the role of cxc chemokines in the transition of chronic - lirias

Biochimica et Biophysica Acta 1825 (2012) 117–129

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Biochimica et Biophysica Acta

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Review

The role of CXC chemokines in the transition of chronic inflammation to esophagealand gastric cancer

Verbeke Hannelien a, Geboes Karel b, Van Damme Jo a,⁎, Struyf Sofie a

a Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven (K.U.Leuven), Belgiumb Division of Morphology and Molecular Pathology, University of Leuven (K.U.Leuven), Belgium

⁎ Corresponding author at: Laboratory of Molecular ITel.: +32 16337348; fax: +32 16337340.

E-mail address: [email protected] (J. V

0304-419X/$ – see front matter © 2011 Elsevier B.V. Aldoi:10.1016/j.bbcan.2011.10.008

a b s t r a c t
a r t i c l e i n f o
Article history:Received 27 July 2011Received in revised form 28 October 2011Accepted 29 October 2011Available online 4 November 2011

Keywords:AngiogenesisChemokineCancerEsophagitisGastritisInflammation

Chronic inflammation may increase the risk to develop cancer, for instance esophagitis or gastritis may leadto development of esophageal or gastric cancer, respectively. The key molecules attracting leukocytes to localinflammatory sites are chemokines. We here provide a systematic review on the impact of CXC chemokines(binding the receptors CXCR1, CXCR2, CXCR3 and CXCR4) on the transition of chronic inflammation in theupper gastrointestinal tract to neoplasia. CXCR2 ligands, including GRO-α,β,γ/CXCL1,2,3, ENA-78/CXCL5and IL-8/CXCL8 chemoattract pro-tumoral neutrophils. In addition, angiogenic CXCR2 ligands stimulate theformation of new blood vessels, facilitating tumor progression. The CXCR4 ligand SDF-1/CXCL12 also pro-motes tumor development by stimulating angiogenesis and by favoring metastasis of CXCR4-positivetumor cells to distant organs producing SDF-1/CXCL12. Furthermore, these angiogenic chemokines alsodirectly enhance tumor cell survival and proliferation. In contrast, the CXCR3 ligands Mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 are angiostatic and attract anti-tumoral T lymphocytes and may therefore mediatetumor growth retardation and regression. Thus, chemokines exert diverging, sometimes dual roles in tumorbiology as described for esophageal and gastric cancer. Therefore extensive research is needed to completelyunravel the complex chemokine code in specific cancers. Possibly, chemokine-targeted cancer therapy willhave to be adapted to the individual's chemokine profile.

© 2011 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182. Gastrointestinal inflammation and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

2.1. Esophageal cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1182.2. Gastric cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118

3. The role of CXC chemokines in inflammation related esophageal and gastric disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193.1. ELR+ CXC chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119

3.1.1. CXCR1 and CXCR2 ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1193.2. ELR− CXC chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

3.2.1. CXCR3 ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1213.2.2. BCA/CXCL13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

4. The role of CXC chemokines in esophageal and gastric cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214.1. ELR+ CXC chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121

4.1.1. CXCR2 ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1214.1.2. IL-8/CXCL8, CXCR1 and CXCR2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

4.2. ELR− CXC chemokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1234.2.1. Mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 and CXCR3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1234.2.2. SDF-1/CXCL12 and CXCR4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

5. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

mmunology, Rega Institute for Medical Research, University of Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.

an Damme).

l rights reserved.

http://dx.doi.org/10.1016/j.bbcan.2011.10.008

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118 V. Hannelien et al. / Biochimica et Biophysica Acta 1825 (2012) 117–129

1. Introduction

Cancer, the leading cause of death in the industrialized world, isinitiated from the progressive growth of a single transformed cell.Highly malignant cells originate from normal cells as a result ofmultiple subsequent changes in the genome and disruptionsin cellular metabolic processes enhancing survival, proliferation andmigration [1,2]. Tumors are not just a collection of mutated cellsgrowing uncontrolled, but also contain multiple other co-optednon-malignant cell types, including fibroblasts, endothelial cellsforming blood and lymphatic vessels and immune cells [1,3].Epithelial–stromal interactions play a critical role in tumor initiationand progression. Notably, cancer-associated stroma, but not normalstroma is known to be tumor-promoting. The interaction be-tween tumor and stromal cells is partially mediated by chemo-kines, which play crucial roles in each step of the process oftumorigenesis.

Chemokines, chemotactic cytokines, are involved in the chemoat-traction of leukocytes to inflammatory sites. Chemokines can be pro-duced by many cell types including leukocytes, endothelial cells,fibroblasts and epithelial cells [4,5]. Nowadays, it has become clearthat chemokines not only play a role in the immune system, butalso mediate the regulation of tumorigenesis and metastasis. Chemo-kines can be subdivided in twomajor subfamilies, CXC and CC chemo-kines, depending on whether the first two conserved cysteineresidues are separated by an amino acid (X) or adjacent, respectively[4–6]. CXC chemokines and their receptors (CXCR) modulate tumorbehavior by three important mechanisms: regulation of angiogenesis,activation of a tumor-specific immune response and stimulation oftumor cell proliferation in an autocrine or paracrine fashion [7]. Alink between inflammation and cancer was discovered already in1863 by Rudolf Virchow who suggested that cancer may originate atsites of inflammation. The presence of leukocytes in the tumor wasinterpreted as an aborted attempt of the immune system to rejectthe tumor [8]. If immune surveillance would be effective, the immunesystemwould protect against nascent cancer by destroying malignantcells before they develop into tumors. However, immune surveillanceis not always successful as some tumor cells might escape the immuneresponse resulting in progressive tumor growth [9,10]. Indeed, it hasbeen shown that patients with sustained esophagitis and gastritisare at increased risk to develop esophageal and gastric cancer,respectively.

The presence or absence of an ELR (Glu–Leu–Arg)-motif, locatedbefore the first conserved cysteine residue, in CXC chemokinesdetermines the biological role within tumor development [6,11,12].In particular, CXC chemokines containing the ELR-motif (e.g.interleukin-8 (IL-8)/CXCL8) have been described to promote tumorgrowth by stimulation of angiogenesis and chemoattraction ofneutrophilic granulocytes [11–13]. Neutrophils in turn promote theangiogenic process, tumor growth and metastasis by releasingmatrix-degrading enzymes (e.g. matrix-metalloprotease-9/MMP-9)and angiogenic and tumor promoting factors (e.g. IL-8, VEGF) [14].In contrast, CXC chemokines lacking the ELR-motif (e.g. interferon-γinducible protein-10 (IP-10)/CXCL10) possess angiostatic activitiesand chemoattract anti-tumoral lymphocytes through binding toCXCR3 [11,13]. Stromal cell-derived factor-1 (SDF-1)/CXCL12 is anexception on this rule as this chemokine lacks the ELR-motif, hasangiogenic properties and mediates the dissemination of CXCR4-positive tumor cells to distant organs [13]. Interestingly, in contrastto the anti-tumoral activities of the CXCR3-binding ELR− CXCchemokines, these chemokines may also favor tumor metastasis ofCXCR3-positive cancer cells to lymph nodes and distant sites[15–17]. Taken together, the intricate chemokine network withinthe tumor is very complex and organ-specific. Here, the role of CXCchemokines in the development of cancer from chronic inflammationof the upper gastrointestinal tract is described.

2. Gastrointestinal inflammation and cancer

2.1. Esophageal cancer

Esophageal cancer is one of the most threatening malignanciesworldwide, owing to a rapid development and fatal prognosis inmost cases [18]. In particular, it is the eighth most common cancerworldwide and the sixth most common cause of cancer-relateddeath [19]. The prognosis of esophageal cancer is generally unfavor-able with a five-year survival of less than 5% [18]. Most esophagealcancers fall into one of the following two classes: squamous cellcarcinoma or adenocarcinoma [18]. For many years, squamous cellcarcinoma of the esophagus has been observed as the most commontype of esophageal malignancy. However, the incidence of adenocar-cinoma of the esophagus is rapidly increasing during the past halfcentury, especially in the Western countries [20]. Esophageal squa-mous cell carcinoma is a malignant tumor of the stratified squamousepithelium. Common risk factors for squamous cell carcinoma of theesophagus are alcohol abuse, smoking, male gender, a diet withoutfruits and vegetables and human papilloma virus infection [18,20].Esophageal adenocarcinoma originates from glandular tissue, inparticular the Barrett's esophagus. Barrett's esophagus is defined asmetaplasia of the normal esophageal squamous epithelium toglandular columnar epithelium with development of specialized,intestinal-type epithelial cells, which is caused by gastroesophageal re-flux disease (GERD) [20,21]. This disease causes chronic inflammation[22]. As a consequence, chemokines released by the infiltrated immunecells and activated epithelial cells may contribute to the progression ofesophageal carcinogenesis. Risk factors for the development ofesophageal adenocarcinoma are alcohol abuse, smoking, a diet contain-ing few vitamins and rich in fat and male gender [20,21]. In contrast,gastric infection with Helicobacter pylori reduces the risk of esophagealadenocarcinoma, which can be ascribed to reduced gastric acid produc-tion and neutralization of the gastric acid by ammonia production [21].The prevalence of H. pylori falls back throughout the world, particularlyin the developed countries, and leads to increased incidence forBarrett's esophagus and esophageal adenocarcinoma [21].

2.2. Gastric cancer

Despite a major decline in the incidence and mortality overseveral decades, stomach cancer is still the fourth most common can-cer and the second to third most frequent cause of cancer death in theworld [19,23]. The prognosis is rather poor, with a five-year survivalbelow 30%. More than 90% of gastric cancers are adenocarcinomas,which are malignant epithelial tumors, originating from glandularepithelium of the gastric mucosa. In the Lauren classification, twomajor histological types of gastric adenocarcinoma can bedistinguished histopathologically: the diffuse and the intestinal type[24]. Intestinal metaplasia with goblet cells is considered to be aprecursor lesion of the intestinal type of gastric adenocarcinoma,which shows tubular differentiation [24]. The diffuse type gastricadenocarcinoma is characterized by non-cohesive single mucocellularcancer cells (signet-ring cells) diffusely infiltrating the stroma [24].The diffuse type gastric adenocarcinoma shows some predominancein the fundus and corpus of the stomach, whereas the intestinaltype gastric adenocarcinoma prevails in the antrum [24]. Further-more, the remaining 10% of gastric malignancies are lymphomas ororiginate from gastrointestinal stromal tissue (soft tissue tumors).The best established risk factor for gastric cancer is H. pylori infection[23]. H. pylori infection specifically increases the risk of cancer in thedistal part of the stomach (antrum, pylorus), whereas there is no in-crease in the risk of proximal (cardia, fundus) cancer [23]. It is also in-volved in the development of gastric lymphoma. Other risk factors forgastric cancer are male gender, smoking and nutritional factors, such

119V. Hannelien et al. / Biochimica et Biophysica Acta 1825 (2012) 117–129

as low intake of fruits [23]. However, there is probably also a smallportion of hereditary cancers.

Over the past decades, a decline in incidence of gastric adenocar-cinoma, especially in the distal part of the stomach, has been noticed,which can be attributed to the decline in H. pylori infection [23]. How-ever, the relatively small proportion of gastric cancers located at theproximal stomach and at the gastroesophageal junction seems to beon a constant rise [23]. The rise in proximal gastric cancer casesmay be ascribed to the decrease in H. pylori infection, similar toesophageal cancer, which in particular protects the proximal part ofthe stomach and the gastroesophageal junction from the destructiveacid fluids (vide supra) [21,23].

3. The role of CXC chemokines in inflammation related esophagealand gastric disorders

3.1. ELR+ CXC chemokines

3.1.1. CXCR1 and CXCR2 ligandsGrowth-regulated oncogene (GRO) has been first purified from

human malignant melanoma cells and has been characterized as anautocrine growth factor [25]. Three different isoforms GRO-α/CXCL1, GRO-β/CXCL2 and GRO-γ/CXCL3 have been described andthey all bind CXCR2, however with a different affinity [26]. Indeed,the chemokines GRO-β and GRO-γ are reported to have reduced ca-pacity to bind to CXCR2 in comparison with GRO-α [27,28]. CXCR2 li-gands also include epithelial cell-derived neutrophil-activatingpeptide-78 (ENA-78)/CXCL5, granulocyte chemotactic protein-2(GCP-2)/CXCL6, neutrophil-activating peptide-2 (NAP-2)/CXCL7 andIL-8/CXCL8 [25,29–32]. All these CXCR2 ligands possess pro-tumoralcapacities by chemoattracting pro-tumoral neutrophils and stimulatingangiogenesis [11,12]. IL-8 is the most potent human neutrophil che-moattractant and activator in vitro and in vivo [33]. IL-8 provokes themigration of neutrophils by interaction with CXCR1 and CXCR2, where-as its angiogenic activity is mediated predominantly by CXCR2 [34].

3.1.1.1. Esophagitis and Barrett's esophagus. The chronic exposure ofnormal esophageal mucosa to acids in patients with chronic refluxsymptoms may stimulate the production of IL-8 by esophageal epi-thelial cells [35,36]. In esophagitis, which is characterized by anacute inflammatory response, the levels of IL-8 detected in the basallayers of the esophageal mucosa and in inflammatory cells, weresignificantly higher than in Barrett's esophagus and non-inflamedsquamous esophagus [36,37]. In turn, secretion of IL-8 by esophagealepithelial cells was higher in Barrett's esophagus than in normalesophageal epithelial cells [38,39]. The higher expression of IL-8 inesophagitis compared with Barrett's esophagus matches with ahigher influx of neutrophils [36–39]. The latter can be seen as anadaptive response to gastro-esophageal reflux exposure. In contrast,other studies implicate a stepwise increase in the expression of IL-8from esophageal reflux disease through Barrett's esophagus to esoph-ageal adenocarcinoma [40,41]. The IL-8 receptors, CXCR1 and CXCR2,are constitutively expressed in esophageal mucosa, especially by epi-thelial cells and infiltrated leukocytes [42,43]. The activation of CXCR1and CXCR2 on esophageal epithelium was found to contribute toepithelial cell proliferation even in the early stage of GERD andcould be eventually linked to carcinogenesis. Indeed, recent studieshave shown that IL-8 exerts mitogenic actions by binding to its recep-tors on epithelial cells [44]. Infiltrated neutrophils also produce IL-8which in turn attracts more neutrophils and induces proliferation ofepithelial cells facilitating the progression of Barrett's esophagusand esophageal adenocarcinoma.

To reduce the evolution of esophagitis to Barrett's esophagus andfinally into esophageal adenocarcinoma, drugs have been developedto eliminate the inflammatory response by reducing the acidic reflux.Indeed, proton pump inhibitors (e.g. lansoprazole) and surgery

reduce the levels of acids and consequently of IL-8, which results inreduced inflammatory response and tissue damage [36,41,45–47].Also the anti-inflammatory compound curcumin, which is a polyphe-nolic pigment isolated from the plant Curcuma longa, was found to in-hibit esophageal activation and IL-8 release in response to acid [48].

3.1.1.2. Gastritis. H. pylori is the major causative agent of chronicgastritis in humans and is considered to be an important etiologicalfactor in the pathogenesis of gastric cancer. Despite the fact thatH. pylori is known to be non-invasive, an extensive inflammatoryreaction is provoked in the gastric mucosa. This reaction is character-ized by a mucosal infiltration of inflammatory cells, especially neutro-phils, which is mediated by enhanced expression of chemokines.Several studies have demonstrated that GRO-α, ENA-78 and IL-8 arepresent at higher levels in gastric mucosa of patients with H. pylori-positive gastritis than in patients with H. pylori-negative gastritis.Moreover, the levels of these CXCR2 ligands correlated with H. pyloridensity and massive infiltration of neutrophils [49–55]. Moreover, theexpression of GRO-α in patients with H. pylori-negative chronicgastritis was significantly higher than in patients with normal gastricmucosa [52]. Additionally, IL-8 and GRO-α have been demonstratedto be higher in patients (suffering from gastritis) with duodenal orpeptic ulcers than in patients without these complications[50,56–59]. Furthermore, expression of GRO-α and ENA-78 wassignificantly increased in H. pylori-infected mucosa of smokerscompared with non-smokers [60]. However, there was no differencein GRO-α and ENA-78 expression in relation to alcohol consumption[60]. Indeed, recent studies suggest that alcohol consumption has aprotective effect in patients infected with H. pylori because of its anti-microbial effect [60].

Although the severity of gastritis depends on the H. pylori strain,the genetic background of the patients and gene alterations such assingle nucleotide polymorphisms (SNPs) may also determine thesusceptibility of these patients to develop gastritis and duodenalulcer. The IL-8 gene contains four exons, three introns and a proximalpromoter region. Three well-characterized SNPs in the IL-8 gene havebeen noticed so far: in the proximal promoter at −251T/A and in in-tron 1 at +396 T/G and +781 C/T [61]. Recent studies have shownthat IL-8−251A allele carriers are at increased risk to develop duode-nal ulcer and gastritis [62,63]. For instance, the heterozygote−251TAand the homozygote −251AA mutant variants were detected withhigher frequency among patients with duodenal ulcer and withgastritis than among the H. pylori-positive controls [62,64]. Even thehomozygote −251AA genotype was more frequent in patients withH. pylori-negative gastritis than in the healthy persons withH. pylori-negative normal mucosa [65]. In addition, the neutrophilinfiltration tended to be higher in IL-8 −251A allele carriers than inpatients with the TT genotype [64]. In contrast, Ohyauchi et al. havedemonstrated that the IL-8 −251A allele frequency was only higherin patients with gastric ulcer compared with controls, whereas nosuch association was observed in patients with duodenal ulcer andgastritis [66].

In situ hybridization and immunohistochemical studies have local-ized GRO-α, ENA-78 and IL-8 expression in gastric epithelium (Fig. 1)[49–51,67]. However, several studies have implicated that the intensityof IL-8 staining in gastric mucosa is not as strong as that of GRO-α[49,53,68]. Moreover, inconsistent results were reportedconcerning the expression of IL-8 in normal gastric epithelial cells[69–71]. It is likely that epithelial cells lining the mucosa are themajor sources of pro-inflammatory factors as H. pylori bacteria colonizethe external surface of the gastric mucosa and do not invade the muco-sa. Indeed, in vitro studies performed on mouse gastric epithelial celllines have confirmed that mouse keratinocyte chemoattractant (KC)/CXCL1 and macrophage inflammatory protein-2 (MIP-2)/CXCL2 (themouse homologues of human GRO-α and GRO-β/γ, respectively) areup-regulated upon infection with H. pylori, through activation of

neuep

attraction

TNF-αα, IL-1β, IL-17, ROS

EC

neu EC

GRO ENA-78

angiogenesis

IL-8

G endocrine

GROENA-78IL-8

gastrin release Reg

MΦ DC

H. pylori

GROENA-78IL-8

?

Fig. 1. Expression and role of GRO, ENA-78 and IL-8 in gastritis. In situ hybridization and immunohistochemical studies have detected expression of GRO-α, ENA-78 and IL-8 in gas-tric epithelium. H. pylori, TNF-α, IL-1β, IL-17 and reactive oxygen species (ROS) are potent inducers of CXCR2 ligand production by gastric epithelial cells (ep). In addition to gastricepithelial cells, a positive staining of GRO-α, ENA-78 and IL-8 was detected in macrophages (MΦ) of the lamina propria. However, it is not yet clear whether H. pylori is able toincrease IL-8 production by macrophages or whether macrophages constitutively release IL-8. In addition, H. pylori activates dendritic cells (DC), neutrophils (neu) and endothelialcells (EC) of small gastric mucosal vessels to release angiogenic IL-8 and/or GRO-α. In this way, H. pylori indirectly stimulates angiogenesis. Increased expression of CXCR2 ligands inH. pylori-positive gastritis has been associated with elevated numbers of neutrophils within the gastric mucosa. Furthermore, IL-8 may also contribute to the progression of gastritisby inducing the release of gastrin from G cells. Finally, IL-8 can indirectly stimulate the growth of gastric mucosal cells by up-regulating the expression of the growth factor Reg inendocrine cells.


NF-κB [72]. Also human gastric epithelial cell lines have been demon-strated to produce increased levels of IL-8 after stimulation withH. pylori in a NF-κB-dependent manner [70,73,74]. Besides H. pylori,TNF-α, IL-1β, IL-17 and reactive oxygen intermediates, which are allfound at elevated levels in H. pylori-infected gastric mucosa, are alsopotent inducers of IL-8 production by gastric epithelial cells (Fig. 1)[75–79]. In addition to gastric epithelial cells, a positive staining ofGRO-α, ENA-78 and IL-8 was detected in macrophages of the laminapropria, especially at sites with neutrophil infiltration (Fig. 1)[49–51,67]. However, it is not yet clear whether H. pylori is able toincrease IL-8 production by macrophages or whether macrophagesconstitutively release IL-8. [80–84]. Nevertheless, H. pylori can stimu-late the maturation and differentiation of dendritic cells (DC) andactivate DC to produce cytokines, including IL-8 [85]. Also neutrophilsand endothelial cells of small gastric mucosal vessels can releaseGRO-α and IL-8 upon infection with H. pylori (Fig. 1) [49,86–88]. Inaddition, H. pylori also induced neutrophil adhesive interactions andtransendothelial migration as well as the release of toxic oxygenmetabolites (O2

– radicals) and proteolytic enzymes [87–89]. Moreover,H. pylori induced internalization and degradation of CXCR1 andCXCR2 in neutrophils [90]. This may suggest that after infiltration inthe gastric mucosa and contact with H. pylori, neutrophils stop migrat-ing and exert antimicrobial functions, such as superoxide generationand production of proteases [90]. Furthermore, it has been describedthat H. pylori stimulates angiogenesis directly or indirectly, byactivating endothelial cells to release angiogenic GRO-α and IL-8, fol-lowing NF-κB activation (Fig. 1) [86,91,92]. However, results obtainedby immunohistochemical staining were slightly different: GRO-α wasdetected in endothelial cells of small gastric mucosal vessels, whereasIL-8 staining was not observed in these cells [49].

GRO, ENA-78 and IL-8 released by gastric epithelial cells, leuko-cytes and endothelial cells upon infection with H. pylori may partici-pate in the progression of gastritis and gastric cancer through the

chemoattraction of neutrophils and stimulation of angiogenesis.Besides, IL-8 may also contribute to the progression of gastritis byinducing the release of gastrin from G cells (Fig. 1). Elevated levelsof the hormone gastrin play a role in the heightened acid secretion,predisposing to duodenal ulceration [93]. Furthermore, IL-8 can indi-rectly stimulate the growth of gastric mucosal cells by up-regulatingthe expression of the growth factor Reg in endocrine cells (Fig. 1)[94]. Therefore, damage of the gastric mucosa caused by H. pylorileads to a compensatory increase in mucosal cell proliferation.

Triple therapy with a proton pump inhibitor and two antibioticshas been widely used to treat gastritis and peptic ulcers and hasbeen shown to reduce the levels of IL-8 and GRO-α in gastric mucosaof H. pylori-infected patients [50,57,95–97]. However, the therapyfails in many patients due to antibiotic resistance. Hence, there is acritical need to search for alternative approaches to prevent H. pylori-induced gastric diseases. A current surge in approaches other thanantimicrobial therapy such as anti-oxidants, probiotics, vitamins andplant extracts has paved new ways to control H. pylori relatedinflammation and disorders. The aluminum hydroxide–magnesiumhydroxide combination drug co-magaldrox, plaunotol (a drugextracted from the Plau-noi tree of Thailand), teprenone (an acylicpolyisoprenoid compound which stimulates mucin secretion in thegastric mucosa), chloroform extracts from the herbal plant Phyllanthusurinaria, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspi-rin, the citrus component auraptene and chalcones have all beenshown to be effective in reducing H. pylori colonization and inhibitingthe H. pylori-induced immune responses [98–104]. The cytoprotectiveeffect of these components on the gastric mucosa was described to bemediated by inhibition of H. pylori-induced IL-8 secretion, which wasin most of cases caused by inhibition of adhesion of H. pylori to gastricepithelial cells [98–100,102–104]. Recently, a novel inhibitor ofH. pylori growth, i.e. difluoromethylornithine has been developed.This drug is able to suppress the expression of the H. pylori virulence


factor cytotoxin associated gene A, its translocation and phosphorylationand consequently the production of IL-8 in gastric epithelial cells [105].Furthermore, rebamipide was shown to inhibit the H. pylori-inducedproduction of IL-8 by acting as an oxygen radical scavenger, thereby pre-venting the oxidant-mediated activation of NF-κB [106]. Troxipide wasshown to inhibit the IL-8-inducedmigration of neutrophils and to reducethe generation of reactive superoxide intermediates [107]. Ecabetsodium, which is derived from pine resin, inhibits the ability of H. pylorito stimulate the production of IL-8 and reactive oxygen intermediates byneutrophils [108]. Besides the use of drugs, probiotica may also besuccessful agents in alleviating the H. pylori-induced inflammation[109–111]. Indeed, lactobacilli have been demonstrated to suppress theproduction of IL-8 in gastric epithelial cells by reducing the adhesion ofH. pylori on gastric epithelial cells [109–111]. Also components in thediet may be beneficial in preventing the progression to gastritis. Indeed,resveratrol, which is highly abundant in red grapes, blueberries andpeanuts, inhibited the secretion of IL-8 and the generation of reactiveoxygen intermediates from H. pylori-infected gastric epithelialcells [112]. Also vitamin C reduced the production of IL-8 by acting as ascavenger of mucosal reactive oxygen intermediates, which are in partresponsible for the increased levels of IL-8 in H. pylori-infected gastricmucosa [113].

Caution should be taken with the administration of acid-suppressive drugs, including omeprazole, for the treatment of refluxesophagitis since they may worsen gastritis in H. pylori-infected pa-tients. In particular, acid suppression increased mucosal IL-8 levels inH. pylori-infected patients [114]. This effect may be mainly attributedto increased colonization by H. pylori, in a less acidic environment.These detrimental effects may be overcome by addition of vitamin C,which scavenges reactive oxygen intermediates [114].

3.2. ELR− CXC chemokines

3.2.1. CXCR3 ligandsThe angiostatic IFN-γ-inducible CXCR3 ligands, monokine-induced

by IFN-γ (Mig)/CXCL9, IFN-γ-induced protein-10 (IP-10)/CXCL10 andinterferon-inducible T cell alpha chemoattractant (I-TAC)/CXCL11, areproduced in vitro by a variety of cells, including endothelial cells, fibro-blasts, mononuclear cells and tumor cells. These ELR− CXC chemokinesare characterized by their anti-tumoral and inflammatory activities asthey act as angiostatic regulators and mediate the infiltration of Tlymphocytes and natural killer (NK) cells [6,12,13].

3.2.1.1. Gastritis. Literature about the presence and roles of CXCR3 li-gands in gastritis is limited. One study has investigated the presenceof IP-10 and Mig in patients with H. pylori-induced gastritis by insitu hybridization and immunohistochemistry [49]. IP-10 and Migwere strongly expressed in the lamina propria at sites of a dense Tlymphocyte infiltration [49]. In some patients, IP-10 and Mig werealso detected in endothelial cells of small gastric mucosal vessels.However, IP-10 was more abundantly expressed than Mig [49].

3.2.2. BCA/CXCL13

3.2.2.1. Esophagitis and Barrett's esophagus. Premalignant conditionswhich develop in the presence of chronic inflammation are often as-sociated with down-regulation of the cell-mediated response. Indeed,the proportion of Th2 effector cells is higher in Barrett's esophagusthan in esophagitis, mainly due to higher numbers of plasma cellsand mast cells and lower numbers of macrophages and cytotoxic Tlymphocytes [115]. Consistent with the observation of a pronouncedhumoral immune response in Barrett's esophagus, lymphoid aggre-gates which include DC, B and T lymphocytes, were more frequentin Barrett's esophagus than in esophagitis. The chemoattraction of Blymphocytes into the B cell zone of isolated lymph follicles fromBarrett's esophagus is mediated by B cell-attracting chemokine-1

(BCA-1)/CXCL13, which was found to be predominantly located inthe peripheral zone of these lymphoid aggregates [115].

4. The role of CXC chemokines in esophageal and gastric cancer

4.1. ELR+ CXC chemokines

4.1.1. CXCR2 ligands

4.1.1.1. Esophageal cancer. The expression and role of GRO and itsreceptor, CXCR2, in esophageal cancer are poorly understood. In2006, GRO-α, GRO-β and CXCR2 were shown to be over-expressedin squamous cell carcinoma compared with adjacent normal tissue(Table 1) [116]. GRO-α and GRO-β were detected in the cytoplasmof the tumor cells, whereas CXCR2 was localized in the cytoplasmand plasma membrane of the cancer cells (Table 2) [116]. Tumorcell proliferation was increased after stimulation of CXCR2 with GROwhich was mediated via the induction of early growth response(EGR)-1, a transcription factor known to regulate the expression ofmany genes involved in tumorigenesis [116,117]. In turn, EGR-1 hasbeen shown to induce GRO expression through the activation ofNF-κB [117]. This positive feedback loop may be responsible for theincreased proliferation of esophageal cancer cells.

4.1.1.2. Gastric cancer. H. pylori contributes to the progression ofgastric cancer by the stimulation of GRO-α and GRO-β production ingastric epithelial cancer cells via the activation of NF-κB [118,119].Immunohistochemical studies showed that GRO-α is expressed almostexclusively by diffuse but not intestinal type carcinoma cells, so onemay speculate that GRO-α is responsible for the divergent growthpattern of different gastric carcinoma types [120]. In addition totumor cells, tumor-infiltrating neutrophils and endothelial cells alsoproduced GRO-α (Fig. 2). Its receptor CXCR2 is expressed by gastricadenocarcinoma cells, macrophages, lymphocytes and a few neutro-phils (Fig. 2) [120]. An overview of the expression of chemokines andtheir receptors in the different cell types within gastrointestinal tumorsis shown in Table 2. In contrast to GRO-α, no significant differenceswere found in expression of CXCR2 between diffuse and intestinalgastric adenocarcinomas [120]. Taken together, the increased expres-sion of GRO-α in gastric cancer may indicate that GRO-α could be aputative biomarker for gastric cancer progression. Jung et al. confirmedthis hypothesis by the demonstration that levels of GRO-α in serumsamples of patients with gastric cancer were significantly highercompared with those in healthy individuals and GRO-α serum levelswere increased according to tumor stage and degree of lymph nodemetastasis [121]. On the contrary, a recent study demonstrated thatover-expression of GRO-α in gastric adenocarcinomas positivelycorrelates with improved survival [122]. This conflicting result can beexplained by the discovery that GRO-α reinforces senescence, a stateof proliferative arrest early in tumorigenesis and might thereby inhibittumor growth [123]. This may indicate a dual role of GRO-α incarcinogenesis.

Conflicting results exist about the in vitro expression of ENA-78 byhuman gastric adenocarcinoma cells stimulated with H. pylori[51,119]. In particular, Rieder et al. demonstrated increased ENA-78expression in H. pylori-stimulated gastric adenocarcinoma cells,whereas in the study of Sieveking et al. ENA-78 secretion was not in-creased following H. pylori infection [51,119]. However, similar toGRO, ENA-78 showed more intense immunohistochemical stainingin gastric cancer than in normal gastric mucosa (Table 1, Fig. 2)[124]. Moreover, the microvessel density tended to be higher intumors with strong ENA-78 expression (Fig. 2) [124]. Furthermore,it has been shown that strong expression of ENA-78 associates withlate stage gastric cancer and nodal metastasis [124]. WhetherENA-78 is beneficial or not in early phases of tumorigenesis is still amatter of debate [125,126].

Table 1CXC chemokines, chemokine receptors and their expression pattern in esophageal and gastric cancer.

Chemokine Receptor Expressiona Reference

ELR+ CXC chemokinesGRO-α/CXCL1 CXCR2 + [116,120–122]GRO-β/CXCL2 CXCR2 = or + [116]GRO-γ/CXCL3 CXCR2 + [116]ENA-78/CXCL5 CXCR2 + [124,126]GCP-2/CXCL6 CXCR1, 2 NDb

NAP-2/CXCL7 CXCR2 NDIL-8/CXCL8 CXCR1, 2 + [40,69,120,127,128,130–132,142,143,145,146,154]

ELR− CXC chemokinesPF-4/CXCL4 CXCR3 NDPF-4var/CXCL4L1 CXCR3 NDMig/CXCL9 CXCR3 + [125]IP-10/CXCL10 CXCR3 + [125]I-TAC/CXCL11 CXCR3, 7 NDSDF-1/CXCL12 CXCR4, 7 − [169]

+ [168,169,177]BCA-1/CXCL13 CXCR3,5 NDBRAKc/CXCL14 Unknown NDSR-PSOX/CXCL16 CXCR6 NDDMCd/CXCL17 Unknown ND

a Enhanced (+), unaltered (=) or reduced (−) expression level of chemokines in upper gastrointestinal cancer compared with normal mucosa.b ND: not determined.c Breast and kidney-expressed chemokine.d Dendritic cell- and monocyte-attracting chemokine-like protein.


4.1.2. IL-8/CXCL8, CXCR1 and CXCR2

4.1.2.1. Esophageal cancer. Elevated levels of IL-8 were observed inesophageal adenocarcinoma compared with normal squamousepithelium (Table 1) [40,127,128]. In addition, the expression ofIL-8 in patients with adenocarcinoma was significantly higher thanits expression in Barrett's esophagus and esophagitis and increasinglevels were noticed in patients with more advanced esophageal ade-nocarcinoma [40]. Furthermore, patients with adenocarcinoma whowere positive for NF-κB had significantly higher levels of IL-8[40,127]. Stimulation of normal esophageal epithelium and epithelialcancer cells e.g. by IL-1, TNF-α or acidic refluxates up-regulates theexpression of NF-κB, which in turn mediates the transcription ofmany cytokines and chemokines including IL-8 [48,129]. This positivefeedback loop causes massive secretion of IL-8 which may mediateangiogenesis, epithelial proliferation and chemoattraction of neutro-phils facilitating tumor progression and metastasis. Indeed, a recent

Table 2Cell types expressing chemokine protein and chemokine receptors in esophageal andgastric cancer.

Chemokines andreceptors

Esophagealcancer

Gastric cancer Reference

GRO Tu Tu, Neu, EC [116,120]ENA-78 ND Tu [124,126]GCP-2 ND NDIL-8 Tu Tu, Neu, T [69,87,120,141–143]

CXCR2 Tu Tu, Ly, MΦ, EC [116,120,147]CXCR1 ND Tu, Neu, T,

MΦ, EC[120,147]

Mig ND Tu, MΦ, DC,EC

[120]

IP-10 ND Tu, MΦ, EC [120]I-TAC ND ND

CXCR3 ND T [120]SDF-1 Tu Tu, EC, Ly,

Fibro[167,168,174–176]

CXCR4 Tu Tu, EC, Leu [164–168,174,176,178,179]CXCR7 ND ND

Abbreviations DC: dendritic cells, EC: endothelial cells, Fibro: fibroblasts, Leu:leukocytes, Ly: lymphocytes (no distinction made between T or B lymphocytes), MΦ:macrophages, ND: not determined, Neu: neutrophils, T: T lymphocytes, Tu: tumor cells.

study has demonstrated that the increased IL-8 expression in esoph-ageal adenocarcinoma is related to a poorer prognosis, confirming thepro-tumoral role of IL-8 [130]. Furthermore, elevated levels of circu-lating IL-8 were noticed in esophageal squamous cell carcinomas incomparison with healthy controls and the increase in serum IL-8levels correlated with tumor size, lymph node and distant metastases[131].

4.1.2.2. Gastric cancer. Although some studies reported that H. pyloricannot inhabit gastric cancer tissue, Yamaoka et al. demonstratedthat some gastric cancer tissues contain H. pylori, however the densityof H. pylori was 100-fold less as compared with biopsies obtainedfrom the normal appearing antrum [132]. In general, H. pylori mayinfect non-cancerous epithelium surrounding the tumor andup-regulate production of angiogenic factors (IL-8, VEGF) and matrix-metalloproteases (MMP-9), and in that way it may indirectly stimulateangiogenesis and invasion of gastric carcinoma at the tumor-normalfront [133].

Several studies have shown that IL-1, TNF-α and infection with H.pylori induce or enhance the secretion of IL-8 by several gastric ade-nocarcinoma cell lines in vitro [73,75,79,134,135]. Also CXCR1 andCXCR2 expression increased in gastric carcinoma cells after infectionby H. pylori [136,137]. Differences in responsiveness of gastric cancercell lines to H. pylori were noticed, which may reflect a difference inthe number of H. pylori-binding molecules on the cell surface or inthe magnitude of the intracellular signal generated by H. pylori[73,134]. The mechanism by which H. pylori stimulates IL-8 expres-sion in gastric cancer cells has not been completely deciphered.Some studies suggest that live bacteria and adherence of theseH. pylori bacteria are necessary to stimulate IL-8 production, whereasother studies argue against these hypotheses [134,135,138–140]. Be-sides neutrophils, also CD8+ infiltrated lymphocytes (TILs) releasedhigher amounts of IL-8, especially in patients with H. pylori-infectedgastric adenocarcinoma [87,141].

In specimens, IL-8 was localized in the epithelium of normal gas-tric mucosa, with particularly strong expression in the surface cells[69]. In human gastric carcinomas, gastric cancer cells over-expressed IL-8 compared with corresponding normal mucosa and theIL-8 expression levels directly correlated with the vascularity of thetumor [69,120,132,142,143]. Moreover, transfection of human gastric

H. pylori

neu EC

neu EC

?

tu

GRO ENA-78

chemoattractionangiogenesis

T MΦΦ

?

tu

proliferation?

?

GROENA-78

Producer

Target

GROENA-78

Fig. 2. Expression and role of GRO and ENA-78 in gastric cancer. H. pylori contributes to the progression of gastric cancer by stimulation of GRO and ENA-78 production in gastricepithelial cancer cells. In addition to tumor cells (tu), tumor-infiltrating neutrophils (neu) and endothelial cells (EC) also produce GRO. Its receptor CXCR2 is expressed by gastricadenocarcinoma cells (tu), macrophages (MΦ), lymphocytes (T) and a few neutrophils (neu). Although a strong expression of ENA-78 in gastric cancer was associated with a highermicrovessel density, its role in the chemoattraction of neutrophils in gastric cancer has to be further elucidated. Similarly, further investigation is needed to explore the biologicalactivities of GRO in gastric cancer.


carcinoma cells with an IL-8 expression vector increased angiogenesisand tumorigenesis in nude mice [144]. Furthermore, Yamaoka et al.have demonstrated that IL-8 levels in gastric cancer tissues weremore than two-fold higher in advanced gastric cancer compared withearly gastric cancer irrespective of H. pylori status, which may indicatethat IL-8 can be produced by an H. pylori-independent pathway [132].In contrast, Zhang et al. showed that the difference in IL-8 expressionbetween advanced and early stage gastric cancer was significantly in-creased in patients with H. pylori infection [141]. Moreover, it hasbeen shown that increased IL-8 levels in gastric neoplasms correlatewith the depth of invasion, venous infiltration and lymphatic invasion[142]. Hence, significantly lower survival rates of patients displayinghigh IL-8 expression levels have been demonstrated [142,145]. In gen-eral, expression of IL-8 in gastric adenocarcinoma is associated with in-creased tumor vascularization, aggressiveness, invasion andmetastasis.In addition, IL-8 may act as a diagnostic marker as it was demonstratedto be significantly elevated in serum samples of patients with gastriccancer [39,146].

The majority of the gastric adenocarcinoma cells, small vessel en-dothelial cells, neutrophils, macrophages and lymphocytes expressedCXCR1 and CXCR2 (Table 2, Fig. 3). [120,147]. In addition, the CXCR1and CXCR2 immunoreactivity in cancer cells was more intense at theinvasive edge, where cancer cells infiltrate lymphatic vessels[120,147]. Expression of CXCR1 and CXCR2 in diffuse and intestinaltype of gastric carcinomas was similar [120]. Whether IL-8 expressionlevels in diffuse versus intestinal type gastric cancer are different is amatter of debate. Some claim that expression levels are similar,whereas others have shown stronger IL-8 expression in the diffusetype [69,120,132,145].

Although the proliferation of gastric carcinoma cells was notaltered after addition of IL-8, IL-8 enhanced the expression of the epi-dermal growth factor receptor (EGFR), MMP-9, VEGF and IL-8 itself(Fig. 3) [143,147,148]. In contrast, several studies demonstrated thatIL-8 may indirectly stimulate the proliferation of gastric cancer cellsby accelerating the processing of EGFR ligands through activation ofproteases [149–151]. Furthermore, IL-8 decreased the expression of

E-cadherin, a molecule responsible for cell–cell adhesion, in gastriccancer (Fig. 3) [147].

Gene alterations such as SNPs may favor tumor development. Asalready mentioned, three well-characterized SNPs have beenidentified in the IL-8 gene [61]. In the IL-8 receptor genes, four SNPshave been identified (one SNP in exon 2 at +2608 of CXCR1 andthree SNPs in exon 3 of CXCR2), but no association between theseSNPs with either gastric cardia carcinoma and squamous cell carcino-ma of the esophagus has been found [61,152]. Similarly, IL-8 genevariations do not affect esophageal squamous cell carcinoma [61].However, homozygous variants of IL-8 −251AA and +396GG wereassociated with an increase in relative risks for gastric cardia adeno-carcinoma [61,153]. Also the risk of non-cardiac gastric cancer andeven the metaplasia scores in the antrum have been observed to besignificantly higher in patients with the IL-8 −251AA genotype[61,64,66,154]. Moreover, the risk of gastric cancer associated withthe IL-8 −251AA polymorphism was elevated in subjects with H.pylori infection in comparison with patients without H. pylori infection[153,155]. However, there was no evidence of an interaction betweenthe IL-8 polymorphism and H. pylori infection [155]. Furthermore, theIL-8 −251AA genotype is associated with higher IL-8 protein expres-sion, more severe neutrophil infiltration, enhanced angiogenesis, espe-cially with secretion of MMP-9 and Angiopoietin-1 and increased riskof poorly differentiated gastric cancer, lymph node and liver metastasis[64,154,156]. Importantly, the correlation between the IL-8 −251AAand−251TA genotypes and the increased risk of gastric adenocarcino-ma, metastasis and decreased survival was mainly found in Japanese,Chinese and Korean patients and could not be confirmed in Europeanpatients [64,66,152–155,157,158].

4.2. ELR− CXC chemokines

4.2.1. Mig/CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 and CXCR3

4.2.1.1. Gastric cancer. It has been described that gastric adenocarcino-ma cell lines constitutively express Mig, IP-10 and I-TAC and that the

neu

TNF-αα, IL-1β

EGFR, MMP-9, VEGF, IL-8E-cadherin

neuEC

tu

IL-8

chemoattractionangiogenesis

Ttu

H. pylori

MΦ

T

?

Producer

Target

Fig. 3. Expression and role of IL-8 in gastric cancer. Several studies have shown that IL-1, TNF-α and infection with H. pylori induced or enhanced the secretion of IL-8 by severalgastric adenocarcinoma cell lines. Besides the secretion of IL-8 by gastric cancer cells (tu), neutrophils (neu) and CD8+ T lymphocytes (T) also released IL-8 upon infection with H.pylori. Although the proliferation rate of gastric carcinoma cells was not altered after addition of IL-8, IL-8 enhanced the expression of EGFR, MMP-9, VEGF and IL-8 itself. In addition,IL-8 decreased the expression of E-cadherin, favoring metastasis. Furthermore, it has been shown that increased levels of IL-8 in gastric cancer correlated with increased neutrophilinfiltration and vascularity. Although the receptors of IL-8 were detected on macrophages (MΦ) and lymphocytes, the effects of IL-8 on these cell types in gastric cancer have to befurther elucidated.


production can be enhanced by IFN-γ in synergy with TNF-α [159]. Incontrast, in vitro infection with H. pylori inhibited the IFN-γ/TNF-α-induced Mig and IP-10 production by gastric cancer cells [159].These results may explain why Eck et al. did not find any immunohis-tochemical staining of Mig and IP-10 in biopsies of patients withgastric cancer, of which the majority was infected with H. pylori[120]. Mig and IP-10 were rather detected in endothelial cells andmacrophages at sites of T cell infiltration (Table 2) [120]. Thesetumor-infiltrating lymphocytes (TILs) have a prominent protectiverole in the development of gastric cancer. Indeed, lymphocyte-richgastric adenocarcinomas are considered to be associated with a betterprognosis compared with conventional gastric cancers withoutlymphocyte infiltration [160]. TILs in lymphocyte-rich gastric cancerexpressed CXCR3 and its ligands Mig and IP-10 were abundantlyexpressed by DC (Table 2) [160]. Nevertheless, IP-10 was lessfrequently expressed by DC than Mig [160]. In contrast to the resultsof Eck and colleagues, a positive staining of Mig and IP-10 in a subsetof cancer cells was observed [120,160]. Furthermore, Rajkumar et al.demonstrated that the plasma levels of Mig and IP-10 were significant-ly elevated in patients with gastric cancer compared with healthy con-trols and a uniform drop in plasma levels of Mig and IP-10 wasobtained after surgery (Table 1) [125]. Altogether, increased expressionof CXCR3 ligands by endothelial cells and mononuclear cells, especiallyantigen-presenting cells, within gastric adenocarcinoma results inchemoattraction and activation of cytotoxic T lymphocytes favoringtumor regression.

4.2.2. SDF-1/CXCL12 and CXCR4Stromal cell-derived factor-1 (SDF-1)/CXCL12, an ELR− CXC che-

mokine, also plays prominent roles in tumorigenesis, but in contrastto the ELR− CXCR3 agonists it is an angiogenic chemokine. SDF-1 mod-ulates the angiogenic process directly by binding to its receptors CXCR4and/or CXCR7 expressed on endothelial cells or indirectly by the in-duced secretion of matrix-metalloproteases or angiogenic factors (e.g.IL-8, VEGF), respectively [161,162]. In addition, SDF-1 also mediates

neovascularization by the attraction of endothelial progenitor cells.Furthermore, SDF-1 regulates the proliferation of cancer cells andaffects their survival [161]. Moreover, the SDF-1/CXCR4 axis is involvedin tumor metastasis to sites which are characterized by high produc-tion of SDF-1 such as liver, lung and bone marrow [161,163].

4.2.2.1. Esophageal cancer. Recently, it has been shown that CXCR4 isexpressed in squamous cell carcinoma and adenocarcinoma of theesophagus, whereas no expression of CXCR4 was found in normalesophageal epithelium [164–166]. In addition, CXCR4 expression wasassociated with poor clinical outcome in patients with esophagealcancer, probably due to promotion of lymph node and bone marrowmetastasis [164–166]. In contrast, Sasaki et al. did not find any correla-tion between CXCR4 and clinical outcome [167]. SDF-1 expression wasdetected in both the membrane and cytoplasm of esophagealsquamous cell carcinoma cells, similar to the staining for CXCR4(Table 2) [167,168]. Particularly, approximately 30 to 50% of the pa-tients showed a positive staining for SDF-1, whereas more than 80%of the patients were positive for CXCR4 [164,167,168]. Furthermore,Sasaki et al. demonstrated that SDF-1 expression correlated withtumor stage, lymphatic invasion and lymph node metastasis. Hence,the overall and disease-free survival rate was lower in patients expres-sing SDF-1 in the esophageal carcinoma cells. In contrast, one reportdescribed that SDF-1 expression is reduced in the majority of esopha-geal cancers in comparison with normal esophageal mucosa (Table 1)[169]. Some authors hypothesize that hypermethylation of thepromoter region of SDF-1 in tumors causes down-regulation [170]. Inaddition, they speculate that reduced expression of SDF-1 in the prima-ry tumor enhances the response of tumor cells to SDF-1 expressed indistant organs and thereby promotes metastasis.

4.2.2.2. Gastric cancer. In gastric cancer, tumor cells have beendescribedto express CXCR4 at high levels, correlating with the development ofperitoneal carcinomatosis, which is caused by dissemination of cancercells into the abdominal cavity. This complication is frequently found


in patients with gastric adenocarcinoma [171–173]. In addition, perito-neal mesothelial cells contained high concentrations of SDF-1, indicat-ing that SDF-1 induces the migration of CXCR4-positive tumor cells tothe peritoneum [172]. Many reports have demonstrated that gastrictumor cells also express high levels of SDF-1 and this elevated expres-sion of SDF-1 correlated with lymph node and liver metastasis ratherthan with peritoneal carcinomatosis [172–177]. Also strong expressionof CXCR4 has been found to be associated with lymph node and distantmetastasis, although contrasting resultswere obtained byHashimoto etal. and Yasumoto et al. [171,172,176,178,179]. Additionally, high ex-pression levels of both SDF-1 and CXCR4 were significantly associatedwith depth of tumor invasion and tumor stage [175,178,179]. Indeed,immunohistochemical staining has shown that CXCR4 and SDF-1were more prominent and more intense in tumor cells at the invasionfront and in lymphatic vessels, respectively [176]. Therefore, patientswith elevated levels of SDF-1 and CXCR4 have been reported to havesignificantly poorer surgical outcome [175,179]. Besides the stimulationof tumor cell migration, SDF-1 has also been demonstrated to enhancethe proliferation, to increase the survival and to induce the secretionof MMPs in CXCR4-positive gastric tumor cells [171,172].

H. pylori infection has been reported to increase tumor invasionand metastasis. In this context, H. pylori increased CXCR4 expressionin gastric cancer through increased secretion of TNF-α [180]. Besidesthe expression of CXCR4 by gastric tumor cells, CXCR4 has also beenfound in leukocytes and microvascular blood vessels, confirming thatSDF-1 binds to endothelial cells (Table 2) [174]. In addition to cancercells, stromal cells such as endothelial cells, tumor-infiltrating lympho-cytes and cancer-associated fibroblasts have been demonstrated toproduce elevated levels of SDF-1 (Table 2) [174,175]. No differencesin SDF-1 expression between the diffuse and intestinal type of gastriccancer were observed and no correlation could be found betweenSNPs in the SDF-1 gene and the risk for gastric cancer [174,177,181].

5. Conclusion

The above reviewed literature supports the hypothesis that thegradual change of a controlled immune reaction to pathological inflam-mation and neoplasia in the esophagus and stomach, is partly orches-trated by chemokines. Chemokines modulate tumor behavior bythree important mechanisms. First, chemokines regulate the formationof new blood vessels allowing tumor growth and metastasis. Second,chemokines are involved in the chemoattraction of either pro-tumoral or anti-tumoral leukocytes. Third, they can act as growth andsurvival factors for the tumor cells. Indeed, ELR+ CXC chemokinesfavor tumor progression by inducing tumor cell proliferation andmigration by promoting angiogenesis, and by attracting neutrophilsloaded with proteases favoring metastasis. Expression of the ELR−

CXCR3 ligands rather protects tumor outgrowth as these mediate theinfiltration of cytotoxic T lymphocytes and inhibit angiogenesis. In con-trast, SDF-1, which is also an ELR− CXC chemokine, promotes tumorgrowth by inducing tumor cell survival, by stimulating the angiogenicprocess and by favoring metastasis of CXCR4-positive tumor cells todistant organs.

The implication of chemokines in the development of premalig-nant lesions in the esophagus and the stomach is until now onlyindirectly evidenced through expression/correlation studies. Howev-er, the scientific tools to demonstrate a direct involvement of chemo-kines and chemokine receptors in tumor development are becomingavailable and have already been used in other tumor models, e.g.pancreatic cancer. Therefore, we expect proof of principle studies inthe near future for upper gastrointestinal tract cancer. Indeed, for cy-tokines, such as IL-6 the link between cytokine expression and tumorprogression was indirectly demonstrated a long time ago, but this hasonly recently been directly evidenced via the application of anti-IL-6antibodies in cancer patients, downregulation of the cytokine signal-ing pathways (i.e. STAT3) and genetically modified animals. Thus,

therapeutic application using chemokine receptor antagonists or neu-tralizing antibodies targeting tumor-promoting chemokines or, alter-natively, using agonists of tumor-suppressing chemokine receptors,has the potential to be beneficial for prevention and treatment ofupper gastrointestinal tract inflammation and tumors, but it is at themoment a rather hypothetical concept waiting for direct evidence.

Acknowledgements

This work was supported by the Concerted Research Actions(G.O.A.) of the Regional Government of Flanders, the Fund for ScientificResearch of Flanders (F.W.O.-Vlaanderen), the Interuniversity Attrac-tion Poles Program (I.A.P.)-Belgian Science Policy, and the EuropeanUnion 6FP EC contract INNOCHEM. The authors thank Prof. Dr. GhislainOpdenakker (Rega Institute, Leuven, Belgium), Prof. Patrick Matthys(Rega Institute, Leuven, Belgium), Prof. Gert De Hertogh (UniversityHospitals, Leuven, Belgium), Prof. Christiane Dinsart (Deutsches Krebs-forschungszentrum, Heidelberg, Germany) and Prof. Daniel Desmecht(Université de Liège, Liège, Belgium) for critically evaluating thismanuscript.

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