL-12p40Low, IL-15Low , TNFaLow, INFcLow) is associated with a HCC metastatic phenotype [82]. Of note, the progression of HBV and HCV related acute hepatitis versus chronic disease is associated with a Th1/Th2 switch [83]. In this scenario, a dominant Th2 microenvironment allows virus persistence and promotes chronic disease progression towards hepatocarcinogenesis [84]. Different mechanisms may contribute to the establishment and maintenance of persistent infection, among these the inhibition of NK cells activation [85], the impairment of antigen presentation by DCs, the alteration in number and function of circulating blood DC, the impairment of T cell maturation, the tolerogenic environment of the liver and the expansion of suppressive T regulatory cells [13]. All together these mechanisms also promote immune evasion of transformed hepatocytes. A different scenario is present in gastric cancers associated with H. pylori infections. This bacterium induces a strong innate and adaptive immune response, which results in a predominant type I response [86,87]. H. pylori interacts with gastric epithelial cells leading to the expression of anti-bacterial products, inflammatory cytokines and chemokines, which promote the recruitment of leukocytes in the inflamed mucosa and amplification of the inflammatory response [88]. Innate immune responses against H. pylori generate mucosa damages, leading to increased exposure of leukocytes to bacteria and consequent amplification of the inflammatory response. Since many of the induced inflammatory mediators (e.g.. IL-8, IL-1, PGE2, TNFa, IL-6) are able to promote epithelial cells proliferation, inflammation triggers both tissue damage and repair [87]. The result of tissue repair in a microenvironment rich of genotoxic insults (ROS, RNS) is the progression of chronic gastritis to atrophic gastritis, intestinal metaplasia, dysplasia and adenocarcinoma. Along with a robust stimulation of innate immune cells H. pylori infections is associated with a dominant Th1 response. Accordingly, the severity of gastritis correlates with the number of IFNcsecreting cells in the gastric mucosa and IFNc alone is able to induce in mice pre-cancerous gastric atrophy, metaplasia and dysplasia [89]. The question is why the immune response does not eliminate H. pylori. Possible explanations may be found in different mechanisms used by H. pylori to escape both innate and adaptive immune control. As an example, H. pylori partially evades phagocytes-mediate

cell killing through the destruction of NADPH oxidase activity by neutralization of toxic ROS, through its catalase activity [90]. Moreover, bacterial proteins, such as CagA [91] and VacA [92–94] can inhibit T cell activation, while triggering the recruitment of Treg in the gastric mucosa [95]. Overall, it appears that partial downregulation of T cell immune functions during the course of infection may provide permissive conditions for both H. pylori and neoplastic cancer cells. Finally, it is suggested that gastric cancers originate from gastric cancer stem cells or progenitor cells [96]. An important mechanism linking H. pylori with gastric cancer might involve the mobilization of bone marrow derived mesenchymal cells (BMDC) [96].

4. Therapy Cancer represents the major public health problem for modern society. Despite major advances in conventional treatment, in the last 20 years the 5-year survival of many cancer patients has increased less than 10%. This poor clinical outcome illustrates an unmet clinical need for new therapeutic approaches. Furthermore an important strategy in fighting against cancer is prevention, as this approach appears more effective and economical than conventional therapies. Since 8–17% of global cancers burden is related to chronic infections (e.g. virus, bacteria and parasite) the development of an effective program of prevention against ‘‘oncopathogens’’ represents an opportunity for cancer prevention. Based on the successful control of viral infections (e.g. smallpox, polio) by prophylactic vaccines, several efforts are focused on the development and implementation of vaccines against onco-viruses. Antiviral vaccines represent one of the best opportunities for reducing cancers also in low resource setting, such as developing countries, where the incidence of virus associated cancer is even three times higher [97]. However, the successful development of ‘‘oncopathogen’’ vaccines requires the convergence of several factors, including an unequivocal causal association of a pathogen with a cancer, sufficient public health implications in developed and/or emerging countries to attract commercial investment, and an effective vaccine candidate [14]. These criteria have clearly been met for HBV and HPV. A prophylactic HBV vaccine was first generated by recombinant DNA technology in 1986. The WHO recommends that all infants should be vaccinated [14]. Because chronic infections induced in infancy are largely responsible for adult-onset HBV-associated HCC, which generally occurs after the age of 40 years, the decreased rates of acute HBV-related hepatitis and carriers will likely result in lower incidence of adult HBV-associated HCC in the upcoming decades. Human papillomavirus (HPV) is the second oncovirus for which a prophylactic vaccine has been developed. Like HBV, it is based on non infectious virus-like particles (VLPs) containing the structural viral protein L1 [98]. Since L1 protein is strain specific, plurivalent VLPs vaccines have been development; they induce a specific immunization against HPV16 and HPV18 which are associated with the highest risk of cervical cancers. In addition, a quadrivalent VLPs vaccine that contains VLPs

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from HPV6 and HPV11 (the causative agents of 90% of external genital warts), is also available. Both bivalent and quadrivalent vaccines have been licensed by FDA. Based on frequency of HPV strains and on the partial cross-protection against the other HPV types, has been estimated that 65– 70% of HPV infections should be prevented by a wide range program of vaccination [14]. Since HPV infections are sexually transmitted and women have a greater risk of HPV associated cancers than men, vaccination are particularly recommended for young (11–12 years old) females. Efforts are underway to develop both prophylactic and therapeutic HCV vaccines. Indeed, even if prevention is the better option, the low efficacy of current therapy, the side effects and the high cost support the need of alternative approaches to cure HCV infections. The major obstacles to the successful development of HCV vaccines is the extreme genetic variability of the virus [99], the feeble immunogenicity of envelope proteins [100] and the weak T cell mediated immune response, due impaired maturation and function of T cells [101]. Currently public and commercial sectors support mainly the development and clinical testing of therapeutic HCV vaccines. Polypeptide or viral vector-based vaccines have been tested in several relatively small clinical trials [99]. Although the track record of vaccines against herpes virus is generally very poor, both prophylactic and therapeutic vaccines against EBV are still in progress. Like HBV and HPV vaccines, recent studies have showed that EBV vaccines based on virus-like particles that express a wide spectrum of structural viral proteins can induce proliferation of EBV-specific CD4 + T cells [102,103]. An open question concerns the importance of immune reactivity against latent viral proteins for strong and long term protection. In this contest experimental studies with cocktail vaccines containing both lytic and latent viral antigens have given promising results [104]. However the efficacy of this approach has not been demonstrated yet. Nowadays, there are no vaccines for KSHV and HTLV1 and no sufficient investments for their development. This is because primary infections are asymptomatic, the worldwide incidence of cancer associated with HTLV1 is very low and KSHV-associated tumors are prevalent in developing countries and in minority groups. As H. pylori is recognized as the causative agents of gastric cancer, one of the most diffuse type of tumors worldwide, many efforts have been invested in the development of a prophylactic and therapeutic vaccines. Immunization with different vaccine formulations, based on the use of selected antigens (e.g. VacA, CagA, and HP-NAP or urease) known to be involved in the pathogenesis of infection, have been shown to prevent experimental infections in animals [105] but their efficacy in human is unclear. Additional information in cellular, molecular and humoral responses are required to view strategies able of full protection against H. pylori. The vaccine formulation consisting of VacA, CagA, and HP-NAP bacterial proteins in aluminium hydroxide adjuvant, represents a promising approach. In phase I study, intramuscular administration of this vaccine has triggered a specific IgG and T cell responses in 86% of the subjects, with mild adverse effects [106]. The research focus on mucosal adjuvant and deliv-

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ery systems should improve the efficacy of vaccine against H. pylori [107]. Currently eradication of H. pylori infections is mainly based on different regiments of antibiotic based therapy and is recommended in selected groups of patients with high risk of progression to gastric cancer. Finally, although only a relative small proportion of infectious-associated cancer are related to helminth infections, the number of people exposed or infected worldwide is so high that a sustainable helminth control in endemic areas, along with health education will likely provide a remarkable reduction of cancers. 5. Conclusions Chronic inflammation is widely recognized as a pathological basis for the development of most of the tumors, including those not etiologically related to infections and a smouldering inflammation has been recently proposed as the 7th hallmark of cancer [108]. Hence, elucidation of the molecular pathways underlying pathogen-induced inflammation is expected to provide novel anticancer strategies. New evidence indicate that certain forms of inflammation are protective in a preventive or therapeutic setting [28,109,110] and an immune response has long been known to contribute to the outcome of chemotherapy [42]. Direct activation of innate immunity cells is an alternative or complementary strategy [111]. IFNc has been shown to re-educate TAM [111] and there is proof of principle evidence for antitumor activity of this molecule in minimal residual disease in humans [112–114]. Inflammatory reactions and macrophages, in particular, can exert a dual influence on tumor growth and progression. Evidence emerges for the signaling pathways involved in the ‘switch’ of macrophage polarization states (i.e. M1–M2) in the early stages of tumor progression [76,115], suggesting the possible development of new therapies aimed at preventing this and/or re-orientating M2 TAM, in favour of a more antitumoral phenotype (M1). Innate immune cells (e.g. macrophages) recognize pathogen-associated molecular patterns (PAMPs) through PRRs. As this interaction promotes pathogen-associated inflammation, new efforts should investigate the inflammatory programs induced by different onco-pathogens (viruses, bacteria and parasites). This information would likely disclose mechanisms beyond the construction of permissive microenvironments for tumor development. In this perspective, the functional plasticity of innate immune cells, macrophages in particular, may potentially offer new targets for the therapeutic use of selected PAMPs, as molecular tools to elicit proper macrophage polarization and anticancer activities. Acknowledgments This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC), Italy; Fondazione Cariplo, Italy; by Ministero Università Ricerca (MUR), Italy; Ministero della Salute and by Regione Piemonte (Project Number 331, August 8th, 2009).

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