Abstract: 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.

趋化因子及其受体在肺癌侵袭与转移过程中的作用

[1]Acosta, J.C., O'Loghlen, A., Banito, A., et al., 2008. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell, 133(6):1006-1018.

[2]Addison, C.L., Belperio, J.A., Burdick, M.D., et al., 2004. Overexpression of the duffy antigen receptor for chemokines (DARC) by NSCLC tumor cells results in increased tumor necrosis. BMC Cancer, 4(1):28.

[3]Almasi, C.E., Drivsholm, L., Pappot, H., et al., 2013. The liberated domain I of urokinase plasminogen activator receptor—a new tumour marker in small cell lung cancer. APMIS, 121(3):189-196.

[4]Al Zobair, A.A., Al Obeidy, B.F., Yang, L., et al., 2013. Concomitant overexpression of EGFR and CXCR4 is associated with worse prognosis in a new molecular subtype of non-small cell lung cancer. Oncol. Rep., 29(4):1524-1532.

[5]Arenberg, D.A., Keane, M.P., DiGiovine, B., et al., 1998. Epithelial-neutrophil activating peptide (ENA-78) is an important angiogenic factor in non-small cell lung cancer. J. Clin. Invest., 102(3):465-472.

[6]Balkwill, F., 2004. The significance of cancer cell expression of the chemokine receptor CXCR4. Semin. Cancer Biol., 14(3):171-179.

[7]Bauer, A.K., Hill III, T., Alexander, C.M., 2013. The involvement of NRF2 in lung cancer. Oxid. Med. Cell. Longev., 2013:746432.

[8]Belperio, J.A., Phillips, R.J., Burdick, M.D., et al., 2004. The SDF-1/CXCL 12/CXCR4 biological axis in non-small cell lung cancer metastases. Chest, 125(Suppl. 5):156S.

[9]Burger, J.A., Kipps, T.J., 2006. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood, 107(5):1761-1767.

[10]Burger, J.A., Gribben, J.G., 2014. The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: insight into disease biology and new targeted therapies. Semin. Cancer Biol., 24:71-81.

[11]Burger, J.A., Stewart, D.J., Wald, O., et al., 2011. Potential of CXCR4 antagonists for the treatment of metastatic lung cancer. Expert Rev. Anticancer Ther., 11(4):621-630.

[12]Cabioglu, N., Gong, Y., Islam, R., et al., 2007. Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer. Ann. Oncol., 18(6):1021-1029.

[13]Cao, M., Deng, H.X., Zhao, J., et al., 2007. Antitumour activity of cationic-liposome-conjugated adenovirus containing the CCL19 [chemokine (C-C motif) ligand 19] gene. Biotechnol. Appl. Biochem., 48(2):109-116.

[14]Caunt, M., Hu, L., Tang, T., et al., 2006. Growth-regulated oncogene is pivotal in thrombin-induced angiogenesis. Cancer Res., 66(8):4125-4132.

[15]Chen, H.J., Edwards, R., Tucci, S., et al., 2012. Chemokine 25-induced signaling suppresses colon cancer invasion and metastasis. J. Clin. Invest., 122(9):3184-3196.

[16]Chen, W., Gao, Q., Han, S., et al., 2015. The CCL2/CCR2 axis enhances IL-6-induced epithelial-mesenchymal transition by cooperatively activating STAT3-Twist signaling. Tumour. Biol., 36(2):973-981.

[17]Damelin, M., Geles, K.G., Follettie, M.T., et al., 2011. Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells. Cancer Res., 71(12):4236-4246.

[18]Dass, K., Ahmad, A., Azmi, A.S., et al., 2008. Evolving role of uPA/uPAR system in human cancers. Cancer Treat. Rev., 34(2):122-136.

[19]Ding, Y., Shimada, Y., Maeda, M., et al., 2003. Association of CC chemokine receptor 7 with lymph node metastasis of esophageal squamous cell carcinoma. Clin. Cancer Res., 9(9):3406-3412.

[20]Dong, J., Dai, J., Shu, Y., et al., 2010. Polymorphisms in EGFR and VEGF contribute to non-small-cell lung cancer survival in a Chinese population. Carcinogenesis, 31(6):1080-1086.

[21]Eramo, A., Lotti, F., Sette, G., et al., 2008. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ., 15(3):504-514.

[22]Feng, L.Y., Ou, Z.L., Wu, F.Y., et al., 2009. Involvement of a novel chemokine decoy receptor CCX-CKR in breast cancer growth, metastasis and patient survival. Clin. Cancer Res., 15(9):2962-2970.

[23]Goldstraw, P., Crowley, J., Chansky, K., et al., 2007. 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., 2(8):706-714.

[24]Gong, L., Cumpian, A.M., Caetano, M.S., et al., 2013. Promoting effect of neutrophils on lung tumorigenesis is mediated by CXCR2 and neutrophil elastase. Mol. Cancer, 12(1):154.

[25]Groome, P.A., Bolejack, V., Crowley, J.J., et al., 2007. 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., 2(8):694-705.

[26]Gupta, P., Sharma, P.K., Mir, H., et al., 2014. CCR9/CCL25 expression in non-small cell lung cancer correlates with aggressive disease and mediates key steps of metastasis. Oncotarget, 5(20):10170-10179.

[27]Hillinger, S., Yang, S.C., Zhu, L., et al., 2003. EBV-induced molecule 1 ligand chemokine (ELC/CCL19) promotes IFN-γ-dependent antitumor responses in a lung cancer model. J. Immunol., 171(12):6457-6465.

[28]Hu, T., Yao, Y., Yu, S., et al., 2014. CXCR4 and Nrf2 expressions in non-small cell lung cancer and their clinical implications. J. South Med. Univ., 34(2):153-158.

[29]Iijima, N., Yanagawa, Y., Clingan, J.M., et al., 2005. CCR7-mediated c-Jun N-terminal kinase activation regulates cell migration in mature dendritic cells. Int. Immunol., 17(9):1201-1212.

[30]Itakura, M., Terashima, Y., Shingyoji, M., et al., 2013. High CC chemokine receptor 7 expression improves postoperative prognosis of lung adenocarcinoma patients. Br. J. Cancer, 109(5):1100-1108.

[31]Johnson-Holiday, C., Singh, R., Johnson, E., et al., 2011. CCL25 mediates migration, invasion and matrix metalloproteinase expression by breast cancer cells in a CCR9-dependent fashion. Int. J. Oncol., 38(5):1279-1285.

[32]Jung, M.J., Rho, J.K., Kim, Y.M., et al., 2013. Upregulation of CXCR4 is functionally crucial for maintenance of stemness in drug-resistant non-small cell lung cancer cells. Oncogene, 32(2):209-221.

[33]Keeley, E.C., Mehrad, B., Strieter, R.M., 2011. Chemokines as mediators of tumor angiogenesis and neovascularization. Exp. Cell Res., 317(5):685-690.

[34]Keith, R.L., Miller, Y.E., 2013. Lung cancer chemoprevention: current status and future prospects. Nat. Rev. Clin. Oncol., 10(6):334-343.

[35]Kudo-Saito, C., Shirako, H., Ohike, M., et al., 2013. CCL2 is critical for immunosuppression to promote cancer metastasis. Clin. Exp. Metastasis, 30(4):393-405.

[36]Lee, N.J., Choi, D.Y., Song, J.K., et al., 2012. 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, 33(12):2520-2528.

[37]Li, X., Tai, H.H., 2013. 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, 8(1):e54073.

[38]Li, X., Tai, H.H., 2014. 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., 53(8):659-666.

[39]Li, Y., Shen, Y., Miao, Y., et al., 2014. Co-expression of uPAR and CXCR4 promotes tumor growth and metastasis in small cell lung cancer. Int. J. Clin. Exp. Pathol., 7(7):3771-3780.

[40]Lo, H.M., Shieh, J.M., Chen, C.L., et al., 2013. 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., 14(5):10090-10106.

[41]Luppi, F., Longo, A.M., de Boer, W.I., et al., 2007. Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation. Lung Cancer, 56(1):25-33.

[42]Majetschak, M., 2011. Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules. J. Leukoc. Biol., 89(2):205-219.

[43]Mango, R.L., Wu, Q.P., West, M., et al., 2014. C-C chemokine receptor 5 on pulmonary mesenchymal cells promotes experimental metastasis via the induction of erythroid differentiation regulator 1. Mol. Cancer Res., 12(2):274-282.

[44]Mantovani, A., Savino, B., Locati, M., et al., 2010. The chemokine system in cancer biology and therapy. Cytokine Growth Factor Rev., 21(1):27-39.

[45]Maxwell, P.J., Gallagher, R., Seaton, A., et al., 2007. HIF-1 and NF-κB-mediated upregulation of CXCR1 and CXCR2 expression promotes cell survival in hypoxic prostate cancer cells. Oncogene, 26(52):7333-7345.

[46]Mazar, A.P., 2008. Urokinase plasminogen activator receptor choreographs multiple ligand interactions: implications for tumor progression and therapy. Clin. Cancer Res., 14(18):5649-5655.

[47]Montuori, N., Bifulco, K., Carriero, M.V., et al., 2011. The cross-talk between the urokinase receptor and fMLP receptors regulates the activity of the CXCR4 chemokine receptor. Cell. Mol. Life Sci., 68(14):2453-2467.

[48]Mukaida, N., Baba, T., 2012. Chemokines in tumor development and progression. Exp. Cell Res., 318(2):95-102.

[49]Muller, A., Homey, B., Soto, H., et al., 2001. Involvement of chemokine receptors in breast cancer metastasis. Nature, 410(6824):50-56.

[50]National Lung Screening Trial Research, 2011. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med., 365(5):395-409.

[51]Numasaki, M., Watanabe, M., Suzuki, T., et al., 2005. 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., 175(9):6177-6189.

[52]Peled, A., Wald, O., Burger, J., 2012. Development of novel CXCR4-based therapeutics. Expert Opin. Investig. Drugs, 21(3):341-353.

[53]Phillips, R.J., Burdick, M.D., Lutz, M., et al., 2003. 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., 167(12):1676-1686.

[54]Phillips, R.J., Mestas, J., Gharaee-Kermani, M., et al., 2005. 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., 280(23):22473-22481.

[55]Ploug, M., Ellis, V., 1994. 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., 349(2):163-168.

[56]Richmond, A., 2002. Nf-κB, chemokine gene transcription and tumour growth. Nat. Rev. Immunol., 2(9):664-674.

[57]Saini, V., Marchese, A., Majetschak, M., 2010. CXC chemokine receptor 4 is a cell surface receptor for extracellular ubiquitin. J. Biol. Chem., 285(20):15566-15576.

[58]Saintigny, P., Burger, J.A., 2012. Recent advances in non-small cell lung cancer biology and clinical management. Discov. Med., 13(71):287-297.

[59]Saintigny, P., Massarelli, E., Lin, S., et al., 2013. CXCR2 expression in tumor cells is a poor prognostic factor and promotes invasion and metastasis in lung adenocarcinoma. Cancer Res., 73(2):571-582.

[60]Sarvaiya, P.J., Guo, D., Ulasov, I., et al., 2013. Chemokines in tumor progression and metastasis. Oncotarget, 4(12):2171-2185.

[61]Scapini, P., Morini, M., Tecchio, C., et al., 2004. CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A. J. Immunol., 172(8):5034-5040.

[62]Schioppa, T., Uranchimeg, B., Saccani, A., et al., 2003. Regulation of the chemokine receptor CXCR4 by hypoxia. J. Exp. Med., 198(9):1391-1402.

[63]Sharma, S., Zhu, L., Srivastava, M.K., et al., 2013. CCL21 chemokine therapy for lung cancer. Int. Trends Immun., 1(1):10-15.

[64]Siegel, R., Naishadham, D., Jemal, A., 2012a. Cancer statistics, 2012. CA Cancer J. Clin., 62(1):10-29.

[65]Siegel, R., DeSantis, C., Virgo, K., et al., 2012b. Cancer treatment and survivorship statistics, 2012. CA Cancer J. Clin., 62(4):220-241.

[66]Singh, R., Stockard, C.R., Grizzle, W.E., et al., 2011. Expression and histopathological correlation of CCR9 and CCL25 in ovarian cancer. Int. J. Oncol., 39(2):373-381.

[67]Singh, S., Singh, U.P., Stiles, J.K., et al., 2004. Expression and functional role of CCR9 in prostate cancer cell migration and invasion. Clin. Cancer Res., 10(24):8743-8750.

[68]Sparmann, A., Bar-Sagi, D., 2004. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell, 6(5):447-458.

[69]Su, L., Zhang, J., Xu, H., et al., 2005. Differential expression of CXCR4 is associated with the metastatic potential of human non-small cell lung cancer cells. Clin. Cancer Res., 11(23):8273-8280.

[70]Sun, H., Chung, W.C., Ryu, S.H., et al., 2008. Cyclic AMP-responsive element binding protein- and nuclear factor-κB-regulated CXC chemokine gene expression in lung carcinogenesis. Cancer Prev. Res. (Phila), 1(5):316-328.

[71]Sun, X., Cheng, G., Hao, M., et al., 2010. CXCL12/CXCR4/CXCR7 chemokine axis and cancer progression. Cancer Metastasis Rev., 29(4):709-722.

[72]Sutherland, K.D., Berns, A., 2010. Cell of origin of lung cancer. Mol. Oncol., 4(5):397-403.

[73]Suzuki, M., Mohamed, S., Nakajima, T., et al., 2008. Aberrant methylation of CXCL12 in non-small cell lung cancer is associated with an unfavorable prognosis. Int. J. Oncol., 33(1):113-119.

[74]Svensson, M., Agace, W.W., 2006. Role of CCL25/CCR9 in immune homeostasis and disease. Expert Rev. Clin. Immunol., 2(5):759-773.

[75]Wagner, P.L., Hyjek, E., Vazquez, M.F., et al., 2009. CXCL12 and CXCR4 in adenocarcinoma of the lung: association with metastasis and survival. J. Thorac. Cardiovasc. Surg., 137(3):615-621.

[76]Wald, O., Izhar, U., Amir, G., et al., 2011. 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., 141(6):1503-1512.

[77]Wang, L., Wang, Z., Liu, X., et al., 2014. 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., 7(6):1871-1876.

[78]Wislez, M., Fujimoto, N., Izzo, J.G., et al., 2006. High expression of ligands for chemokine receptor CXCR2 in alveolar epithelial neoplasia induced by oncogenic kras. Cancer Res., 66(8):4198-4207.

[79]Wu, F.Y., Fan, J., Tang, L., et al., 2013. Atypical chemokine receptor D6 inhibits human non-small cell lung cancer growth by sequestration of chemokines. Oncol. Lett., 6(1):91-95.

[80]Xie, S., Zeng, W., Fan, G., et al., 2014. 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., 7(4):941-947.

[81]Yan, L., Cai, Q., Xu, Y., 2013. The ubiquitin-CXCR4 axis plays an important role in acute lung infection-enhanced lung tumor metastasis. Clin. Cancer Res., 19(17):4706-4716.

[82]Yanagawa, J., Walser, T.C., Zhu, L.X., et al., 2009. Snail promotes CXCR2 ligand-dependent tumor progression in non-small cell lung carcinoma. Clin. Cancer Res., 15(22):6820-6829.

[83]Yang, L., Li, L., Chen, Y., et al., 2005a. Mortality time trends and the incidence and mortality estimation and projection for lung cancer in China. Chin. J. Lung Cancer, 8(4):274-278.

[84]Yang, L., Parkin, D.M., Ferlay, J., et al., 2005b. Estimates of cancer incidence in China for 2000 and projections for 2005. Cancer Epidemiol. Biomarkers Prev., 14(1):243-250.

[85]Zhang, Q., Sun, L., Yin, L., et al., 2013. CCL19/CCR7 upregulates heparanase via specificity protein-1 (Sp1) to promote invasion of cell in lung cancer. Tumour. Biol., 34(5):2703-2708.

[86]Zhang, X.W., Qin, X., Qin, C.Y., et al., 2013. Expression of monocyte chemoattractant protein-1 and CC chemokine receptor 2 in non-small cell lung cancer and its significance. Cancer Immunol. Immunother., 62(3):563-570.

[87]Zlotnik, A., Yoshie, O., 2000. Chemokines: a new classification system and their role in immunity. Immunity, 12(2):121-127.