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World J Gastroenterol. Apr 28, 2014; 20(16): 4586-4596
Published online Apr 28, 2014. doi: 10.3748/wjg.v20.i16.4586
Inflammation-related factors predicting prognosis of gastric cancer
Wen-Jun Chang, Yan Du, Xin Zhao, Li-Ye Ma, Guang-Wen Cao
Wen-Jun Chang, Yan Du, Guang-Wen Cao, Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
Xin Zhao, Li-Ye Ma, Department of General Surgery, Changhai Hospital, Second Military Medical University, Shanghai 200438, China
Author contributions: Chang WJ, Du Y and Zhao X collected data, drafted the manuscript and contributed equally to this work; Ma LY critically read this paper; Cao GW supervised and revised the manuscript.
Supported by National Natural Science Fund for China No. 81025015, No. 81372671 and No. 91129301
Correspondence to: Guang-Wen Cao, MD, PhD, Professor of Medicine, Chairman, Department of Epidemiology, Second Military Medical University, 800 Xiangyin Rd., Shanghai 200433, China. gcao@smmu.edu.cn
Telephone: +86-21-81871060 Fax: +86-21-81871060
Received: October 29, 2013
Revised: December 24, 2013
Accepted: January 20, 2014
Published online: April 28, 2014

Abstract

Gastric cancer (GC), which is mainly induced by Helicobacter pylori (H. pylori) infection, is one of the leading causes of cancer-related death in the developing world. Active inflammation initiated by H. pylori infection and maintained by inherent immune disorders promotes carcinogenesis and postoperative recurrence. However, the presence with H. pylori in tumors has been linked to a better prognosis, possibly due to the induction of antitumor immunity. Tumor infiltrations of tumor-associated macrophages, myeloid-derived suppressor cells, neutrophils, Foxp3+ regulatory T cells are correlated with poor prognosis. Tumor infiltrating CD8+ cytotoxic T lymphocytes, dendritic cells, and CD45RO T cells are generally associated with good prognosis of GC, although some subsets of these immune cells have inverse prognosis prediction values. High ratios of Foxp3+/CD4+ and Foxp3+/CD8+ in tumors are associated with a poor prognosis; whereas high Th1/Th2 ratio in tumors predicts a good prognosis. High levels of interleukin (IL)-6, IL-10, IL-32, and chemokine C-C motif ligands (CCL)7 and CCL21 in circulation, high expression of CXC chemokine receptor 4, chemokine C-C motif receptor (CCR)3, CCR4, CCR5, CCR7, hypoxia-inducible factor-1α, signal transducer activator of transcription-3, cyclooxygenase-2, and orphan nuclear receptor 4A2 in tumors are associated with an unfavorable prognosis. Increased serum levels of matrix metalloproteinases (MMP)-3, MMP-7, and MMP-11 and increased levels of MMP-9, MMP-12, and MMP-21 in tumors are consistently associated with poor survival of GC. Further emphasis should be put on the integration of these biomarkers and validation in large cohorts for personalized prediction of GC postoperative prognosis.

Key Words: Gastric cancer, Inflammation, Biomarker, Prognosis

Core tip: The prognosis of gastric cancer (GC) is not satisfactory, and is associated with Helicobacter pylori and/or Epstein-Barr virus infection, as well as host inflammation-related factors. In this article, we summarize the inflammation-related microbial and host factors that are reported to be associated with GC prognosis from different specimens and populations. So far, few simple panels have been clinically used for predicting GC prognosis. It is necessary to integrate different biomarkers with clinicopathological variables for personalized prediction of GC prognosis. The prognostic values of integrated predicators should be validated in large prospective cohorts before clinical application.



INTRODUCTION

Gastric cancer (GC) is the fourth most common cancer in men and the fifth in women worldwide. Almost one million new cases are diagnosed annually. More than 70% of new cases and deaths occur in developing countries[1]. To date, surgical resection remains the mainstay of curative treatment for GC. However, a subset of patients will develop local relapses and metachronous metastases after resection of the primary tumor. The overall 5-year survival rate of patients with GC in the United States is about 26%, while the rate improves to 63% if detected at an early stage. Similar low 5-year survival rates (≤ 30%) are also seen in European countries. However, higher 5-year survival rates (up to 50%) are reported from East Asia such as Japan, mainly due to its early detection and treatment services[2]. In addition, other measurable or unmeasurable factors including differences in proximal versus distal cancer incidences, environmental exposures, dominant pathological types, surgical factors, and neoadjuvant/adjuvant treatment protocols may also contribute to the differences in postoperative survival of GC patients. Because of the heterogeneity of GC prognosis, searching for more accurate predictors of GC prognosis has become a growing interest in GC research. Chronic infections of Helicobacter pylori (H. pylori) contribute to more than 75% of GC[3], and about 10% of GC may be caused by Epstein-Barr virus (EBV) infection[4]. Although a causal relationship of EBV infection with nasopharyngeal cancer has been identified, the association of EBV infection with GC has not been confirmed so far. Interestingly, H. pylori induce EBV reactivation in the gastric epithelium of GC patients latently infected with EBV[5]. A population-based intervention trial has demonstrated that a selective cyclooxygenase-2 (COX-2) inhibitor, celecoxib, or H. pylori eradication alone had beneficial effects on the regression of advanced gastric lesions[6]. Regular use of non-steroidal anti-inflammatory drugs in individuals with H. pylori infection can effectively reduce the risk of GC[7], indicating chronic inflammation following H. pylori infection contributes to the onset of GC. Accumulating evidence indicates that inflammation-related factors also play an important role in recurrence and metastasis of some types of cancers including GC. Both systemic inflammatory responses, such as primary or modified Glasgow prognostic score[8-11] and blood neutrophil-to-lymphocyte ratio[11-15], and local inflammatory responses such as the infiltration of various immune cells and their subsets in tumors (e.g., infiltrating S100A9+ inflammatory cells[16]) are associated with the prognosis of GC. Here, we review and summarize the inflammation-related microbial pathogen (Table 1) and host (Table 2) factors that have been shown to be associated with GC prognosis.

Table 1 Important pathogens associated with the prognosis of gastric cancer.
FactorsSourceSampleSample sizeCut-off value or characterizationTime of measurementPrognostic role
H. pyloriGermanySera166PositivityPrior to gastrectomyIncreased OS and RFS[17]
H. pyloriChinaTumor tissue162PositivityAt the time of surgeryDecreased OS and RFS[18]
H. pyloriBrazilTumor tissue68PositivityAt the time of surgeryNo difference[19]
H. pyloriSouth KoreaSera274NegativityAt the time of surgery and adjuvant chemotherapyDecreased OS[20]
H. pyloriItalySera and tumor tissue297NegativityAt the time of surgeryDecreased OS[21]
H. pyloriBrazilian, Asian and CaucasianSera2454PositivityAt the time of surgeryIncreased OS and DFS[22]
EBVTaiwanSera150PositivityPrior to gastrectomyIncreased OS[27]
EBVKoreaSera123ExpressionAt the time of surgeryIncreased OS and DFS[28]
EBVAsia, Europe and Latin AmericaSera4599PositivityAt the time of surgeryIncreased OS[29]
Table 2 Important inflammation-related host factors with prognostic values for gastric cancer.
FactorsSourceSample sizeCut-off value or characterizationTime of measurementPrognostic role
In peripheral blood
MIFChina97> 6600 pg/mLPrior to gastrectomyDecreased 5-year survival rate[45]
Th1/Th2 ratioJapan157HighAfter curative gastrectomyIncreased DFS[61]
Th17China51High levelsPrior to gastrectomyDecreased OS[62]
Th22China51High levelsPrior to gastrectomyDecreased OS[62]
CD57+ T cellsJapan48≥ 18%At the time of gastrectomyDecreased OS[68]
NLRSouth Korea775> 3.79Prior to gastrectomyDecreased 5-year survival rate[12]
NLRChina46> 2.5Prior to gastrectomyDecreased PFS and OS[13]
TLR9China314TLR9-1486CPrior to gastrectomyDecreased OS[73]
IL-1B + IL-1RNItaly123IL-1B-511C/T and IL-1B-31T/C + Wide-type IL-1RNPrior to gastrectomyDecreased PFS and OS[76]
IL-6Poland99> 288.7 pg/mLAt the time of gastrectomyIncreased overall complications and infective complications[83]
IL-2RJapan96High expressionPrior to gastrectomyDecreased OS[88]
IL-32Japan182Positive expressionAt the time of gastrectomyDecreased OS[89]
VAP-1Japan107Low levelsPrior to gastrectomyDecreased OS[91]
MDSCsUnited Kingdom25Increasing percentagePrior to gastrectomyIncreased the risk of death[50]
MMP-11China86Low levels at the 75th percentile in the total groupAfter chemotherapyDecreased median survival time and 1-year survival rate[104]
MMP-12China165Positive expressionPrior to chemotherapyDecreased OS[105]
In tumor
TAMJapan, Germany, Ukraine449Positive expressionPrior to chemotherapyDecreased OS[44]
CD68+Japan111High numbersAt the time of gastrectomyDecreased OS[45]
NitrotyrosineChina66Intermediate or high expressionsAt the time of gastrectomyDecreased 5-year survival rate[51]
CD33+/p-STAT+ cellsChina100> 11 cells/HPFAfter curative gastrectomyDecreased 5-year survival rate[52]
DCsJapan174High levelsAt the time of gastrectomyIncreased 5-year survival rate[53]
DCsBulgaria55Low numbersAt the time of gastrectomyDecreased 5-year survival rate[54]
CD208+Japan128High expression levelsAt the time of gastrectomyDecreased postoperative outcome[55]
CD15+ TINsJapan115< 21.60 cells/HPFAt the time of gastrectomyIncreased OS[56]
HIF-1αJapan, China, South Korea, United Kingdom1268High expressionPrior to gastrectomyDecreased OS[77]
HIF-1αJapan, China, South Korea, United Kingdom1555High expressionPrior to gastrectomyDecreased OS[78]
S100A9 proteinChina176> 200 positive cells/HPFAt the time of gastrectomyIncreased OS[16]
Stroma FoxP3+TILsGermany52> 125.9/mm2At the time of gastrectomyIncreased NED-survival and OS[113]
Stroma CD68+/Foxp3+Germany52High cell ratiosAt the time of gastrectomyIncreased median survivals[113]
Tc17China103Percentage ≥ 2.75% or cell number ≥ 484.37 per millionAt the time of gastrectomyDecreased DFS and OS[60]
FOXP3+ TregsChina107High numbersAt the time of gastrectomyIncreased OS[47]
CD45RO+ T cellsJapan101High levelsAt the time of gastrectomyIncreased OS and DFS[67]
Foxp3+/CD8+ ratioChina133HighAt the time of gastrectomyDecreased OS[65]
Foxp3+/CD4+ ratioSouth Korea180HighAt the time of gastrectomyLoco-regional recurrence[66]
T-bet+ TILsChina152High numbersAt the time of gastrectomyIncreased OS and DFS[69]
CD19+ cellsChina846> 7.91% ± 2.98%At the time of gastrectomyIncreased DFS[70]
CD20+ B cellsChina100High densityPrior to gastrectomyIncreased OS and DFS[52]
Natural killer cellsBrazil72> 15 NK cells/10 HPFAt the time of gastrectomyIncreased OS and DFS[71]
COX-2South Korea457Lack of expressionAt the time of gastrectomyDecreased OS and DFS[79]
STAT3South Korea100> 10% stained cellsAt the time of gastrectomyDecreased OS and DFS[81]
NR4A2China245Immunoreactive score ≥ 3At the time of gastrectomyDecreased OS and DFS[85]
IL-12Japan85High densityAt the time of gastrectomyIncreased OS and DFS[86]
IL-10Poland136> 10 pg/mLAt the time of gastrectomyDecreased OS and DFS[87]
Annexin A1Taiwan118High expressionAt the time of gastrectomyDecreased OS[90]
CCL7 and CCL21China194Higher expressionAt the time of gastrectomyDecreased OS[92]
CXCR4China97Higher expressionAt the time of gastrectomyDecreased OS[94]
HighCXCR4/high SDF-1αSouth Korea221ExpressionAt the time of gastrectomyDecreased 5-year survival rate[95]
CCR3Japan48Positive expressionAt the time of gastrectomyDecreased OS[96]
CCR5Japan60Positive expressionAt the time of gastrectomyDecreased OS[96]
CCR4South Korea753Positive expressionAt the time of gastrectomyDecreased 5-year survival rate[97]
CCR7Japan224> 10% positivityAt the time of gastrectomyDecreased OS[98]
CX3CL1Japan158High expressionAt the time of gastrectomyDecreased DFS[100]
CCL18China59High expressionAt the time of gastrectomyIncreased OS and DFS[48]
MMP-9China, Finland, The Netherlands, Poland, Spain1700High expressionAt the time of gastrectomyDecreased DFS[102]
MMP-21China296High expressionAt the time of gastrectomyDecreased OS[106]
MMP 14China205Positive expressionPrior to chemotherapyDecreased OS[107]
MT1-MMP, CD11b+ immunocytes and LNRChina184MT1-MMP positive, low CD11b+ immunocytes and high LNRAt the time of gastrectomyIncreased OS[110]
Inflammation gene signatureBrazil51High expression patternAt the time of gastrectomyDecreased OS[112]
MICROBIAL PATHOGEN FACTORS
H. pylori

Chronic infection with H. pylori is the major cause of GC. It is well established that H. pylori infection contributes greatly to the carcinogenesis of GC. However, the role of H. pylori infection in predicting the survival of GC patients is less well understood. Interestingly, a prospective study has demonstrated that GC patients with positive H. pylori infection frequently showed better relapse-free survival and better overall survival (OS) after curative resection[17], which is contradictory to the notion that H. pylori acts as a risk factor of GC during the carcinogenesis process. Although this finding is in contrast to some studies[18,19], other studies[20,21] especially a recent meta-analysis containing 2454 cases[22] have demonstrated that H. pylori infection is an independent protective factor for GC progression. This protective effect is also consistent among different ethnic groups, using various H. pylori evaluation methods and quality assessment measures[22]. The suppressive effect of H. pylori on GC progression is possibly due to the induction of some antitumor immunity[17]. CagA, CagE, VacA and protein modifications (e.g., CagA phosphorylation) of H. pylori have been associated with gastric carcinogenesis[23-26], but the association between these factors and GC prognosis is still unclear.

EBV

About 10% of GC cases are infected with EBV, while the prognostic value of EBV is poorly understood. Lymphoepithelioma-like carcinoma (LELC) is a special subtype of GC, and over 90% of LELC are EBV positive. LELC tends to have a lower frequency of lymph node metastasis and a better survival rate than other GC subtypes[27,28]. A recent meta-analysis including 4599 GC patients from 13 studies has shown that EBV positivity in tumors by in situ hybridization is associated with lower mortality (HR = 0.72; 95%CI: 0.61-0.86) and might serve as a valuable prognostic factor[29]. Furthermore, the protective effect is quite stable across patients or tumor types. However, these studies cannot clarify whether EBV infection itself or EBV-associated inflammatory responses and/or their interactions result in the protective effect. EBV-associated GC (EBV-GC) is a recently recognized entity defined by the presence of EBV in GC cells. After stratification of EBV-GC by host inflammatory response, it was found that EBV-GC patients with a Crohn’s disease-like lymphocyte reaction had significantly longer OS and disease-free survival (DFS) than other EBV-GC patients, indicating that inflammation induced by EBV-GC could affect the prognosis of GC[28]. Mechanisms of the heterogeneity of induced inflammatory responses by EBV-GC need to be explored further.

HOST INFLAMMATION-RELATED FACTORS

There is a renaissance of research into the connection between inflammation and cancer[30-32]. Most current research support that acute inflammation triggered by tumor-infiltrating leukocytes does not exert normal immunoprotective mechanisms that lead to eradication of the evolving cancer (antitumor immunity). Excessively and chronically produced pro-inflammatory mediators may contribute to tumor promotion and progression[31-34]. Inadequate pathogen eradication, prolonged inflammatory signaling, and defects in anti-inflammatory mechanisms can lead to chronic inflammation and benefit tumor development[35]. In an inflammatory state, there is a high rate of cell turnover and the microenvironment is often highly oxidative and nitrosative, thus increasing the opportunities for DNA damage and somatic mutation. Chronic inflammation can promote an environment that is conducive to carcinogenesis, and it is involved in tumor initiation, promotion, and progression[31,36-39]. The tumor microenvironment is created by the tumor and dominated by tumor-induced interactions[40]. In the inflammatory microenvironment, there is a delicate balance between antitumor immunity and tumor-originated pro-inflammatory activity, which weakens antitumor immunity[33,41]. The tumor not only manages to escape from the host immune system (tumor escape), but it effectively contrives to benefit from infiltrating cells by modifying their functions to create the microenvironment favorable to tumor progression[40]. The net outcome of a persistent inflammatory microenvironment is enhanced tumor promotion, accelerated tumor progression, invasion of the surrounding tissues, angiogenesis, and often metastasis[31]. Cancer-associated inflammation is characterized by infiltration of immune cells including tumor infiltrating lymphocytes (TILs)[42], expression of cytokines and chemokines, tissue remodeling, and angiogenesis. The diverse cells communicate with each other by means of direct contact or through cytokines and chemokines, therefore exerting their functions of tumor promotion or suppression. Cancer cells can also release chemokines and recruit immune cells to constitute the inflammatory microenvironment. The inflammation-related molecules such as nuclear factor-κB (NF-κB) and signal transducer activator of transcription-3 (STAT3), primary inflammatory cytokines, secondary inflammatory cytokines, chemokines and matrix metalloproteinases (MMPs) form an inflammatory molecular network, playing an active role in maintaining tumor-promoting inflammation or antitumor immunity. Although tumor infiltrating immune cells and their interactions can reflect the host-tumor-pathogen immune response, immune cells and molecules in peripheral blood are also important for exploring the characteristics of the complex tumor-related inflammation.

TIMs

TIMs are the major type of infiltrating inflammatory cells regulating antitumor immunity and are represented by mature cells such as macrophages, granulocytes, and dendritic cells (DCs), as well as by pathologically activated immature myeloid-derived suppressor cells (MDSCs)[43]. Macrophages, one of the most important components of the inflammatory infiltration in tumors, include M1-like and M2-like subtypes. M1-like macrophages facilitate anti-tumor immunity, while M2-like macrophages promote tumor progression. M2-like macrophages are strongly affected by the tumor microenvironment, and are also termed tumor-associated macrophages (TAMs). A meta-analysis of 55 studies with 8692 patients has shown that higher TAM infiltration is associated with worse OS in several cancers, including GC (RR = 0.52; 95%CI: 0.35-0.77)[44]. Thymidine phosphorylase (TP) expression is significantly correlated with the extent of infiltrating macrophages, and increased percentages of TP-positive macrophages and CD68+ macrophages in tumors also indicate poor outcomes in patients with GC[45]. Macrophage migration inhibitory factor (MIF) can inactivate p53. Serum MIF positively correlates with MIF expression in GC, and increased serum MIF (> 6600 pg/mL) predicts a lower 5-year survival rate compared with those with lower serum MIF[46]. However, GC patients with high intratumoral macrophages and regulatory T cells (Tregs) have better 5-survival rates than those with low intratumoral macrophages and Tregs[47]. A high level of CCL18, mainly expressed in infiltrating macrophages that are preferentially located at the tumor invasion front, is also associated with favorable OS and DFS of GC patients[48]. The possible explanation for this inconsistency could be the presence of heterogenic subpopulations of macrophages in the tumor microenvironment.

MDSCs are a heterogeneous population of cells characterized by their myeloid origin, immature state and the ability to suppress T cell responses. The MDSC population expands rapidly during inflammation and cancer, which is associated with advanced GC stage and reduced survival[49,50]. Production of reactive oxygen species (ROS) and reactive nitrogen species is one of the major characteristics of all activated myeloid cells. Increased activity of free radical peroxynitrite is followed by ROS production, and peroxynitrite modification of chemokine (C-C motif) ligand 2 (CCL2) inhibits intratumoral migration of effector CD8+ T cells. Nitrosylation, a marker of peroxynitrite activity, has been reported to be associated with poor survival of GC patients[51]. High CD33+/p-STAT+ cells representing a subset of MDSCs, are also associated with poor prognosis at stage IIIa GC[52].

The major functions of DCs are to process and present antigens for the activation of T cells. Maintaining enough density of mature DCs in tumors prolongs the survival of patients with advanced GC[53,54]. Contrary to the typical functions of DCs, intratumoral density of CD208+ DCs has an inverse correlation with postoperative outcome in GC patients[55]. Among immune cells, neutrophils have a protumorigenic role by promoting neoangiogenesis and reducing antitumor immune response. In GC patients, tumor infiltrating neutrophils with positive CD15 are independently associated with an unfavorable OS[56]. S100A9, specifically expressed by inflammatory cells such as macrophages and neutrophils in early GC, is associated with a good prognosis[16]. In addition, S100A9 secreted into gastric fluid also has a prognostic monitoring value for GC[57].

TILs

TILs are another major component of infiltrating immune cells, and are represented by T cells, B cells, and natural killer (NK) cells. The subsets of T cells include CD8+ cytotoxic T cell (CTL), CD4+ T helper cell, CD45RO memory T cells, FOXP3+ Tregs, and nature killer T cells. CD8+ CTLs play an active role in directly killing tumor cells, indicating a favorable outcome[58,59]. However, CD8+ T cells that produce interleukin (IL)-17 (Tc17 cells) promote the progression of inflammation and are possibly associated with poor prognosis[60]. CD4+ lymphocytes include a group of heterogeneous T lymphocytes [e.g., T helper (Th)1, Th2, Th3, Th17, Treg, T follicular helper, and Th22] which can secret diverse cytokines. Th1 cells (interferon γ-producing CD4+ T cells) can activate CTLs, and Th2 cells (IL4-producing CD4+ T cells) stimulate humeral immunity. Th1 activation is more effective than Th2 activation in inducing antitumor immunity. Consistently, high Th1/Th2 ratio in peripheral blood of GC significantly predicts a good postoperative prognosis[61]. High circulating Th17 and Th22 cells are associated with tumor progression and poor survival in GC[62]. CD4+ Tregs suppress effector T lymphocytes, which are characterized with positive Foxp3 expression. High Foxp3+ Tregs are correlated with GC progression and associated with a poor survival[63-65]. The balances between Foxp3+ T cells and CD4+ T cells as well as Foxp3+ T cells and CD8+ T cells are important for the suppression of metastasis, and higher Foxp3+/CD4+ ratio[66] and higher Foxp3+/CD8+ ratio[65] in resected tumor specimens are associated with a poor prognosis. High CD45RO T cell infiltration is significantly related to postoperative prognosis in advanced GC but not in early GC[67]. NK-like T cells comprising the subsets of CD56+ cells and CD57+ cells play an important role in modulating immune responses. In advanced GC, an increased proportion of CD57+ cells in the circulation indicates a poor prognosis[68]. T-bet, a key master transcription factor for type 1 immune response, mainly expresses on CD4+, CD8+, and CD56+ TILs. High T-bet TILs in tumor are associated with a better DFS and OS of GC patients[69]. The principal functions of B cells are to generate antibodies against antigens, but its functions related to tumor progression are less known. Recently, it has been reported that CD19+ and CD20+ B cells are associated with a favorable outcome in patients with GC[52,70]. NK cells directly clear tumor cells, representing an antitumor immunity. GC patients with high density of NK cells in the tumors exhibit a higher survival rate when compared to those patients with low density of NK cells, especially for those at advanced stages[71].

TRANSCRIPTION FACTORS AND PRIMARY INFLAMMATORY CYTOKINES

In terms of cancer-related inflammation, a few molecules can serve as primary drivers (endogenous promoters), mainly including transcription factors such as NF-κB and STAT3 and primary inflammatory cytokines such as IL-1, IL-6, and tumor-necrosis factor (TNF)-α. NF-κB is a key orchestrator of innate inflammation and is aberrantly activated in many cancers. In GC, activated NF-κB is frequently identified in early-stage tumors and usually predicts a favorable prognosis[72]. The toll-like receptor (TLR)-MyD88 pathway and the primary inflammatory cytokines TNF-α and IL-1α can activate NF-κB. It has been reported that polymorphisms in NF-κB pathway genes such as TLR9, IL-1β, IL-1Ra, and TNF-α, are significantly associated with the prognosis of GC patients[73-76]. NF-κB can also be activated in response to hypoxia inducible factor (HIF)-1α. Accumulating evidence indicates that the interactions and compensations between NF-κB and HIF-1α relate to immunity in the hypoxic condition. Two meta-analyses both reported that HIF-1α expression was significantly correlated with poor prognosis of GC patients mainly from East Asian countries[77,78]. NF-κB induces the expression of inflammatory cytokines, adhesion molecules, and key enzymes in the prostaglandin synthase pathway such as COX-2. Immunohistochemical analysis has shown that COX-2 expression is an independent prognostic factor of DFS and OS of GC patients[79]. Along with NF-κB, STAT3 is a point of convergence for numerous oncogenic signaling pathways. In tumors, the maintenance of NF-κB activation requires STAT3[80]. STAT3 is constitutively activated both in cancer cells and immune cells, and higher STAT3 and STAT3 phosphorylation (Tyr705) in GCs indicate a poor prognosis[81,82]. IL-6 is mainly produced by TIMs under the regulation of the NF-κB signaling pathway. IL-6 is also linked with STAT3, and has multi-functions of growth-promoting and anti-apoptotic activities. Preoperative high IL-6 levels have been proposed as a poor prognostic factor for recurrence and OS of GC patients[83]. Nuclear receptor subfamily 4, group A, member 2 (NR4A2), a transcription factor belonging to the steroid orphan nuclear receptor superfamily, is also regulated by the NF-κB signaling pathway and COX-2 derived prostaglandin E2[84]. Expression of NR4A2 in GC cells confers chemoresistance of GC cell lines and predicts an unfavorable postoperative survival of GC patients, especially for those treated with postoperative chemotherapy[85].

Cytokines, chemokines, and matrix metalloproteinases

Cytokines including IL-1, IL-6, and TNF-α are regulators of host responses to infection and cancers, and play different roles in cancer-related inflammation network. Some cytokines facilitate the development of cancer-related inflammation, whereas others act as suppressors. T lymphocytes are a major source of cytokines. Cytokines produced by Th1 and Th2 are known as Th1-type cytokines (e.g., TNF-α, IFN-γ, IL-12) and Th2-type cytokines (e.g., IL-4, IL-5, IL-10, IL-13), and are characterized by pro-inflammatory and anti-inflammatory roles, respectively. High IL-12-positive cell density in surgical specimens may be a significant independent predictor of better prognosis of advanced GC patients[86]. Conversely, an increased level of IL-10 is an independent unfavorable prognostic factor in patients with GC[87]. The relative balance between Th1 and Th2 cytokines appears important in cancer-related inflammation. A high circulating soluble IL-2 receptor level is associated with worse prognosis of GC patients[88]. IL-32 is a recently identified pro-inflammatory cytokine characterized by the induction of NF-κB activation, and the expression of IL-32 is associated with more severe metastatic conditions in GC[89]. Additionally, annexin A1 is a glucocorticoid-regulated anti-inflammatory protein. High tissue annexin A1 expression is an independent risk factor for poor OS in GC patients[90]. Vascular adhesion protein-1 (VAP-1) regulates leukocyte tissue infiltration. Serum soluble VAP-1 is a candidate prognostic marker in GC, and low levels of serum VAP-1 are associated with poor prognosis in GC patients[91].

Chemokines are 8-10 kDa secreted proteins with 20%-70% homology in structure, and share the common functional activity as being chemotactic for leucocytes. Over 40 chemokines have been identified so far. Although chemoattractants constitute a diverse array of molecules, they have to act together with a family of G protein-coupled receptors to communicate with leukocytes. Inflammatory chemokines are produced under pro-inflammatory stimuli (e.g., IL-1, TNF-α, lipopolysaccharide, or pathogens) and determine the migration of inflammatory cells. CCL7 is a type of monocyte-specific chemokine, and CCL21 is a specific chemokine in DC cells and effecter T cells. Over-expressed CCL7 and CCL21 in GCs are related to lymph node metastasis and poor prognosis[92]. Stromal-derived-factor (SDF)-1 is strongly chemotactic for lymphocytes, and is found in GC metastasized to lymph nodes[93]. CXC chemokine receptor 4 (CXCR4) is a receptor specific to SDF-1. Interestingly, upregulated intratumoral CXCR4 expression is associated with poor OS in patients with GC[94], and high CXCR4/high SDF-1α expression indicates the worst prognosis in GC patients[95]. Chemokine (C-C motif) receptor 3 (CCR3), CCR4, CCR5, and CCR7 have been shown to have prognostic values for an unfavorable outcome in patients with GC[96-98]. Intratumoral high CXCR4, CCL3, CCR4, CCR5, and CCR7 are associated with unfavorable prognosis. IL-8 is a chemokine produced by macrophages and other cell types. It induces chemotaxis in neutrophils to migrate toward the site of inflammation. Polymorphism of IL-8 is associated with prognosis in patients with GC, and the IL-8 251 A/A genotype may indicate a poor prognosis in GC patients[99]. CX3CL1 is the only CX3C chemokine that can chemoattract NK cells, CD8+ T cells, monocytes, and dendritic cells, and is one of the independent prognostic factors of DFS in GC patients[100].

An increased expression of the MMP family members is observed in almost every inflammation site. Studies in animal models have demonstrated that MMPs act broadly in the inflammation process, including regulation of inflammatory cytokine and chemokine activities, and generation of chemokine gradients. Pathogens such as H. pylori infection upregulate the expression of MMPs, which act on pro-inflammatory cytokines, chemokines and other proteins to regulate diverse aspects of inflammation. Elevated MMP-3 and MMP-7 in H. pylori-related GC can serve as biomarkers for a poor survival[101]. MMP-9 gene expression is a predictor of outcome in patients with metastatic GC[102], which is further confirmed by a meta-analysis[103]. Serum levels of MMP-11 in Chinese patients with advanced GC are not associated with the response to front-line chemotherapy, but could play an important role in predicting lymph node metastasis and prognosis[104]. Increased MMP-12 and MMP-21 in tissues are associated with poor survival in patients with GC[105,106]. MMP-14 is a negative prognostic marker for patients with GC[107]. Although MMPs have been linked to GC prognosis, the precise mechanisms need to be clarified. It is possible that only some MMPs can truncate the inflammatory cytokines or chemokines and participate in the regulation of tumor-related inflammation.

CONCLUSION

The progression of GC after surgical resection is closely associated with microbial pathogens and host inflammatory factors. Positive H. pylori and/or positive EBV infection can serve as prognostic factors for a better survival of GC patients. Intratumoral TAMs, MDSCs, neutrophils, and Tregs are usually correlated with poor prognosis of GC. Tumor-infiltrating CD8+ CTLs, DCs, CD45RO T cells are generally correlated with better prognosis of GC, although some subsets of these cells have inverse prognostic prediction values. A high NF-κB indicates a favorable prognosis, while high HIF-1α, STAT3, NR4A2, and preoperative high IL-6 predict a poor prognosis. Polymorphisms of TNF-α, IL-1α, and TLR9, which might affect the expression and/or function of these genes, are associated with the prognosis of GC patients. Increased IL-10, IL-32, CCL7, CCL21 and intratumoral high CXCR4, CCR3, CCR4, CCR5, and CCR7 are associated with unfavorable prognosis. Increased serum levels of MMP-3, MMP-7, MMP-11 and increased expression of MMP-9, MMP-12, and MMP-21 in tumors are consistently associated with poor GC survival.

In this article, we summarized the inflammatory factors associated with the prognosis of GC. As inflammation provides “fertile field” for the evolution of cancer-initiating cells, tumor growth-promoting molecules predominantly expressed in cancer-initiating cells also represent a cluster of prognosis-predicting biomarkers and/or therapeutic targets[108]. Since many studies are conducted in East Asian populations as summarized in Tables 1 and 2, the prognostic values of these molecules need to be tested in other populations. Furthermore, with the advancement of systems biology and vast amount of ‘omics’ data, it is of great importance to evaluate these data with clinical and pathological variables to more accurately predict cancer outcomes. Studies have already looked at combining gene expression data with clinicopathological data to better predict different types of cancer prognosis[109-111]. However, only a few studies have been conducted in the field of GC research[112,113]. Further emphases should be placed on the integration of diverse biomarkers and their validation in large cohorts for personalized prediction of GC postoperative prognosis.

Footnotes

P- Reviewers: Kim H, Sousa H S- Editor: Qi Y L- Editor: Cant MR E- Editor: Zhang DN

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