Chemokines and their receptors in lung cancer progression and metastasis

Chemokines and their receptors in lung cancer progression and metastasis 趋化因子及其受体在肺癌侵袭与转移过程中的作用 1 2 first-author 1 1 3 3 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:zhengjianghua2014@163.comzhangzy@shaphc.org †E-mail:zhengjianghua2014@163.comzhangzy@shaphc.org zhengjianghua2014@163.com 1 corresp ‡Corresponding Author ‡Corresponding Author †E-mail:zhengjianghua2014@163.comzhangzy@shaphc.org †E-mail:zhengjianghua2014@163.comzhangzy@shaphc.org zhengjianghua2014@163.com Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China Department of Radiology, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China Department of Radiology, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, China Department of Clinical Laboratory, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China Department of Clinical Laboratory, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China Lung cancer is the leading cause of cancer-related mortality around the world. Despite advancements in diagnosis, surgical techniques, and neoadjuvant chemoradiotherapy over the last decade, the mortality rate is still high and the 5-year survival is a dismal 15%. Fortunately, early detection by low-dose computed tomography (LDCT) scans has reduced mortality by 20%; yet, overall, 5-year-survival remains low at less than 20%. Therefore, in order to ameliorate this situation, a thorough understanding of the underlying molecular mechanisms is urgently needed. Chemokines and their receptors, crucial microenvironmental factors, play important roles in lung tumor genesis, progression, and metastasis, and exploring the mechanisms of this might bring new insights into early diagnosis and precisely targeted treatment. Consequently, this review will mainly focus on recent advancements on the axes of chemokines and their receptors of lung cancer. 本文对近年来与肺癌侵袭、转移相关的趋化因子轴及其可能的机制进行综述，为靶向治疗提供理论线索，并预测促癌趋化因子轴的激活与抑癌趋化因子轴的失活可能导致了肺癌的侵袭与转移。 Lung cancer Chemokines Tumor progression Metastasis 肺癌 趋化因子 肿瘤进展 转移 Introduction 1 Lung cancer is the leading cause of cancer-related mortality in both genders worldwide. In China, with its serious air pollution and high tobacco consumption, the incidence and mortality of lung cancer have increased rapidly in recent years. It has been reported that approximately 500 000 patients were diagnosed and 430 000 died from lung cancer in 2005, and the number of deaths is anticipated to be more than one million by 2025 (Yang et al., 2005a 2005a ; 2005b 2005b ; Dong et al., 2010 2010 ). Histologically, lung cancer has been classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); the former, originating from respiratory epithelial cells, accounts for 80% of cases with subtypes of adenocarcinoma, squamous cell carcinoma, and large cell carcinoma in order of incidence rate; the latter, from cells with differentiation in neuroendocrine along the bronchial tree, accounts for the remaining 20% (Goldstraw et al., 2007 2007 ; Groome et al., 2007 2007 ; Sutherland and Berns, 2010 2010 ). Despite advances in diagnosis, staging, surgical techniques, and neoadjuvant chemoradiotherapy over the last decade, the mortality rate of lung cancer is still high and 5-year survival is only 15% (Siegel et al., 2012a 2012a ; 2012b 2012b ). As a result of a lack of early specific signs and symptoms, most of these patients are diagnosed at advanced stages where surgery is no longer feasible. Fortunately, early detection with a lung cancer screening program using low-dose computed tomography (LDCT) scans has recently brought bright prospects, and the mortality rate has reduced by 20% (National Lung Screening Trial Research, 2011 2011 ). Nevertheless, overall, 5-year-survival remains low, at less than 20% (Keith and Miller, 2013 2013 ). Therefore, early detection is only the first step; personalized precise treatments following detection, based on molecular mechanisms, are also crucial; these treatments either fight tumor cells directly or modify the tumor microenvironment indirectly (Burger and Gribben, 2014 2014 ). Chemokines seem to be central in this microenvironment by promoting leukocyte infiltration and tumorogenesis (Mukaida and Baba, 2012 2012 ). Chemokines, a superfamily of inducible, secreted, heparin-binding proteins, are structurally homologous and are involved in tumor growth and metastasis (Keeley et al., 2011 2011 ). The receptors, a superfamily of seven transmembrane spanning proteins coupled to G-protein-coupled-receptors (GPCRs), are classified into four major groups based on the pattern of cysteine residues: CXC, CC, C, and CX3C, where C stands for cysteine and X for non-cysteine amino acids (Zlotnik and Yoshie, 2000 2000 ). Functionally speaking, chemokines are grouped into inflammatory and homeostatic; the former are induced by inflammation while the latter are constitutively expressed and involved in homeostatic immune regulation (Sarvaiya et al., 2013 2013 ). Their binding leads to conformational changes and the following activation of signaling pathways, which play an important role in both normal inflammatory reactions if the expression is regular and abnormal reactions if aberrant, leading to constitutive activation of oncogenes, inactivation of tumor suppressor genes, or altered expression of transcription factors. This consequently results in tumor angiogenesis, growth, epithelial mesenchymal transition (EMT), and further metastasis (Richmond, 2002 2002 ; Sparmann and Bar-Sagi, 2004 2004 ; Mantovani et al., 2010 2010 ). To date, the most studied chemokine axis in lung cancer is CXCL12/CXCR4, which has been proved to be related to greater invasiveness and higher potential for metastasis (Burger et al., 2011 2011 ; Saintigny and Burger, 2012 2012 ), and many new drugs targeting this axis are under development (Peled et al., 2012 2012 ). It is the case that other chemokine axes have also been investigated. Therefore, it is necessary to review the role of chemokines and their receptors in lung cancer (Table 1 1 ), particularly the most common histological type, NSCLC, in progression and metastasis, which might provide insights into the molecular mechanisms of lung tumorigenesis and progression, and consequently assist early diagnoses and targeted treatments. Nrf2: NF-E2-related factor 2; EGFR: epidermal growth factor receptor; uPAR: urokinase plasminogen activator receptor; Ub: ubiquitin; DARC: Duffy antigen receptor for chemokines; CCX-CKR: ChemocentryX chemokine receptor. References in bold: chemokines/receptors with anti-tumor effect Chemokine/Receptor Pro-tumor Anti-tumor Reference CXCL12/CXCR4 (co-expression: Nrf2/EGFR/uPAR) √ Phillips et al., 2003 2003 ; Belperio et al., 2004 2004 ; Su et al., 2005 2005 ; Eramo et al., 2008 2008 ; Wagner et al., 2009 2009 ; Damelin et al., 2011 2011 ; Montuori et al., 2011 2011 ; Wald et al., 2011; Almasi et al., 2013 2013 ; Jung et al., 2013 2013 ; Hu et al., 2014 2014 ; Li and Tai, 2014 2014 ; Wang et al., 2014 2014 Ub/CXCR4 (extracellular Ub) √ Majetschak, 2011 2011 ; Yan et al., 2013 2013 CXCL1/5/8/CXCR2 √ √ Luppi et al., 2007 2007 ; Maxwell et al., 2007 2007 ; Acosta et al., 2008 ; Sun et al., 2008 2008 ; Yanagawa et al., 2009 2009 ; Saintigny et al., 2013 2013 CCL2/CCR2 √ √ Li and Tai, 2013 2013 ; 2014 2014 ; Zhang X.W. et al., 2013 2013 ; Chen et al., 2015 2015 ; CCL19/21/CCR7 √ √ Muller et al., 2001 2001 ; Hillinger et al., 2003 2003 ; Cabioglu et al., 2007 2007 ; Cao et al., 2007 2007 ; Itakura et al., 2013 2013 ; Sharma et al., 2013 2013 ; Zhang Q. et al., 2013 2013 CCL25/CCR9 √ Gupta et al., 2014 2014 CCL4/CCR5 √ Lee et al., 2012 2012 ; Mango et al., 2014 2014 Atypical chemokine receptors (DARC/D6/CCX-CKR) √ Addison et al., 2004 2004 ; Wu et al., 2013 2013 CXCL12/CXCR4 1 CXCR4, the most frequently overexpressed and thoroughly studied chemokine receptor in malignancies, is present in many different types of human cancers, including lung cancer (Balkwill, 2004 2004 ; Burger and Kipps, 2006 2006 ), the expression of which is upregulated in hypoxia, as might be encountered in a tumor microenvironment (Schioppa et al., 2003 2003 ; Phillips et al., 2005 2005 ). The corresponding ligand, CXCL12, is constitutively expressed in tissues that are targets of metastases (Burger and Kipps, 2006 2006 ). In lung cancer, the CXCL12/CXCR4 axis plays a crucial role in migration and metastasis. NSCLC cells expressing CXCR4 were noticed to migrate to tissues or organs with a high level of CXCL12, such as lymph nodes, contralateral lung, liver, brain, and bone marrow (Phillips et al., 2003 2003 ; Belperio et al., 2004 2004 ; Su et al., 2005 2005 ; Wagner et al., 2009 2009 ), even if the primary tumor was resected, just as Wang et al. ( 2014 2014 ) found that a high expression level of CXCR4 correlated with brain-specific metastasis following complete resection of NSCLC. In addition, the axis can promote cell proliferation, tumor growth, and angiogenesis (Phillips et al., 2003 2003 ; Wald et al., 2011 2011 ), and CXCR4 also appears to have an effect on the biology of cancer stem cells, which possess high self-renewal capacities, potential recapitulation of tumors in ectopic settings, and drug-resistant properties in NSCLC (Eramo et al., 2008 2008 ; Wald et al., 2011 2011 ). NSCLC cells expressing CXCR4 are strong candidates for those stem cells that maintain their property of self-renewal through a CXCR4-mediated signal transducer and activator of transcription 3 (STAT3) pathway (Jung et al., 2013 2013 ). In addition, CXCR4 might act to the transcriptional factor 5T4 downstream in EMT and consequently in migration (Damelin et al., 2011 2011 ). Hence, high expression of CXCL12/CXCR4 is correlated with poor prognosis in NSCLC (Suzuki et al., 2008 2008 ), and a substantial body of literature supports the fact that interruption of this ligand-receptor interaction can inhibit cancer cell migration and metastasis (Burger and Kipps, 2006 2006 ; Sun et al., 2010 2010 ; Xie et al., 2014 2014 ). Besides the above, some co-expression proteins and receptors can produce synergistic effects. Nrf2, a key transcriptional factor, regulates antioxidant response to accumulated oxidative reaction with tumor growth (Bauer et al., 2013 2013 ). Its abnormal expression, together with CXCR4, was noticed to contribute to large tumor size, poor differentiation, an advanced TNM stage, lymph node metastasis, and distant metastasis in NSCLC (Hu et al., 2014 2014 ). However, the mechanism underlying this needs to be elaborated. Concomitant overexpression of EGFR and CXCR4 is associated with a worse prognosis in NSCLC, and EGFR can enhance the expression of CXCR4 in NSCLC cells through the PI-3K pathway (Al Zobair et al., 2013 2013 ). Urokinase plasminogen activator receptor (uPAR), a glycoprotein of the Ly-6 family, takes effect in tumorigenesis (Ploug and Ellis, 1994 1994 ; Dass et al., 2008 2008 ). In human malignancies, uPAR overexpression is associated with an increased propensity for cancer progression and metastasis (Mazar, 2008 2008 ), and intact uPAR and its cleaved forms are testified to be associated with poor prognosis in NSCLC and SCLC (Almasi et al., 2013 2013 ). uPAR could interfere in CXCR4 activity and regulate the adhesive and migratory ability of CXCR4-expressing cells (Montuori et al., 2011 2011 ). Co-expression of uPAR and CXCR4 promotes tumor growth and metastasis in SCLC (Li and Tai, 2014 2014 ). Therefore, the role of the CXCL12/CXCR4 axis in lung tumor progression and metastasis can be enhanced when these proteins are aberrantly co-expressed. Targeting these proteins together with the CXCL12/CXCR4 axis would hamper lung cancer progression. Ubiquitin/CXCR4 1 Ubiquitin (Ub), a post-translational protein modifier inside the cell, was detected in increased concentrations during various disease processes (Majetschak, 2011 2011 ). Extracellular Ub, a recently identified new ligand for CXCR4, was found to act as an anti-inflammatory immune modulator in hematopoietic cells, and to induce suppressive and apoptotic effects on these cells (Saini et al., 2010 2010 ; Majetschak, 2011 2011 ). Recent studies on the potential role of extracellular Ub in non-hematological cells found that it had anti-apoptotic effects via activation of the PI3K pathway and was related to cell migration in epithelial cells. To date, only a few investigations have been carried out on the Ub-CXCR4 axis, which showed that it played an important part in acute lung infection-enhanced lung tumor metastasis (Majetschak, 2011 2011 ; Yan et al., 2013 2013 ). Nevertheless, the effect on human lung tumors with or without acute inflammation setting of the axis should be further investigated and the mechanism should be elucidated in the future. CXCL1/CXCR2 1 CXCL1, also called growth-related oncogene protein-α (GRO-α) or melanoma growth stimulatory activity factor (MGSA), is a polypeptide initially isolated from Hs294 human melanoma cells, and belongs to the Glu-Leu-Arg (ELR+) chemokine family that is primarily chemotactic for endothelial cells and neutrophils. These chemokines are potent promoters of angiogenesis by recruiting neutrophils to synthesize and store angiogenic molecules like vascular endothelial growth factors (VEGFs) (Scapini et al., 2004 2004 ), which can induce CXCL1 release via JNK and PI-3K-dependent pathways in human lung carcinoma epithelial cells (Lo et al., 2013 2013 ). CXCL1 was also found to play a pivotal role in thrombin-induced angiogenesis (Caunt et al., 2006 2006 ). CXCR2, a member of GPCRs, is the receptor of ELR+CXC chemokines such as CXCL1, CXCL2, CXCL3, CXCL5, and CXCL7 (PPBP). CXCL6 and CXCL8 (interleukin-8 (IL-8)) are shared ligands of CXCR1 and CXCR2. Alveolar epithelial cells transformed by oncogenic KRAS were reported to express high levels of CXCR2 ligands, which recruited inflammatory and endothelial cells and promoted progression of premalignant alveolar lesions to lung adenocarcinoma (Wislez et al., 2006 2006 ), and biopsy specimens of NSCLC had also been found to express high concentrations of CXCR2 ligands (CXCL1, CXCL5, and CXCL8) and type-2 cytokines (IL-4, IL-5, IL-10, and IL-13) (Arenberg et al., 1998 1998 ). NSCLC cell lines and lung adenocarcinomas expressing CXCR2 were noticed to be associated with smoking, CXCL5 expression and poor prognosis by promoting invasion and metastasis (Saintigny et al., 2013 2013 ). In addition, IL-17 was reported to augment secretion of an array of angiogenic CXC chemokines, including CXCL1, CXCL5, CXCL6, and CXCL8 by three different NSCLC cell lines (Numasaki et al., 2005 2005 ), and activation of the IL-8/CXCR2 axis, followed by neutrophils recruitments and eutrophil elastase release, was found to promote lung tumorigenesis in the inflammation settings (Gong et al., 2013 2013 ). The role of CXCR2 in tumor cells is debatable. Some studies have shown that it could promote cell proliferation, migration, and invasion (Luppi et al., 2007 2007 ; Sun et al., 2008 2008 ; Yanagawa et al., 2009 2009 ) and also assist cancer cells in evading stress-induced apoptosis (Maxwell et al., 2007 2007 ), suggesting that it is a poor prognostic factor, while others have reported recently that depletion of CXCR2 could not only delay replicative senescence but also impair the senescence response to oncogenic signals, suggesting its role in tumor suppression (Acosta et al., 2008 2008 ). Hence, more studies should be conducted to testify the exact role of this axis hereafter. CCL2/CCR2 1 CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), interacts with its receptor CCR2 and then takes effect not only on mediation of monocytes recruitment during inflammation and immunological reaction, but also on tumor progression and metastasis (Kudo-Saito et al., 2013 2013 ). Investigations from human lung adenocarcinoma cells showed that the expression of MCP-1/CCL2 was induced by activation of protease-activated receptor 2 (PAR2) through matrix metalloproteinase-1 (MMP-1) release which was mediated by the thromboxane A2 receptor (Li and Tai, 2014 2014 ), and activation of the latter receptor could increase the expression of MCP-1/CCL2 and recruit macrophages, thereby promoting lung cancer invasion (Li and Tai, 2013 2013 ). In addition, it has been recently reported that the CCL2/CCR2 axis could activate STAT3-Twist signaling corporately and subsequently enhance EMT induced by IL-6 (Chen et al., 2015 2015 ), thus leading to lung cancer metastasis. Nevertheless, a study of 134 NSCLC surgical specimens revealed that MCP-1/CCL2 was detected much more than CCR2 with no positive correlation, and overexpression of MCP-1/CCL2 was a good independent prognostic factor for NSCLC patients (Zhang X.W. et al., 2013 2013 ). Therefore, more studies are warranted to testify the real role of this axis in human lung cancers. CCL19/21/CCR7 1 CCR7, another member of GPCRs, has two ligands, CCL19 and CCL21, is preferentially expressed on naive T cells and mature dendritic cells (DCs), and binds to its ligands in promotion of migration, invasion, and chemotaxis of some cells, including T cells, B cells, natural killer (NK) cells, mature DCs, and some tumor cells (Ding et al., 2003 2003 ; Iijima et al., 2005 2005 ). Overexpression of CCR7 was demonstrated to closely correlate with invasion and metastasis of NSCLC in most investigations (Muller et al., 2001 2001 ; Cabioglu et al., 2007 2007 ), and the underlying mechanism might be up-regulation of heparanase via specificity protein-1 (Sp1) to promote invasion (Zhang Q. et al., 2013 2013 ). However, other studies found that CCL19 had an antitumor effect with corroboration of its promoting interferon (IFN)-γ-dependent antitumor responses in a lung cancer model (Hillinger et al., 2003 2003 ; Cao et al., 2007 2007 ); and high CCR7 expression was strongly related to CrkL and c-ABL kinase mRNA expression and could improve postoperative prognosis of lung adenocarcinoma patients (Itakura et al., 2013 2013 ). In addition, a phase-1 clinical trial of immunotherapy found that DCs expressing CCR7 receptor ligand CCL21 administrated into lung tumors could enhance immunity and subsequently make the tumor shrink (Sharma et al., 2013 2013 ). Consequently, this chemokine axis is like a double-edged sword acting for both good and bad according to the particular microenvironment during lung cancer progression and metastasis. CCL25/CCR9 1 The natural ligand of CCR9, CCL25, is a thymus-expressed chemokine, which has been found primarily in the involvement of immune homeostasis and then in human solid tumors such as colorectal, prostate, ovarian, and breast cancers with relation to tumor invasion and metastasis (Singh et al., 2004 2004 ; Svensson and Agace, 2006 2006 ; Johnson-Holiday et al., 2011 2011 ; Singh et al., 2011 2011 ; Chen et al., 2012 2012 ). However, the study of the CCL25/CCR9 axis on lung cancer is limited; so far, only one study has found that its expression correlated with aggressiveness and mediated key steps of metastasis in clinical samples and cell lines of NSCLC, especially in adenocarcinomas compared with squamous cell carcinomas, due to differential expression of matrix metalloproteinases and tissue inhibitor of metalloproteinases under the influence of CCL25 (Gupta et al., 2014 2014 ). Further and more studies are needed to explore the exact effect of the CCL25/CCR9 axis on lung cancer. If it does act as a pro-metastasis factor, targeting it would be of assistance in comprehensive tumor treatments. CCL4/CCR5 1 CCL4, the ligand of CCR5, was found to enhance expression of stromal-derived factor-erythroid differentiation regulator 1 (ERDR1), which could promote cancer cell survival. CCR5 on pulmonary mesenchymal cells could promote experimental metastasis via the induction of ERDR1 (Mango et al., 2014 2014 ), while deficiency of CCR5 suppressed tumor development by means of inactivation of nuclear factor-κB (NF-κB) and inhibition of monocyte chemoattractant protein-1 (MCP-1) in an urethane-induced lung tumor model (Lee et al., 2012 2012 ). Accordingly, the CCL4/CCR5 axis seems to play a role in lung tumor progression and metastasis. Investigations of lung cancer patients should be conducted to test the effect in the future. Atypical chemokine receptors 1 Atypical chemokine receptors including three members, the Duffy antigen receptor for chemokines (DARC), D6, and the ChemocentryX chemokine receptor (CCX-CKR), differ from other typical chemokine receptors, because they can efficiently internalize their cognate chemokine ligands without inducing a signaling cascade acting as chemokine scavengers. In lung cancer, DARC-expressing A549 cells were observed to have a significant reduction in cellularity, increased levels of necrosis, lower microvessel density, and decreased metastasis (Addison et al., 2004 2004 ). D6 could inhibit human NSCLC growth by sequestration of some chemokines like CCL2, CCL4, and CCL5 (Wu et al., 2013 2013 ). It was reported that CCX-CKR acted as a negative regulator of growth and metastasis in breast cancer mainly by sequestration of homeostatic chemokines such as CCL19, CCL21, CCL25, and CXCL13, and subsequent inhibition of intratumoral neovascularity (Feng et al., 2009 2009 ). However, studies on CCX-CKR expression status and its relation to tumor progression and invasion are lacking for lung cancer to date. Conclusions 1 In conclusion, a group of chemokines and their receptors are aberrantly expressed during lung tumorigenesis, progression, and metastasis, leading to an unbalance of the tumor microenvironment. Overexpressed pro-tumor chemokines and receptors are correlated with poor prognosis, and thus diagnoses and treatments targeted at them could bring a bright future for lung cancer patients. Although normally expressed anti-tumor chemokines and their receptors may be correlated with better prognosis, further studies are needed to elucidate them for human lung cancers and translate this into clinical utilization. References JC Acosta , A O'Loghlen , A Banito , 等 . Chemokine signaling via the CXCR2 receptor reinforces senescence . Cell , 2008 . 133 ( 6 ): 1006 - 1018 . (Available from: http://dx.doi.org/10.1016/j.cell.2008.03.038 http://dx.doi.org/10.1016/j.cell.2008.03.038 ) . Chemokine signaling via the CXCR2 receptor reinforces senescence CL Addison , JA Belperio , MD Burdick , 等 . Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis . BMC Cancer , 2004 . 4 ( 1 ): 28 (Available from: http://dx.doi.org/10.1186/1471-2407-4-28 http://dx.doi.org/10.1186/1471-2407-4-28 ) . Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis CE Almasi , L Drivsholm , H Pappot , 等 . The liberated domain I of urokinase plasminogen activator receptor–a new tumour marker in small cell lung cancer . APMIS , 2013 . 121 ( 3 ): 189 - 196 . (Available from: http://dx.doi.org/10.1111/j.1600-0463.2012.02955.x http://dx.doi.org/10.1111/j.1600-0463.2012.02955.x ) . The liberated domain I of urokinase plasminogen activator receptor–a new tumour marker in small cell lung cancer AA Al Zobair , BF Al Obeidy , L Yang , 等 . Concomitant overexpression of EGFR and CXCR4 is associated with worse prognosis in a new molecular subtype of non-small cell lung cancer . Oncol Rep , 2013 . 29 ( 4 ): 1524 - 1532 . (Available from: http://dx.doi.org/10.3892/or.2013.2254 http://dx.doi.org/10.3892/or.2013.2254 ) . Concomitant overexpression of EGFR and CXCR4 is associated with worse prognosis in a new molecular subtype of non-small cell lung cancer DA Arenberg , MP Keane , B DiGiovine , 等 . Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer . J Clin Invest , 1998 . 102 ( 3 ): 465 - 472 . (Available from: http://dx.doi.org/10.1172/JCI3145 http://dx.doi.org/10.1172/JCI3145 ) . Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer F Balkwill . The significance of cancer cell expression of the chemokine receptor CXCR4 . Semin Cancer Biol , 2004 . 14 ( 3 ): 171 - 179 . (Available from: http://dx.doi.org/10.1016/j.semcancer.2003.10.003 http://dx.doi.org/10.1016/j.semcancer.2003.10.003 ) . The significance of cancer cell expression of the chemokine receptor CXCR4 AK Bauer , T Hill III , CM Alexander . The involvement of NRF2 in lung cancer . Oxid Med Cell Longev , 2013 . 2013 746432 (Available from: http://dx.doi.org/10.1155/2013/746432 http://dx.doi.org/10.1155/2013/746432 ) . The involvement of NRF2 in lung cancer JA Belperio , RJ Phillips , MD Burdick , 等 . The SDF-1/CXCL 12/CXCR4 biological axis in non-small cell lung cancer metastases . Chest , 2004 . 125 ( Suppl. 5 ): 156S (Available from: http://dx.doi.org/10.1378/chest.125.5_suppl.156S http://dx.doi.org/10.1378/chest.125.5_suppl.156S ) . The SDF-1/CXCL 12/CXCR4 biological axis in non-small cell lung cancer metastases JA Burger , TJ Kipps . CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment . Blood , 2006 . 107 ( 5 ): 1761 - 1767 . (Available from: http://dx.doi.org/10.1182/blood-2005-08-3182 http://dx.doi.org/10.1182/blood-2005-08-3182 ) . CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment JA Burger , JG Gribben . The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies . Semin Cancer Biol , 2014 . 24 71 - 81 . (Available from: http://dx.doi.org/10.1016/j.semcancer.2013.08.011 http://dx.doi.org/10.1016/j.semcancer.2013.08.011 ) . The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies JA Burger , DJ Stewart , O Wald , 等 . Potential of CXCR4 antagonists for the treatment of metastatic lung cancer . Expert Rev Anticancer Ther , 2011 . 11 ( 4 ): 621 - 630 . (Available from: http://dx.doi.org/10.1586/era.11.11 http://dx.doi.org/10.1586/era.11.11 ) . Potential of CXCR4 antagonists for the treatment of metastatic lung cancer N Cabioglu , Y Gong , R Islam , 等 . Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer . Ann Oncol , 2007 . 18 ( 6 ): 1021 - 1029 . (Available from: http://dx.doi.org/10.1093/annonc/mdm060 http://dx.doi.org/10.1093/annonc/mdm060 ) . Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer M Cao , HX Deng , J Zhao , 等 . Antitumour activity of cationic-liposome-conjugated adenovirus containing the CCL19 [chemokine (C-C motif) ligand 19] gene . Biotechnol Appl Biochem , 2007 . 48 ( 2 ): 109 - 116 . . Antitumour activity of cationic-liposome-conjugated adenovirus containing the CCL19 [chemokine (C-C motif) ligand 19] gene M Caunt , L Hu , T Tang , 等 . Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis . Cancer Res , 2006 . 66 ( 8 ): 4125 - 4132 . (Available from: http://dx.doi.org/10.1158/0008-5472.CAN-05-2570 http://dx.doi.org/10.1158/0008-5472.CAN-05-2570 ) . Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis HJ Chen , R Edwards , S Tucci , 等 . Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis . J Clin Invest , 2012 . 122 ( 9 ): 3184 - 3196 . (Available from: http://dx.doi.org/10.1172/JCI62110 http://dx.doi.org/10.1172/JCI62110 ) . Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis W Chen , Q Gao , S Han , 等 . The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling . Tumour Biol , 2015 . 36 ( 2 ): 973 - 981 . (Available from: http://dx.doi.org/10.1007/s13277-014-2717-z http://dx.doi.org/10.1007/s13277-014-2717-z ) . The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling M Damelin , KG Geles , MT Follettie , 等 . Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells . Cancer Res , 2011 . 71 ( 12 ): 4236 - 4246 . (Available from: http://dx.doi.org/10.1158/0008-5472.CAN-10-3919 http://dx.doi.org/10.1158/0008-5472.CAN-10-3919 ) . Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells K Dass , A Ahmad , AS Azmi , 等 . Evolving role of uPA/uPAR system in human cancers . Cancer Treat Rev , 2008 . 34 ( 2 ): 122 - 136 . (Available from: http://dx.doi.org/10.1016/j.ctrv.2007.10.005 http://dx.doi.org/10.1016/j.ctrv.2007.10.005 ) . Evolving role of uPA/uPAR system in human cancers Y Ding , Y Shimada , M Maeda , 等 . Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma . Clin Cancer Res , 2003 . 9 ( 9 ): 3406 - 3412 . . Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma J Dong , J Dai , Y Shu , 等 . Polymorphisms in EGFR and VEGF contribute to non-small-cell lung cancer survival in a Chinese population . Carcinogenesis , 2010 . 31 ( 6 ): 1080 - 1086 . (Available from: http://dx.doi.org/10.1093/carcin/bgq079 http://dx.doi.org/10.1093/carcin/bgq079 ) . Polymorphisms in EGFR and VEGF contribute to non-small-cell lung cancer survival in a Chinese population A Eramo , F Lotti , G Sette , 等 . Identification and expansion of the tumorigenic lung cancer stem cell population . Cell Death Differ , 2008 . 15 ( 3 ): 504 - 514 . (Available from: http://dx.doi.org/10.1038/sj.cdd.4402283 http://dx.doi.org/10.1038/sj.cdd.4402283 ) . Identification and expansion of the tumorigenic lung cancer stem cell population LY Feng , ZL Ou , FY Wu , 等 . Involvement of a novel chemokine decoy receptor CCX-CKR in breast cancer growth, metastasis and patient survival . Clin Cancer Res , 2009 . 15 ( 9 ): 2962 - 2970 . (Available from: http://dx.doi.org/10.1158/1078-0432.CCR-08-2495 http://dx.doi.org/10.1158/1078-0432.CCR-08-2495 ) . Involvement of a novel chemokine decoy receptor CCX-CKR in breast cancer growth, metastasis and patient survival P Goldstraw , J Crowley , K Chansky , 等 . The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of Malignant Tumours . J Thorac Oncol , 2007 . 2 ( 8 ): 706 - 714 . (Available from: http://dx.doi.org/10.1097/JTO.0b013e31812f3c1a http://dx.doi.org/10.1097/JTO.0b013e31812f3c1a ) . The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of Malignant Tumours L Gong , AM Cumpian , MS Caetano , 等 . Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase . Mol Cancer , 2013 . 12 ( 1 ): 154 (Available from: http://dx.doi.org/10.1186/1476-4598-12-154 http://dx.doi.org/10.1186/1476-4598-12-154 ) . Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase PA Groome , V Bolejack , JJ Crowley , 等 . The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours . J Thorac Oncol , 2007 . 2 ( 8 ): 694 - 705 . (Available from: http://dx.doi.org/10.1097/JTO.0b013e31812d05d5 http://dx.doi.org/10.1097/JTO.0b013e31812d05d5 ) . The IASLC Lung Cancer Staging Project: validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours P Gupta , PK Sharma , H Mir , 等 . CCR9/CCL25 expression in non-small cell lung cancer correlates with aggressive disease and mediates key steps of metastasis . Oncotarget , 2014 . 5 ( 20 ): 10170 - 10179 . (Available from: http://dx.doi.org/10.18632/oncotarget.2526 http://dx.doi.org/10.18632/oncotarget.2526 ) . CCR9/CCL25 expression in non-small cell lung cancer correlates with aggressive disease and mediates key steps of metastasis S Hillinger , SC Yang , L Zhu , 等 . EBV-induced molecule 1 ligand chemokine (ELC/CCL19) promotes IFN-γ-dependent antitumor responses in a lung cancer model . J Immunol , 2003 . 171 ( 12 ): 6457 - 6465 . (Available from: http://dx.doi.org/10.4049/jimmunol.171.12.6457 http://dx.doi.org/10.4049/jimmunol.171.12.6457 ) . EBV-induced molecule 1 ligand chemokine (ELC/CCL19) promotes IFN-γ-dependent antitumor responses in a lung cancer model T Hu , Y Yao , S Yu , 等 . CXCR4 and Nrf2 expressions in non-small cell lung cancer and their clinical implications . J South Med Univ , 2014 . 34 ( 2 ): 153 - 158 . . CXCR4 and Nrf2 expressions in non-small cell lung cancer and their clinical implications N Iijima , Y Yanagawa , JM Clingan , 等 . CCR7-mediated c-Jun N-terminal kinase activation regulates cell migration in mature dendritic cells . Int Immunol , 2005 . 17 ( 9 ): 1201 - 1212 . (Available from: http://dx.doi.org/10.1093/intimm/dxh297 http://dx.doi.org/10.1093/intimm/dxh297 ) . CCR7-mediated c-Jun N-terminal kinase activation regulates cell migration in mature dendritic cells M Itakura , Y Terashima , M Shingyoji , 等 . High CC chemokine receptor 7 expression improves postoperative prognosis of lung adenocarcinoma patients . Br J Cancer , 2013 . 109 ( 5 ): 1100 - 1108 . (Available from: http://dx.doi.org/10.1038/bjc.2013.440 http://dx.doi.org/10.1038/bjc.2013.440 ) . High CC chemokine receptor 7 expression improves postoperative prognosis of lung adenocarcinoma patients C Johnson-Holiday , R Singh , E Johnson , 等 . CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion . Int J Oncol , 2011 . 38 ( 5 ): 1279 - 1285 . (Available from: http://dx.doi.org/10.3892/ijo.2011.953 http://dx.doi.org/10.3892/ijo.2011.953 ) . CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion MJ Jung , JK Rho , YM Kim , 等 . Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells . Oncogene , 2013 . 32 ( 2 ): 209 - 221 . (Available from: http://dx.doi.org/10.1038/onc.2012.37 http://dx.doi.org/10.1038/onc.2012.37 ) . Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells EC Keeley , B Mehrad , RM Strieter . Chemokines as mediators of tumor angiogenesis and neovascularization . Exp Cell Res , 2011 . 317 ( 5 ): 685 - 690 . (Available from: http://dx.doi.org/10.1016/j.yexcr.2010.10.020 http://dx.doi.org/10.1016/j.yexcr.2010.10.020 ) . Chemokines as mediators of tumor angiogenesis and neovascularization RL Keith , YE Miller . Lung cancer chemoprevention: current status and future prospects . Nat Rev Clin Oncol , 2013 . 10 ( 6 ): 334 - 343 . (Available from: http://dx.doi.org/10.1038/nrclinonc.2013.64 http://dx.doi.org/10.1038/nrclinonc.2013.64 ) . Lung cancer chemoprevention: current status and future prospects C Kudo-Saito , H Shirako , M Ohike , 等 . CCL2 is critical for immunosuppression to promote cancer metastasis . Clin Exp Metastasis , 2013 . 30 ( 4 ): 393 - 405 . (Available from: http://dx.doi.org/10.1007/s10585-012-9545-6 http://dx.doi.org/10.1007/s10585-012-9545-6 ) . CCL2 is critical for immunosuppression to promote cancer metastasis NJ Lee , DY Choi , JK Song , 等 . Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-κB and inhibition of monocyte chemoattractant protein-1 in urethane-induced lung tumor model . Carcinogenesis , 2012 . 33 ( 12 ): 2520 - 2528 . (Available from: http://dx.doi.org/10.1093/carcin/bgs265 http://dx.doi.org/10.1093/carcin/bgs265 ) . Deficiency of C-C chemokine receptor 5 suppresses tumor development via inactivation of NF-κB and inhibition of monocyte chemoattractant protein-1 in urethane-induced lung tumor model X Li , HH Tai . Activation of thromboxane A2 receptor (TP) increases the expression of monocyte chemoattractant protein-1 (MCP-1)/chemokine (C-C motif) ligand 2 (CCL2) and recruits macrophages to promote invasion of lung cancer cells . PLoS ONE , 2013 . 8 ( 1 ): e54073 . Activation of thromboxane A2 receptor (TP) increases the expression of monocyte chemoattractant protein-1 (MCP-1)/chemokine (C-C motif) ligand 2 (CCL2) and recruits macrophages to promote invasion of lung cancer cells X Li , HH Tai . Thromboxane A2 receptor-mediated release of matrix metalloproteinase-1 (MMP-1) induces expression of monocyte chemoattractant protein-1 (MCP-1) by activation of protease-activated receptor 2 (PAR2) in A549 human lung adenocarcinoma cells . Mol Carcinog , 2014 . 53 ( 8 ): 659 - 666 . . Thromboxane A2 receptor-mediated release of matrix metalloproteinase-1 (MMP-1) induces expression of monocyte chemoattractant protein-1 (MCP-1) by activation of protease-activated receptor 2 (PAR2) in A549 human lung adenocarcinoma cells Y Li , Y Shen , Y Miao , 等 . Co-expression of uPAR and CXCR4 promotes tumor growth and metastasis in small cell lung cancer . Int J Clin Exp Pathol , 2014 . 7 ( 7 ): 3771 - 3780 . . Co-expression of uPAR and CXCR4 promotes tumor growth and metastasis in small cell lung cancer HM Lo , JM Shieh , CL Chen , 等 . Vascular endothelial growth factor induces CXCL1 chemokine release via JNK and PI-3K-dependent pathways in human lung carcinoma epithelial cells . Int J Mol Sci , 2013 . 14 ( 5 ): 10090 - 10106 . (Available from: http://dx.doi.org/10.3390/ijms140510090 http://dx.doi.org/10.3390/ijms140510090 ) . Vascular endothelial growth factor induces CXCL1 chemokine release via JNK and PI-3K-dependent pathways in human lung carcinoma epithelial cells F Luppi , AM Longo , WI de Boer , 等 . Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation . Lung Cancer , 2007 . 56 ( 1 ): 25 - 33 . (Available from: http://dx.doi.org/10.1016/j.lungcan.2006.11.014 http://dx.doi.org/10.1016/j.lungcan.2006.11.014 ) . Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation M Majetschak . Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules . J Leukoc Biol , 2011 . 89 ( 2 ): 205 - 219 . (Available from: http://dx.doi.org/10.1189/jlb.0510316 http://dx.doi.org/10.1189/jlb.0510316 ) . Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules RL Mango , QP Wu , M West , 等 . C-C chemokine receptor 5 on pulmonary mesenchymal cells promotes experimental metastasis via the induction of erythroid differentiation regulator 1 . Mol Cancer Res , 2014 . 12 ( 2 ): 274 - 282 . (Available from: http://dx.doi.org/10.1158/1541-7786.MCR-13-0164 http://dx.doi.org/10.1158/1541-7786.MCR-13-0164 ) . C-C chemokine receptor 5 on pulmonary mesenchymal cells promotes experimental metastasis via the induction of erythroid differentiation regulator 1 A Mantovani , B Savino , M Locati , 等 . The chemokine system in cancer biology and therapy . Cytokine Growth Factor Rev , 2010 . 21 ( 1 ): 27 - 39 . (Available from: http://dx.doi.org/10.1016/j.cytogfr.2009.11.007 http://dx.doi.org/10.1016/j.cytogfr.2009.11.007 ) . The chemokine system in cancer biology and therapy PJ Maxwell , R Gallagher , A Seaton , 等 . HIF-1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells . Oncogene , 2007 . 26 ( 52 ): 7333 - 7345 . (Available from: http://dx.doi.org/10.1038/sj.onc.1210536 http://dx.doi.org/10.1038/sj.onc.1210536 ) . HIF-1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells AP Mazar . Urokinase plasminogen activator receptor choreographs multiple ligand interactions: implications for tumor progression and therapy . Clin Cancer Res , 2008 . 14 ( 18 ): 5649 - 5655 . (Available from: http://dx.doi.org/10.1158/1078-0432.CCR-07-4863 http://dx.doi.org/10.1158/1078-0432.CCR-07-4863 ) . Urokinase plasminogen activator receptor choreographs multiple ligand interactions: implications for tumor progression and therapy N Montuori , K Bifulco , MV Carriero , 等 . The cross-talk between the urokinase receptor and fMLP receptors regulates the activity of the CXCR4 chemokine receptor . Cell Mol Life Sci , 2011 . 68 ( 14 ): 2453 - 2467 . (Available from: http://dx.doi.org/10.1007/s00018-010-0564-7 http://dx.doi.org/10.1007/s00018-010-0564-7 ) . The cross-talk between the urokinase receptor and fMLP receptors regulates the activity of the CXCR4 chemokine receptor N Mukaida , T Baba . Chemokines in tumor development and progression . Exp Cell Res , 2012 . 318 ( 2 ): 95 - 102 . (Available from: http://dx.doi.org/10.1016/j.yexcr.2011.10.012 http://dx.doi.org/10.1016/j.yexcr.2011.10.012 ) . Chemokines in tumor development and progression A Muller , B Homey , H Soto , 等 . Involvement of chemokine receptors in breast cancer metastasis . Nature , 2001 . 410 ( 6824 ): 50 - 56 . (Available from: http://dx.doi.org/10.1038/35065016 http://dx.doi.org/10.1038/35065016 ) . Involvement of chemokine receptors in breast cancer metastasis National Lung Screening Trial Research Reduced lung-cancer mortality with low-dose computed tomographic screening . N Engl J Med , 2011 . 365 ( 5 ): 395 - 409 . (Available from: http://dx.doi.org/10.1056/NEJMoa1102873 http://dx.doi.org/10.1056/NEJMoa1102873 ) . Reduced lung-cancer mortality with low-dose computed tomographic screening M Numasaki , M Watanabe , T Suzuki , 等 . IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis . J Immunol , 2005 . 175 ( 9 ): 6177 - 6189 . (Available from: http://dx.doi.org/10.4049/jimmunol.175.9.6177 http://dx.doi.org/10.4049/jimmunol.175.9.6177 ) . IL-17 enhances the net angiogenic activity and in vivo growth of human non-small cell lung cancer in SCID mice through promoting CXCR-2-dependent angiogenesis A Peled , O Wald , J Burger . Development of novel CXCR4-based therapeutics . Expert Opin Investig Drugs , 2012 . 21 ( 3 ): 341 - 353 . (Available from: http://dx.doi.org/10.1517/13543784.2012.656197 http://dx.doi.org/10.1517/13543784.2012.656197 ) . Development of novel CXCR4-based therapeutics RJ Phillips , MD Burdick , M Lutz , 等 . The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases . Am J Respir Crit Care Med , 2003 . 167 ( 12 ): 1676 - 1686 . (Available from: http://dx.doi.org/10.1164/rccm.200301-071OC http://dx.doi.org/10.1164/rccm.200301-071OC ) . The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases RJ Phillips , J Mestas , M Gharaee-Kermani , 等 . Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1α . J Biol Chem , 2005 . 280 ( 23 ): 22473 - 22481 . . Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1α M Ploug , V Ellis . Structure-function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom α-neurotoxins . FEBS Lett , 1994 . 349 ( 2 ): 163 - 168 . . Structure-function relationships in the receptor for urokinase-type plasminogen activator. Comparison to other members of the Ly-6 family and snake venom α-neurotoxins A Richmond . Nf-κB, chemokine gene transcription and tumour growth . Nat Rev Immunol , 2002 . 2 ( 9 ): 664 - 674 . (Available from: http://dx.doi.org/10.1038/nri887 http://dx.doi.org/10.1038/nri887 ) . Nf-κB, chemokine gene transcription and tumour growth V Saini , A Marchese , M Majetschak . CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin . J Biol Chem , 2010 . 285 ( 20 ): 15566 - 15576 . (Available from: http://dx.doi.org/10.1074/jbc.M110.103408 http://dx.doi.org/10.1074/jbc.M110.103408 ) . CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin P Saintigny , JA Burger . Recent advances in non-small cell lung cancer biology and clinical management . Discov Med , 2012 . 13 ( 71 ): 287 - 297 . . Recent advances in non-small cell lung cancer biology and clinical management P Saintigny , E Massarelli , S Lin , 等 . CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma . Cancer Res , 2013 . 73 ( 2 ): 571 - 582 . (Available from: http://dx.doi.org/10.1158/0008-5472.CAN-12-0263 http://dx.doi.org/10.1158/0008-5472.CAN-12-0263 ) . CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma PJ Sarvaiya , D Guo , I Ulasov , 等 . Chemokines in tumor progression and metastasis . Oncotarget , 2013 . 4 ( 12 ): 2171 - 2185 . . Chemokines in tumor progression and metastasis P Scapini , M Morini , C Tecchio , 等 . CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A . J Immunol , 2004 . 172 ( 8 ): 5034 - 5040 . . CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A T Schioppa , B Uranchimeg , A Saccani , 等 . Regulation of the chemokine receptor CXCR4 by hypoxia . J Exp Med , 2003 . 198 ( 9 ): 1391 - 1402 . (Available from: http://dx.doi.org/10.1084/jem.20030267 http://dx.doi.org/10.1084/jem.20030267 ) . Regulation of the chemokine receptor CXCR4 by hypoxia S Sharma , L Zhu , MK Srivastava , 等 . CCL21 chemokine therapy for lung cancer . Int Trends Immun , 2013 . 1 ( 1 ): 10 - 15 . . CCL21 chemokine therapy for lung cancer R Siegel , D Naishadham , A Jemal . Cancer statistics, 2012 . CA Cancer J Clin , 2012 . 62 ( 1 ): 10 - 29 . (Available from: http://dx.doi.org/10.3322/caac.20138 http://dx.doi.org/10.3322/caac.20138 ) . Cancer statistics, 2012 R Siegel , C DeSantis , K Virgo , 等 . Cancer treatment and survivorship statistics, 2012 . CA Cancer J Clin , 2012 . 62 ( 4 ): 220 - 241 . (Available from: http://dx.doi.org/10.3322/caac.21149 http://dx.doi.org/10.3322/caac.21149 ) . Cancer treatment and survivorship statistics, 2012 R Singh , CR Stockard , WE Grizzle , 等 . Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer . Int J Oncol , 2011 . 39 ( 2 ): 373 - 381 . (Available from: http://dx.doi.org/10.3892/ijo.2011.1059 http://dx.doi.org/10.3892/ijo.2011.1059 ) . Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer S Singh , UP Singh , JK Stiles , 等 . Expression and functional role of CCR9 in prostate cancer cell migration and invasion . Clin Cancer Res , 2004 . 10 ( 24 ): 8743 - 8750 . (Available from: http://dx.doi.org/10.1158/1078-0432.CCR-04-0266 http://dx.doi.org/10.1158/1078-0432.CCR-04-0266 ) . Expression and functional role of CCR9 in prostate cancer cell migration and invasion A Sparmann , D Bar-Sagi . Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis . Cancer Cell , 2004 . 6 ( 5 ): 447 - 458 . (Available from: http://dx.doi.org/10.1016/j.ccr.2004.09.028 http://dx.doi.org/10.1016/j.ccr.2004.09.028 ) . Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis L Su , J Zhang , H Xu , 等 . Differential expression of CXCR4 is associated with the metastatic potential of human non-small cell lung cancer cells . Clin Cancer Res , 2005 . 11 ( 23 ): 8273 - 8280 . . Differential expression of CXCR4 is associated with the metastatic potential of human non-small cell lung cancer cells H Sun , WC Chung , SH Ryu , 等 . Cyclic AMP-responsive element binding protein- and nuclear factor-κB-regulated CXC chemokine gene expression in lung carcinogenesis . Cancer Prev Res (Phila) , 2008 . 1 ( 5 ): 316 - 328 . (Available from: http://dx.doi.org/10.1158/1940-6207.CAPR-07-0002 http://dx.doi.org/10.1158/1940-6207.CAPR-07-0002 ) . Cyclic AMP-responsive element binding protein- and nuclear factor-κB-regulated CXC chemokine gene expression in lung carcinogenesis X Sun , G Cheng , M Hao , 等 . CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression . Cancer Metastasis Rev , 2010 . 29 ( 4 ): 709 - 722 . (Available from: http://dx.doi.org/10.1007/s10555-010-9256-x http://dx.doi.org/10.1007/s10555-010-9256-x ) . CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression KD Sutherland , A Berns . Cell of origin of lung cancer . Mol Oncol , 2010 . 4 ( 5 ): 397 - 403 . (Available from: http://dx.doi.org/10.1016/j.molonc.2010.05.002 http://dx.doi.org/10.1016/j.molonc.2010.05.002 ) . Cell of origin of lung cancer M Suzuki , S Mohamed , T Nakajima , 等 . Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis . Int J Oncol , 2008 . 33 ( 1 ): 113 - 119 . . Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis M Svensson , WW Agace . Role of CCL25/CCR9 in immune homeostasis and disease . Expert Rev Clin Immunol , 2006 . 2 ( 5 ): 759 - 773 . (Available from: http://dx.doi.org/10.1586/1744666X.2.5.759 http://dx.doi.org/10.1586/1744666X.2.5.759 ) . Role of CCL25/CCR9 in immune homeostasis and disease PL Wagner , E Hyjek , MF Vazquez , 等 . CXCL12 and CXCR4 in adenocarcinoma of the lung: association with metastasis and survival . J Thorac Cardiovasc Surg , 2009 . 137 ( 3 ): 615 - 621 . (Available from: http://dx.doi.org/10.1016/j.jtcvs.2008.07.039 http://dx.doi.org/10.1016/j.jtcvs.2008.07.039 ) . CXCL12 and CXCR4 in adenocarcinoma of the lung: association with metastasis and survival O Wald , U Izhar , G Amir , 等 . Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: role in non-small cell lung cancer tumor proliferation . J Thorac Cardiovasc Surg , 2011 . 141 ( 6 ): 1503 - 1512 . (Available from: http://dx.doi.org/10.1016/j.jtcvs.2010.11.056 http://dx.doi.org/10.1016/j.jtcvs.2010.11.056 ) . Interaction between neoplastic cells and cancer-associated fibroblasts through the CXCL12/CXCR4 axis: role in non-small cell lung cancer tumor proliferation L Wang , Z Wang , X Liu , 等 . High-level C-X-C chemokine receptor type 4 expression correlates with brain-specific metastasis following complete resection of non-small cell lung cancer . Oncol Lett , 2014 . 7 ( 6 ): 1871 - 1876 . . High-level C-X-C chemokine receptor type 4 expression correlates with brain-specific metastasis following complete resection of non-small cell lung cancer M Wislez , N Fujimoto , JG Izzo , 等 . High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras . Cancer Res , 2006 . 66 ( 8 ): 4198 - 4207 . (Available from: http://dx.doi.org/10.1158/0008-5472.CAN-05-3842 http://dx.doi.org/10.1158/0008-5472.CAN-05-3842 ) . High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras FY Wu , J Fan , L Tang , 等 . Atypical chemokine receptor D6 inhibits human non-small cell lung cancer growth by sequestration of chemokines . Oncol Lett , 2013 . 6 ( 1 ): 91 - 95 . (Available from: http://dx.doi.org/10.3892/ol.2013.1358 http://dx.doi.org/10.3892/ol.2013.1358 ) . Atypical chemokine receptor D6 inhibits human non-small cell lung cancer growth by sequestration of chemokines S Xie , W Zeng , G Fan , 等 . Effect of CXCL12/CXCR4 on increasing the metastatic potential of non-small cell lung cancer is inhibited through the downregulation of CXCR4 chemokine receptor expression . Oncol Lett , 2014 . 7 ( 4 ): 941 - 947 . . Effect of CXCL12/CXCR4 on increasing the metastatic potential of non-small cell lung cancer is inhibited through the downregulation of CXCR4 chemokine receptor expression L Yan , Q Cai , Y Xu . The ubiquitin-CXCR4 axis plays an important role in acute lung infection-enhanced lung tumor metastasis . Clin Cancer Res , 2013 . 19 ( 17 ): 4706 - 4716 . (Available from: http://dx.doi.org/10.1158/1078-0432.CCR-13-0011 http://dx.doi.org/10.1158/1078-0432.CCR-13-0011 ) . The ubiquitin-CXCR4 axis plays an important role in acute lung infection-enhanced lung tumor metastasis J Yanagawa , TC Walser , LX Zhu , 等 . Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma . Clin Cancer Res , 2009 . 15 ( 22 ): 6820 - 6829 . (Available from: http://dx.doi.org/10.1158/1078-0432.CCR-09-1558 http://dx.doi.org/10.1158/1078-0432.CCR-09-1558 ) . Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma L Yang , L Li , Y Chen , 等 . Mortality time trends and the incidence and mortality estimation and projection for lung cancer in China . Chin J Lung Cancer , 2005 . 8 ( 4 ): 274 - 278 . . Mortality time trends and the incidence and mortality estimation and projection for lung cancer in China L Yang , DM Parkin , J Ferlay , 等 . Estimates of cancer incidence in China for 2000 and projections for 2005 . Cancer Epidemiol Biomarkers Prev , 2005 . 14 ( 1 ): 243 - 250 . . Estimates of cancer incidence in China for 2000 and projections for 2005 Q Zhang , L Sun , L Yin , 等 . CCL19/CCR7 upregulates heparanase via specificity protein-1 (Sp1) to promote invasion of cell in lung cancer . Tumour Biol , 2013 . 34 ( 5 ): 2703 - 2708 . (Available from: http://dx.doi.org/10.1007/s13277-013-0822-z http://dx.doi.org/10.1007/s13277-013-0822-z ) . CCL19/CCR7 upregulates heparanase via specificity protein-1 (Sp1) to promote invasion of cell in lung cancer XW Zhang , X Qin , CY Qin , 等 . Expression of monocyte chemoattractant protein-1 and CC chemokine receptor 2 in non-small cell lung cancer and its significance . Cancer Immunol Immunother , 2013 . 62 ( 3 ): 563 - 570 . (Available from: http://dx.doi.org/10.1007/s00262-012-1361-y http://dx.doi.org/10.1007/s00262-012-1361-y ) . Expression of monocyte chemoattractant protein-1 and CC chemokine receptor 2 in non-small cell lung cancer and its significance A Zlotnik , O Yoshie . Chemokines: a new classification system and their role in immunity . Immunity , 2000 . 12 ( 2 ): 121 - 127 . . Chemokines: a new classification system and their role in immunity Compliance with ethics guidelines Zeng-hui CHENG, Yu-xin SHI, Min YUAN, Dan XIONG, Jiang-hua ZHENG, and Zhi-yong ZHANG declare that they have no conflict of interest. This article does not contain any studies with human or animal subjects performed by any of the authors. 10.1631/jzus.B1500258 Project supported by the Science and Technology Commission of Shanghai Municipality (No. 14140901400), the Natural Science Foundation of Shanghai (No. 13ZR1435000), and the National Natural Science Foundation of China (No. 81372318) 2015-10-27 2016-04-15 2016-01-05 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2016 2016 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 05 17