TNF-α诱导人肝癌细胞分泌IL-8及其调节机制
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摘要
研究背景及目的
肝细胞肝癌(Hepatocellular Carcinoma, HCC)是世界上的最常见的恶性肿瘤之一,全球发病率居恶性肿瘤第6位；病死率居第3位。每年新增病例达62.6万,其中超过半数来自中国,中国的肝癌患者大多有肝炎背景。趋化因子作为炎症反应中重要调节因素之一,除了参与调节炎症细胞向炎症部位的迁移及其它机体的免疫反应外,还与肿瘤细胞的侵袭和转移密切相关。白介素8(Interleukin 8, IL-8)是慢性炎症反应中常见的趋化因子,在调节局部炎症反应中起重要作用。肿瘤坏死因子-α(Tumor Necrosis Factor-alpha, TNF-α)是肿瘤微环境常见的促炎细胞因子,具有强大的促进炎症反应作用,是炎症反应中重要的调节因子。
本研究选用了人肝癌细胞系MHCC-97H,首先检测其是否分泌IL-8及TNF-α对其分泌IL-8的影响,进而探讨了p38丝裂原活化蛋白激酶(p38 Mitogen-activated protein kinase, p38 MAPK)、细胞外调节蛋白激酶(Extracellular Regulated Protein Kinases, ERK)和PI3K/Akt (Phosphoinositide 3-kinase/Protein Kinase B, PI3K/Akt)信号通路是否参与了MHCC-97H分泌IL-8的调节,p38 MAPK是否通过NF-κB通路调节IL-8的分泌,以及CCR1, CCR2和CCR3信号通路对IL-8分泌的影响。研究方法
通过酶联免疫吸附(ELISA)检测MHCC-97H细胞未干预及TNF-α干预后细胞上清液中IL-8的浓度；Western blot方法分析TNF-α刺激MHCC-97H细胞后p38MAPK; ERK和Akt通路磷酸化蛋白表达,免疫荧光方法分析了磷酸化p38 MAPK, ERK和Akt蛋白在细胞内的表达和分布；用通过免疫荧光和非放射性NF-κB p50/p65转录因子活性试剂盒检测了核蛋白中NF-κB p65的含量；用MTT比色法检测了TNF-α及其它信号通路抑制剂对MHCC-97H增殖的影响。研究结果
1. MHCC-97H在无TNF-α干预的情况下分泌少量的IL-8, TNF-α刺激后可以明显促进MHCC-97H细胞分泌大量的IL-8,并随着时间的延长而增加(p<0.05)。IL-8的生成与TNF-α的浓度相关,不同浓度组之间有显著的统计学差异(p<0.01)。
2. TNF-α、SB203580(p38 MAPK通路抑制剂)、PD98059(ERK通路抑制剂)、LY294002和Wortmannin(均为PI3K通路抑制剂)均可显著抑制细胞的增殖(p<0.05)。
3. Western blot:TNF-α刺激MHCC-97H细胞后可上调p38 MAPK、ERK和PI3K/Akt磷酸化水平,其中p38通路最为显著。
4.免疫荧光：与对照组相比,MHCC-97H经TNF-α干预1h后,p38 MAPK、ERK和Akt磷酸化蛋白明显增加,细胞浆和细胞核内均有分布,与western blot结果一致。
5.研究不同信号通路对TNF-α诱导MHCC-9H分泌IL-8的实验结果显示,与对照组(仅用TNF-α干预组)相比,SB203580、PD98059、LY294002和Wortmannin可以显著抑制TNF-α诱导的IL-8分泌(p<0.05),且具有浓度依赖性。
6. TNF-α对NF-κB通路的影响。TNF-α可以显著促进NF-κB p65蛋白的核转位,并且具有浓度依赖性(p<0.05)。免疫荧光结果：对照组中NF-κB p65主要分布在细胞浆中,TNF-α干预后,细胞核内NF-κB p65明显增多。
7. p38 MAPK通路抑制剂(SB203580)对TNF-α诱导的NF-κB核转位的影响。与对照组相比,SB203580可以部分抑制NF-κB p65的核转位,且具有浓度依赖性(p<0.01)。
8.CCR1、CCR2和CCR3信号通路对TNF-α诱导MHCC-9H分泌IL-8的影响。ELISA检测结果提示,UCB35625(CCR1抑制剂)和RS504393(CCR2抑制剂)对TNF-α诱导的IL-8分泌无影响,SB328437(CCR3抑制剂)可以抑制TNF-α诱导的IL-8分泌,不同浓度组间具有明显差异明显(p<0.05)。
主要结论
1.MHCC-97H细胞在无TNF-α干预的情况下分泌少量的IL-8, TNF-α显著增加MHCC-97H分泌IL-8。
2. p38 MAPK、ERK和PI3K/Akt信号途径参与了TNF-α调节MHCC-97H细胞分泌IL-8; p38MAPK通路通过NF-κB信号途径调节IL-8的分泌。
3. TNF-α诱导人肝癌细胞系MHCC-97H分泌IL-8与CCR3信号通路存在交叉对话。
Background and Aims:Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high rate of metastasis, responsible for the main cause of deat. There are more than 626,000 new cases and 598,000 deaths per year. Chemokine and their receptors play a key role in the tumor-associated inflammation, associated with the tumor metastasis. Interleukin-8 is a common chemokines in chronic inflammatory response, play an important role in regulating the local inflammatory response. TNF-αact as a key coordinator between inflammation and cancer. The present studies aimed at exploring the pattern and potential mechanism of IL-8 production from HCC, the involvement of the intracellular signaling pathways, and the potential role of CCR1, CCR2 and CCR3 signaling pathway on IL-8 production induced by TNF-α.
Methods:The concentrations of IL-8 from MHCC-97H cells were measured by an enzyme-linked immunosorbent assay (ELISA). The phosphorylation of p38 MAPK, ERK, and Akt were analyzed by Western blot and immunofluorescence. NF-κB p65 protein nuclear translocation was determined by non-radioactive NF-κB p50/p65 transcription factor activity kit. The proliferation of cell was detected by MTT colorimetric assay.
Results:
1. The IL-8 production from MHCC-97H cells challenged with TNF-αsignificantly increased in a time-dependent and dose-dependent manners, as compared with those without TNFa challenge.
2. TNF-αand SB203580 (p38 MAPK pathway inhibitor), PD98059 (ERK pathway inhibitor), LY294002 (PI3K pathway inhibitor) and Wortmannin (PI3K pathway inhibitor) significantly inhibited the cell proliferation.
3. TNF-αup-regulated the phosphorylation levels of p38 MAPK, ERK and Akt in MHCC-97H cells, of which the p38 phosphorylation showed more obvious.
4. TNF-αcould significantly increase the phosphorylation of 38MAPK, ERK and Akt protein in both cytoplasm and nucleus.
5. The administrations with SB203580, PD98059, LY294002 and Wortmannin could inhibit TNF-α-induced IL-8 production in a dose-dependent manner.
6. TNF-αcould significantly increase the translocation of NF-κB p65 protein into the nucleus in a dose-dependent manner, proved by immunofluorescence staining.
7. p38 MAPK pathway inhibitor (SB203580) could block TNF-αinduced NF-κB p65 nuclear translocation and partially inhibited NF-κB p65 nuclear translocation in a dose-dependent manner(p<0.01).
8. SB328437 (CCR3 inhibitors) could significantly inhibit TNF-α-induced IL-8 production in a dose dependent manner, rather than UCB35625 (CCR1 inhibitor) and RS504393 (CCR2 inhibitor).
Conclusions:TNF-αcould increase the production of IL-8 in MHCC-97H cells probably through p38 MAPK, ERK and Akt signaling pathways. The p38 and NF-κB pathways seem to play more central role in the signal regulation of IL-8 production. Our results indicate that TNF-α-induced IL-8 production in MHCC-97H cells through a potential cross-talking with CCR3 signal pathway. Thus, our data suggest that IL-8 may be one of critical chemoattratic factors responsible for the development of tumor-associated inflammation, as the potential therapeutic target for HCC.
肝细胞肝癌(Hepatocellular Carcinoma, HCC)是世界上的最常见的恶性肿瘤之一,全球发病率居恶性肿瘤第6位；病死率居第3位。每年新增病例达62.6万,其中超过半数来自中国,中国的肝癌患者大多有肝炎背景。趋化因子作为炎症反应中重要调节因素之一,除了参与调节炎症细胞向炎症部位的迁移及其它机体的免疫反应外,还与肿瘤细胞的侵袭和转移密切相关。白介素8(Interleukin 8, IL-8)是慢性炎症反应中常见的趋化因子,在调节局部炎症反应中起重要作用。肿瘤坏死因子-α(Tumor Necrosis Factor-alpha, TNF-α)是肿瘤微环境常见的促炎细胞因子,具有强大的促进炎症反应作用,是炎症反应中重要的调节因子。
本研究选用了人肝癌细胞系MHCC-97H,首先检测其是否分泌IL-8及TNF-α对其分泌IL-8的影响,进而探讨了p38丝裂原活化蛋白激酶(p38 Mitogen-activated protein kinase, p38 MAPK)、细胞外调节蛋白激酶(Extracellular Regulated Protein Kinases, ERK)和PI3K/Akt (Phosphoinositide 3-kinase/Protein Kinase B, PI3K/Akt)信号通路是否参与了MHCC-97H分泌IL-8的调节,p38 MAPK是否通过NF-κB通路调节IL-8的分泌,以及CCR1, CCR2和CCR3信号通路对IL-8分泌的影响。研究方法
通过酶联免疫吸附(ELISA)检测MHCC-97H细胞未干预及TNF-α干预后细胞上清液中IL-8的浓度；Western blot方法分析TNF-α刺激MHCC-97H细胞后p38MAPK; ERK和Akt通路磷酸化蛋白表达,免疫荧光方法分析了磷酸化p38 MAPK, ERK和Akt蛋白在细胞内的表达和分布；用通过免疫荧光和非放射性NF-κB p50/p65转录因子活性试剂盒检测了核蛋白中NF-κB p65的含量；用MTT比色法检测了TNF-α及其它信号通路抑制剂对MHCC-97H增殖的影响。研究结果
1. MHCC-97H在无TNF-α干预的情况下分泌少量的IL-8, TNF-α刺激后可以明显促进MHCC-97H细胞分泌大量的IL-8,并随着时间的延长而增加(p<0.05)。IL-8的生成与TNF-α的浓度相关,不同浓度组之间有显著的统计学差异(p<0.01)。
2. TNF-α、SB203580(p38 MAPK通路抑制剂)、PD98059(ERK通路抑制剂)、LY294002和Wortmannin(均为PI3K通路抑制剂)均可显著抑制细胞的增殖(p<0.05)。
3. Western blot:TNF-α刺激MHCC-97H细胞后可上调p38 MAPK、ERK和PI3K/Akt磷酸化水平,其中p38通路最为显著。
4.免疫荧光：与对照组相比,MHCC-97H经TNF-α干预1h后,p38 MAPK、ERK和Akt磷酸化蛋白明显增加,细胞浆和细胞核内均有分布,与western blot结果一致。
5.研究不同信号通路对TNF-α诱导MHCC-9H分泌IL-8的实验结果显示,与对照组(仅用TNF-α干预组)相比,SB203580、PD98059、LY294002和Wortmannin可以显著抑制TNF-α诱导的IL-8分泌(p<0.05),且具有浓度依赖性。
6. TNF-α对NF-κB通路的影响。TNF-α可以显著促进NF-κB p65蛋白的核转位,并且具有浓度依赖性(p<0.05)。免疫荧光结果：对照组中NF-κB p65主要分布在细胞浆中,TNF-α干预后,细胞核内NF-κB p65明显增多。
7. p38 MAPK通路抑制剂(SB203580)对TNF-α诱导的NF-κB核转位的影响。与对照组相比,SB203580可以部分抑制NF-κB p65的核转位,且具有浓度依赖性(p<0.01)。
8.CCR1、CCR2和CCR3信号通路对TNF-α诱导MHCC-9H分泌IL-8的影响。ELISA检测结果提示,UCB35625(CCR1抑制剂)和RS504393(CCR2抑制剂)对TNF-α诱导的IL-8分泌无影响,SB328437(CCR3抑制剂)可以抑制TNF-α诱导的IL-8分泌,不同浓度组间具有明显差异明显(p<0.05)。
主要结论
1.MHCC-97H细胞在无TNF-α干预的情况下分泌少量的IL-8, TNF-α显著增加MHCC-97H分泌IL-8。
2. p38 MAPK、ERK和PI3K/Akt信号途径参与了TNF-α调节MHCC-97H细胞分泌IL-8; p38MAPK通路通过NF-κB信号途径调节IL-8的分泌。
3. TNF-α诱导人肝癌细胞系MHCC-97H分泌IL-8与CCR3信号通路存在交叉对话。
Background and Aims:Hepatocellular carcinoma (HCC) is one of the most common malignancies with a high rate of metastasis, responsible for the main cause of deat. There are more than 626,000 new cases and 598,000 deaths per year. Chemokine and their receptors play a key role in the tumor-associated inflammation, associated with the tumor metastasis. Interleukin-8 is a common chemokines in chronic inflammatory response, play an important role in regulating the local inflammatory response. TNF-αact as a key coordinator between inflammation and cancer. The present studies aimed at exploring the pattern and potential mechanism of IL-8 production from HCC, the involvement of the intracellular signaling pathways, and the potential role of CCR1, CCR2 and CCR3 signaling pathway on IL-8 production induced by TNF-α.
Methods:The concentrations of IL-8 from MHCC-97H cells were measured by an enzyme-linked immunosorbent assay (ELISA). The phosphorylation of p38 MAPK, ERK, and Akt were analyzed by Western blot and immunofluorescence. NF-κB p65 protein nuclear translocation was determined by non-radioactive NF-κB p50/p65 transcription factor activity kit. The proliferation of cell was detected by MTT colorimetric assay.
Results:
1. The IL-8 production from MHCC-97H cells challenged with TNF-αsignificantly increased in a time-dependent and dose-dependent manners, as compared with those without TNFa challenge.
2. TNF-αand SB203580 (p38 MAPK pathway inhibitor), PD98059 (ERK pathway inhibitor), LY294002 (PI3K pathway inhibitor) and Wortmannin (PI3K pathway inhibitor) significantly inhibited the cell proliferation.
3. TNF-αup-regulated the phosphorylation levels of p38 MAPK, ERK and Akt in MHCC-97H cells, of which the p38 phosphorylation showed more obvious.
4. TNF-αcould significantly increase the phosphorylation of 38MAPK, ERK and Akt protein in both cytoplasm and nucleus.
5. The administrations with SB203580, PD98059, LY294002 and Wortmannin could inhibit TNF-α-induced IL-8 production in a dose-dependent manner.
6. TNF-αcould significantly increase the translocation of NF-κB p65 protein into the nucleus in a dose-dependent manner, proved by immunofluorescence staining.
7. p38 MAPK pathway inhibitor (SB203580) could block TNF-αinduced NF-κB p65 nuclear translocation and partially inhibited NF-κB p65 nuclear translocation in a dose-dependent manner(p<0.01).
8. SB328437 (CCR3 inhibitors) could significantly inhibit TNF-α-induced IL-8 production in a dose dependent manner, rather than UCB35625 (CCR1 inhibitor) and RS504393 (CCR2 inhibitor).
Conclusions:TNF-αcould increase the production of IL-8 in MHCC-97H cells probably through p38 MAPK, ERK and Akt signaling pathways. The p38 and NF-κB pathways seem to play more central role in the signal regulation of IL-8 production. Our results indicate that TNF-α-induced IL-8 production in MHCC-97H cells through a potential cross-talking with CCR3 signal pathway. Thus, our data suggest that IL-8 may be one of critical chemoattratic factors responsible for the development of tumor-associated inflammation, as the potential therapeutic target for HCC.
引文
1. Mantovani, A., P. Allavena, A. Sica, et al., Cancer-related inflammation. Nature,2008.454(7203):p.436-44.
2. Coussens, L.M. and Z. Werb, Inflammation and cancer. Nature,2002. 420(6917):p.860-7.
3. Waugh, D.J. and C. Wilson, The interleukin-8 pathway in cancer. Clin Cancer Res,2008.14(21):p.6735-41.
4. Yuan, A., J.J. Chen, P.L. Yao, et al., The role of interleukin-8 in cancer cells and microenvironment interaction. Front Biosci,2005.10:p.853-65.
5. Akiba, J., H. Yano, S. Ogasawara, et al., Expression and function of interleukin-8 in human hepatocellular carcinoma. International Journal of Oncology,2001.18(2):p.257-264.
6. Kubo, F., S. Ueno, K. Hiwatashi, et al., Interleukin 8 in human hepatocellular carcinoma correlates with cancer cell invasion of vessels but not with tumor angiogenesis. Ann Surg Oncol,2005.12(10):p.800-7.
7. Balkwill, F., Tumour necrosis factor and cancer. Nat Rev Cancer,2009.9(5): p.361-71.
8. Wu, Y. and B.P. Zhou, TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. Br J Cancer,2010.102(4):p.639-44.
9. Li, Y, B. Tian, J. Yang, et al., Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol,2004.130(8):p.460-8.
10. Tian, J., Z.Y Tang, S.L. Ye, et al., New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer,1999.81(5): p.814-21.
11. Vicari, A.P. and C. Caux, Chemokines in cancer. Cytokine & Growth Factor Reviews,2002.13(2):p.143-154.
12. Balkwill, F., Chemokine biology in cancer. Seminars in Immunology,2003. 15(1):p.49-55.
13. Sica, A., P. Larghi, A. Mancino, et al., Macrophage polarization in tumour progression. Seminars in Cancer Biology,2008.18(5):p.349-355.
14. Shin, E.C., YH. Choi, J.S. Kim, et al., Expression patterns of cytokines and chemokines genes in human hepatoma cells. Yonsei Med J,2002.43(5):p. 657-64.
15. Mantovani, A., T. Schioppa, C. Porta, et al., Role of tumor-associated macrophages in tumor progression and invasion. Cancer and Metastasis Reviews,2006.25(3):p.315-322.
16. Balkwill, F., Tumour necrosis factor and cancer. Nature Reviews Cancer,2009. 9(5):p.361-371.
17. Sethi, G, B. Sung, and B.B. Aggarwal, TNF:A master switch for inflammation to cancer. Frontiers in Bioscience,2008.13:p.5094-5107.
18. Pikarsky, E., R.M. Porat, I. Stein, et al., NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature,2004.431(7007):p. 461-6.
19. Kim, C.H., Chemokine-chemokine receptor network in immune cell trafficking. Curr Drug Targets Immune Endocr Metabol Disord,2004.4(4):p.343-61.
20. Lazennec, G. and A. Richmond, Chemokines and chemokine receptors:new insights into cancer-related inflammation. Trends Mol Med,2010.16(3):p. 133-144.
21. Waugh, D.J.J. and C. Wilson, The Interleukin-8 Pathway in Cancer. Clinical Cancer Research,2008.14(21):p.6735-6741.
22. Xie, K.P., Interleukin-8 and human cancer biology. Cytokine & Growth Factor Reviews,2001.12(4):p.375-391.
23. Miyamoto, M., Y. Shimizu, K. Okada, et al., Effect of interleukin-8 on production of tumor-associated substances and autocrine growth of human liver and pancreatic cancer cells. Cancer Immunol Immunother,1998.47(1): p.47-57.
24. Sakamoto, K., T. Masuda, S. Mita, et al., interleukin-8 is constitutively and commonly produced by various human carcinoma cell-lines. International Journal of Clinical & Laboratory Research,1992.22(4):p.216-219.
25. 白冰.,欧周罗.,侯意枫.,et al.,人肝癌细胞系MHCC97中趋化因子差异表达研究.中华实验外科杂志,2004.21(8)：p.925-927.
26. Li, J., S. Kartha, S. Iasvovskaia, et al., Regulation of human airway epithelial cell IL-8 expression by MAP kinases. Am J Physiol Lung Cell Mol Physiol, 2002.283(4):p. L690-9.
27. Lee, H.J., J.W. Cho, S.C. Kim, et al., Roles of p38 and ERK MAP kinases in IL-8 expression in TNF-alpha-and dexamethasone-stimulated human periodontal ligament cells. Cytokine,2006.35(1-2):p.67-76.
28. Fernandes, A.F., Q. Bian, J.K. Jiang, et al., Proteasome inactivation promotes p38 mitogen-activated protein kinase-dependent phosphatidylinositol 3-kinase activation and increases interleukin-8 production in retinal pigment epithelial cells. Mol Biol Cell,2009.20(16):p.3690-9.
29. Kim, K.S., V. Rajagopal, C. Gonsalves, et al., A novel role of hypoxia-inducible factor in cobalt chloride-and hypoxia-mediated expression of IL-8 chemokine in human endothelial cells. J Immunol,2006.177(10):p. 7211-24.
30. Han, D., M.D. Ybanez, S. Ahmadi, et al., Redox regulation of tumor necrosis factor signaling. Antioxid Redox Signal,2009.11(9):p.2245-63.
31. Kyriakis, J.M. and J. Avruch, Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev,2001.81(2):p.807-69.
32. Osaki, M., M. Oshimura, and H. Ito, PI3K-Akt pathway:its functions and alterations in human cancer. Apoptosis,2004.9(6):p.667-76.
33. Courtney, K.D., R.B. Corcoran, and J.A. Engelman, The P13K pathway as drug target in human cancer. J Clin Oncol,2010.28(6):p.1075-83.
34. Kaur, J., R.C. Woodman, and P. Kubes, P38 MAPK:critical molecule in thrombin-induced NF-kappa B-dependent leukocyte recruitment. Am J Physiol Heart Circ Physiol,2003.284(4):p. H1095-103.
35. Parhar, K., A. Ray, U. Steinbrecher, et al., The p38 mitogen-activated protein kinase regulates interleukin-1 beta-induced IL-8 expression via an effect on the IL-8 promoter in intestinal epithelial cells. Immunology,2003.108(4):p. 502-12.
36. Wan, F. and M.J. Lenardo, The nuclear signaling of NF-kappaB:current knowledge, new insights, and future perspectives. Cell Res,2010.20(1):p. 24-33.
37. Wajant, H., K. Pfizenmaier, and P. Scheurich, Tumor necrosis factor signaling. Cell Death Differ,2003.10(1):p.45-65.
38. Liu, S., G. Feng, G.L. Wang, et al., p38MAPK inhibition attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. Eur J Pharmacol,2008.584(1):p.159-65.
39. Ghosh, S. and M.S. Hayden, New regulators of NF-kappaB in inflammation. Nat Rev Immunol,2008.8(11):p.837-48.
40. Liu, R.Y., C. Fan, G. Liu, et al., Activation of p38 mitogen-activated protein kinase is required for tumor necrosis factor-alpha-supported proliferation of leukemia and lymphoma cell lines. J Biol Chem,2000.275(28):p.21086-93.
41. Mackay, C.R., Chemokines:immunology's high impact factors. Nat Immunol, 2001.2(2):p.95-101.
42. Chen, J.J.W., Y.C. Lin, P.L. Yao, et al., Tumor-associated macrophages:The double-edged sword in cancer progression. Journal of Clinical Oncology, 2005.23(5):p.953-964.
43. Charo, I.F. and R.M. Ransohoff, The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med,2006.354(6):p.610-21.
44. Sica, A., A. Saccani, A. Borsatti, et al., Bacterial lipopolysaccharide rapidly inhibits expression of C-C chemokine receptors in human monocytes. J Exp Med,1997.185(5):p.969-74.
45. Bonecchi, R., N. Polentarutti, W. Luini, et al., Up-regulation of CCR1 and CCR3 and induction of chemotaxis to CC chemokines by IFN-gamma in human neutrophils. J Immunol,1999.162(1):p.474-9.
46. Slettenaar, V.I. and J.L. Wilson, The chemokine network:a target in cancer biology? Adv Drug Deliv Rev,2006.58(8):p.962-74.
47. Azenshtein, E., G. Luboshits, S. Shina, et al., The CC chemokine RANTES in breast carcinoma progression:regulation of expression and potential mechanisms of promalignant activity. Cancer Res,2002.62(4):p.1093-102.
48. Mburu, Y.K., J. Wang, M.A. Wood, et al., CCR7 mediates inflammation-associated tumor progression. Immunol Res,2006.36(1-3):p. 61-72.
49. Maekawa, S., A. Iwasaki, T. Shirakusa, et al., Association between the expression of chemokine receptors CCR7 and CXCR3, and lymph node metastatic potential in lung adenocarcinoma. Oncology Reports,2008.19(6): p.1461-1468.
50. 王晓颖.,樊嘉.,周俭.,et al., CCR1趋化因子受体在人肝癌组织中表达及其临床意义.中华肝胆外科杂志,2006.12(2)：p.101-104.
51. Wu, X., J. Fan, X. Wang, et al., Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion. Biochem Biophys Res Commun,2007. 355(4):p.866-71.
52. Xue, T.C., R.X. Chen, S.L. Ye, et al., Different expressions of chemokine receptors in human hepatocellular carcinoma cell lines with different metastatic potentials. Zhonghua Gan Zang Bing Za Zhi,2007.15(4):p.261-5.
53. Barbieri, F., A. Bajetto, and T. Florio, Role of chemokine network in the development and progression of ovarian cancer:a potential novel pharmacological target. J Oncol,2010.2010:p.426956.
54. Issa, A., T.X. Le, A.N. Shoushtari, et al., Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype. Cancer Res,2009.69(1):p.349-57.
55. Porcile, C., A. Bajetto, F. Barbieri, et al., Stromal cell-derived factor-1 alpha (SDF-1 alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor trans activation. Exp Cell Res,2005.308(2):p.241-53.
56. Huang, C.D., A.J. Ammit, O. Tliba, et al., G-protein-coupled receptor agonists differentially regulate basal or tumor necrosis factor-alpha-stimulated activation of interleukin-6 and RANTES in human airway smooth muscle cells. J Biomed Sci,2005.12(5):p.763-76.
57. Lloyd, C.M., T. Delaney, T. Nguyen, et al., CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo. J Exp Med,2000.191(2):p.265-74.
58. Jamaluddin, M.S., X. Wang, H. Wang, et al., Eotaxin increases monolayer permeability of human coronary artery endothelial cells. Arterioscler Thromb Vasc Biol,2009.29(12):p.2146-52.
59. Bandeira-Melo, C., M. Phoofolo, and R.F. Weller, Extranuclear lipid bodies, elicited by CCR3-mediated signaling pathways, are the sites of chemokine-enhanced leukotriene C4 production in eosinophils and basophils. J Biol Chem,2001.276(25):p.22779-87.
60. Yamamura, K., T. Adachi, T. Masuda, et al., Intracellular protein phosphorylation in eosinophils and the functional relevance in cytokine production. Int Arch Allergy Immunol,2009.149 Suppl 1:p.45-50.
1. Mackay, C.R., Chemokines:immunology's high impact factors. Nature Immunology,2001.2(2):p.95-101.
2. Kulbe, H., N.R. Levinson, F. Balkwill, et al., The chemokine network in cancer-much more than directing cell movement. International Journal of Developmental Biology,2004.48(5-6):p.489-496.
3. Olson, T.S. and K. Ley, Chemokines and chemokine receptors in leukocyte trafficking. American Journal of Physiology-Regulatory Integrative and Comparative Physiology,2002.283(1):p. R7-R28.
4. O'Hayre, M., C.L. Salanga, T.M. Handel, et al., Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochemical Journal,2008.409:p.635-649.
5. Balkwill, F., Cancer and the chemokine network. Nature Reviews Cancer, 2004.4(7):p.540-550.
6. Kakinuma, T. and S.T. Hwang, Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol,2006.79(4):p.639-51.
7. Strieter, R.M., J.A. Belperio, R.J. Phillips, et al., CXC chemokines in angiogenesis of cancer. Seminars in Cancer Biology,2004.14(3):p.195-200.
8. Vandercappellen, J., J. Van Damme, and S. Struyf, The role of CXC chemokines and their receptors in cancer. Cancer Lett,2008.267(2):p. 226-44.
9. Singh, S., A. Sadanandam, and R.K. Singh, Chemokines in tumor angiogenesis and metastasis. Cancer and Metastasis Reviews,2007.26(3-4):p. 453-467.
10. Raman, D., P.J. Baugher, Y.M. Thu, et al., Role of chemokines in tumor growth. Cancer Letters,2007.256(2):p.137-165.
11. Kryczek, I., S. Wei, E. Keller, et al., Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol,2007.292(3):p. C987-95.
12. Busillo, J.M. and J.L. Benovic, Regulation of CXCR4 signaling. Biochimica Et Biophysica Acta-Biomembranes,2007.1768(4):p.952-963.
13. Strieter, R.M., M.D. Burdick, B.N. Gomperts, et al., CXC chemokines in angiogenesis. Cytokine & Growth Factor Reviews,2005.16(6):p.593-609.
14. Mantovani, A., S. Sozzani, M. Locati, et al., Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in Immunology,2002.23(11):p.549-555.
15. Porta, C., B.S. Kumar, P. Larghi, et al., Tumor promotion by tumor-associated macrophages, in Advances in Molecular Oncology.2007. p.67-86.
16. Milliken, D., C. Scotton, S. Raju, et al., Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites. Clin Cancer Res, 2002.8(4):p.1108-14.
17. Balkwill, F. and A. Mantovani, Inflammation and cancer:back to Virchow? Lancet,2001.357(9255):p.539-545.
18. Skinnider, B.F. and T.W. Mak, The role of cytokines in classical Hodgkin lymphoma. Blood,2002.99(12):p.4283-97.
19. Wilson, J. and F. Balkwill, The role of cytokines in the epithelial cancer microenvironment. Semin Cancer Biol,2002.12(2):p.113-20.
20. Holland, J.D., M. Kochetkova, C. Akekawatchai, et al., Differential functional activation of chemokine receptor CXCR4 is mediated by G proteins in breast cancer cells. Cancer Res,2006.66(8):p.4117-24.
21. Mori, T., R. Doi, M. Koizumi, et al., CXCR4 antagonist inhibits stromal cell-derived factor I-induced migration and invasion of human pancreatic cancer. Mol Cancer Ther,2004.3(1):p.29-37.
22. Sun, Y.X., A. Schneider, Y. Jung, et al., Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. J Bone Miner Res,2005.20(2):p.318-29.
23. Chu, H., H. Zhou, Y. Liu, et al., Functional expression of CXC chemokine recepter-4 mediates the secretion of matrix metalloproteinases from mouse hepatocarcinoma cell lines with different lymphatic metastasis ability. Int J Biochem Cell Biol,2007.39(1):p.197-205.
24. Sutton, A., V. Friand, S. Brule-Donneger, et al., Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol Cancer Res,2007.5(1):p.21-33.
25. Schimanski, C.C., R. Bahre, I. Gockel, et al., Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4. Br J Cancer,2006. 95(2):p.210-7.
26. Koizumi, K., S. Hojo, T. Akashi, et al., Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. Cancer Science,2007.98(11):p.1652-1658.
27. Bromley, S.K., S.Y. Thomas, and A.D. Luster, Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat Immunol,2005.6(9):p.895-901.
28. Sancho, M., J.M. Vieira, C. Casalou, et al., Expression and function of the chemokine receptor CCR7 in thyroid carcinomas. J Endocrinol,2006.191(1): p.229-38.
29. Mburu, Y.K., J. Wang, M.A. Wood, et al., CCR7 mediates inflammation-associated tumor progression. Immunol Res,2006.36(1-3):p. 61-72.
30. Mashino, K., N. Sadanaga, H. Yamaguchi, et al., Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res,2002.62(10):p.2937-41.
31. Ishigami, S., S. Natsugoe, A. Nakajo, et al., Prognostic value of CCR7 expression in gastric cancer. Hepatogastroenterology,2007.54(76):p.1025-8.
32. Li, A., M.L. Varney, J. Valasek, et al., Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis,2005.8(1):p.63-71.
33. Addison, C.L., T.O. Daniel, M.D. Burdick, et al., The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+CXC chemokine-induced angiogenic activity. J Immunol,2000.165(9):p.5269-77.
34. De Larco, J.E., B.R. Wuertz, K.A. Rosner, et al., A potential role for interleukin-8 in the metastatic phenotype of breast carcinoma cells. Am J Pathol,2001.158(2):p.639-46.
35. Akiba, J., H. Yano, S. Ogasawara, et al., Expression and function of interleukin-8 in human hepatocellular carcinoma. Int J Oncol,2001.18(2):p. 257-64.
36. Haraguchi, M., K. Komuta, A. Akashi, et al., Elevated IL-8 levels in the drainage vein of resectable Dukes'C colorectal cancer indicate high risk for developing hepatic metastasis. Oncol Rep,2002.9(1):p.159-65.
37. Lu, P.R., Y. Nakamoto, Y. Nemoto-Sasaki, et al., Potential interaction between CCR1 and its ligand, CCL3, induced by endogenously produced interleukin-1 in human hepatomas. American Journal of Pathology,2003.162(4):p. 1249-1258.
38. Wu, X.F., J. Fan, X.Y Wang, et al., Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion. Biochemical and Biophysical Research Communications,2007.355(4):p.866-871.
39. Rubie, C., V.O. Frick, M. Wagner, et al., Enhanced expression and clinical significance of CC-chemokine MIP-3 alpha in hepatocellular carcinoma. Scand J Immunol,2006.63(6):p.468-77.
40. Uchida, H., Y. Iwashita, A. Sasaki, et al., Chemokine receptor CCR6 as a prognostic factor after hepatic resection for hepatocellular carcinoma. Journal of Gastroenterology and Hepatology,2006.21(1):p.161-168.
2. Coussens, L.M. and Z. Werb, Inflammation and cancer. Nature,2002. 420(6917):p.860-7.
3. Waugh, D.J. and C. Wilson, The interleukin-8 pathway in cancer. Clin Cancer Res,2008.14(21):p.6735-41.
4. Yuan, A., J.J. Chen, P.L. Yao, et al., The role of interleukin-8 in cancer cells and microenvironment interaction. Front Biosci,2005.10:p.853-65.
5. Akiba, J., H. Yano, S. Ogasawara, et al., Expression and function of interleukin-8 in human hepatocellular carcinoma. International Journal of Oncology,2001.18(2):p.257-264.
6. Kubo, F., S. Ueno, K. Hiwatashi, et al., Interleukin 8 in human hepatocellular carcinoma correlates with cancer cell invasion of vessels but not with tumor angiogenesis. Ann Surg Oncol,2005.12(10):p.800-7.
7. Balkwill, F., Tumour necrosis factor and cancer. Nat Rev Cancer,2009.9(5): p.361-71.
8. Wu, Y. and B.P. Zhou, TNF-alpha/NF-kappaB/Snail pathway in cancer cell migration and invasion. Br J Cancer,2010.102(4):p.639-44.
9. Li, Y, B. Tian, J. Yang, et al., Stepwise metastatic human hepatocellular carcinoma cell model system with multiple metastatic potentials established through consecutive in vivo selection and studies on metastatic characteristics. J Cancer Res Clin Oncol,2004.130(8):p.460-8.
10. Tian, J., Z.Y Tang, S.L. Ye, et al., New human hepatocellular carcinoma (HCC) cell line with highly metastatic potential (MHCC97) and its expressions of the factors associated with metastasis. Br J Cancer,1999.81(5): p.814-21.
11. Vicari, A.P. and C. Caux, Chemokines in cancer. Cytokine & Growth Factor Reviews,2002.13(2):p.143-154.
12. Balkwill, F., Chemokine biology in cancer. Seminars in Immunology,2003. 15(1):p.49-55.
13. Sica, A., P. Larghi, A. Mancino, et al., Macrophage polarization in tumour progression. Seminars in Cancer Biology,2008.18(5):p.349-355.
14. Shin, E.C., YH. Choi, J.S. Kim, et al., Expression patterns of cytokines and chemokines genes in human hepatoma cells. Yonsei Med J,2002.43(5):p. 657-64.
15. Mantovani, A., T. Schioppa, C. Porta, et al., Role of tumor-associated macrophages in tumor progression and invasion. Cancer and Metastasis Reviews,2006.25(3):p.315-322.
16. Balkwill, F., Tumour necrosis factor and cancer. Nature Reviews Cancer,2009. 9(5):p.361-371.
17. Sethi, G, B. Sung, and B.B. Aggarwal, TNF:A master switch for inflammation to cancer. Frontiers in Bioscience,2008.13:p.5094-5107.
18. Pikarsky, E., R.M. Porat, I. Stein, et al., NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature,2004.431(7007):p. 461-6.
19. Kim, C.H., Chemokine-chemokine receptor network in immune cell trafficking. Curr Drug Targets Immune Endocr Metabol Disord,2004.4(4):p.343-61.
20. Lazennec, G. and A. Richmond, Chemokines and chemokine receptors:new insights into cancer-related inflammation. Trends Mol Med,2010.16(3):p. 133-144.
21. Waugh, D.J.J. and C. Wilson, The Interleukin-8 Pathway in Cancer. Clinical Cancer Research,2008.14(21):p.6735-6741.
22. Xie, K.P., Interleukin-8 and human cancer biology. Cytokine & Growth Factor Reviews,2001.12(4):p.375-391.
23. Miyamoto, M., Y. Shimizu, K. Okada, et al., Effect of interleukin-8 on production of tumor-associated substances and autocrine growth of human liver and pancreatic cancer cells. Cancer Immunol Immunother,1998.47(1): p.47-57.
24. Sakamoto, K., T. Masuda, S. Mita, et al., interleukin-8 is constitutively and commonly produced by various human carcinoma cell-lines. International Journal of Clinical & Laboratory Research,1992.22(4):p.216-219.
25. 白冰.,欧周罗.,侯意枫.,et al.,人肝癌细胞系MHCC97中趋化因子差异表达研究.中华实验外科杂志,2004.21(8)：p.925-927.
26. Li, J., S. Kartha, S. Iasvovskaia, et al., Regulation of human airway epithelial cell IL-8 expression by MAP kinases. Am J Physiol Lung Cell Mol Physiol, 2002.283(4):p. L690-9.
27. Lee, H.J., J.W. Cho, S.C. Kim, et al., Roles of p38 and ERK MAP kinases in IL-8 expression in TNF-alpha-and dexamethasone-stimulated human periodontal ligament cells. Cytokine,2006.35(1-2):p.67-76.
28. Fernandes, A.F., Q. Bian, J.K. Jiang, et al., Proteasome inactivation promotes p38 mitogen-activated protein kinase-dependent phosphatidylinositol 3-kinase activation and increases interleukin-8 production in retinal pigment epithelial cells. Mol Biol Cell,2009.20(16):p.3690-9.
29. Kim, K.S., V. Rajagopal, C. Gonsalves, et al., A novel role of hypoxia-inducible factor in cobalt chloride-and hypoxia-mediated expression of IL-8 chemokine in human endothelial cells. J Immunol,2006.177(10):p. 7211-24.
30. Han, D., M.D. Ybanez, S. Ahmadi, et al., Redox regulation of tumor necrosis factor signaling. Antioxid Redox Signal,2009.11(9):p.2245-63.
31. Kyriakis, J.M. and J. Avruch, Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev,2001.81(2):p.807-69.
32. Osaki, M., M. Oshimura, and H. Ito, PI3K-Akt pathway:its functions and alterations in human cancer. Apoptosis,2004.9(6):p.667-76.
33. Courtney, K.D., R.B. Corcoran, and J.A. Engelman, The P13K pathway as drug target in human cancer. J Clin Oncol,2010.28(6):p.1075-83.
34. Kaur, J., R.C. Woodman, and P. Kubes, P38 MAPK:critical molecule in thrombin-induced NF-kappa B-dependent leukocyte recruitment. Am J Physiol Heart Circ Physiol,2003.284(4):p. H1095-103.
35. Parhar, K., A. Ray, U. Steinbrecher, et al., The p38 mitogen-activated protein kinase regulates interleukin-1 beta-induced IL-8 expression via an effect on the IL-8 promoter in intestinal epithelial cells. Immunology,2003.108(4):p. 502-12.
36. Wan, F. and M.J. Lenardo, The nuclear signaling of NF-kappaB:current knowledge, new insights, and future perspectives. Cell Res,2010.20(1):p. 24-33.
37. Wajant, H., K. Pfizenmaier, and P. Scheurich, Tumor necrosis factor signaling. Cell Death Differ,2003.10(1):p.45-65.
38. Liu, S., G. Feng, G.L. Wang, et al., p38MAPK inhibition attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. Eur J Pharmacol,2008.584(1):p.159-65.
39. Ghosh, S. and M.S. Hayden, New regulators of NF-kappaB in inflammation. Nat Rev Immunol,2008.8(11):p.837-48.
40. Liu, R.Y., C. Fan, G. Liu, et al., Activation of p38 mitogen-activated protein kinase is required for tumor necrosis factor-alpha-supported proliferation of leukemia and lymphoma cell lines. J Biol Chem,2000.275(28):p.21086-93.
41. Mackay, C.R., Chemokines:immunology's high impact factors. Nat Immunol, 2001.2(2):p.95-101.
42. Chen, J.J.W., Y.C. Lin, P.L. Yao, et al., Tumor-associated macrophages:The double-edged sword in cancer progression. Journal of Clinical Oncology, 2005.23(5):p.953-964.
43. Charo, I.F. and R.M. Ransohoff, The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med,2006.354(6):p.610-21.
44. Sica, A., A. Saccani, A. Borsatti, et al., Bacterial lipopolysaccharide rapidly inhibits expression of C-C chemokine receptors in human monocytes. J Exp Med,1997.185(5):p.969-74.
45. Bonecchi, R., N. Polentarutti, W. Luini, et al., Up-regulation of CCR1 and CCR3 and induction of chemotaxis to CC chemokines by IFN-gamma in human neutrophils. J Immunol,1999.162(1):p.474-9.
46. Slettenaar, V.I. and J.L. Wilson, The chemokine network:a target in cancer biology? Adv Drug Deliv Rev,2006.58(8):p.962-74.
47. Azenshtein, E., G. Luboshits, S. Shina, et al., The CC chemokine RANTES in breast carcinoma progression:regulation of expression and potential mechanisms of promalignant activity. Cancer Res,2002.62(4):p.1093-102.
48. Mburu, Y.K., J. Wang, M.A. Wood, et al., CCR7 mediates inflammation-associated tumor progression. Immunol Res,2006.36(1-3):p. 61-72.
49. Maekawa, S., A. Iwasaki, T. Shirakusa, et al., Association between the expression of chemokine receptors CCR7 and CXCR3, and lymph node metastatic potential in lung adenocarcinoma. Oncology Reports,2008.19(6): p.1461-1468.
50. 王晓颖.,樊嘉.,周俭.,et al., CCR1趋化因子受体在人肝癌组织中表达及其临床意义.中华肝胆外科杂志,2006.12(2)：p.101-104.
51. Wu, X., J. Fan, X. Wang, et al., Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion. Biochem Biophys Res Commun,2007. 355(4):p.866-71.
52. Xue, T.C., R.X. Chen, S.L. Ye, et al., Different expressions of chemokine receptors in human hepatocellular carcinoma cell lines with different metastatic potentials. Zhonghua Gan Zang Bing Za Zhi,2007.15(4):p.261-5.
53. Barbieri, F., A. Bajetto, and T. Florio, Role of chemokine network in the development and progression of ovarian cancer:a potential novel pharmacological target. J Oncol,2010.2010:p.426956.
54. Issa, A., T.X. Le, A.N. Shoushtari, et al., Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype. Cancer Res,2009.69(1):p.349-57.
55. Porcile, C., A. Bajetto, F. Barbieri, et al., Stromal cell-derived factor-1 alpha (SDF-1 alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor trans activation. Exp Cell Res,2005.308(2):p.241-53.
56. Huang, C.D., A.J. Ammit, O. Tliba, et al., G-protein-coupled receptor agonists differentially regulate basal or tumor necrosis factor-alpha-stimulated activation of interleukin-6 and RANTES in human airway smooth muscle cells. J Biomed Sci,2005.12(5):p.763-76.
57. Lloyd, C.M., T. Delaney, T. Nguyen, et al., CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo. J Exp Med,2000.191(2):p.265-74.
58. Jamaluddin, M.S., X. Wang, H. Wang, et al., Eotaxin increases monolayer permeability of human coronary artery endothelial cells. Arterioscler Thromb Vasc Biol,2009.29(12):p.2146-52.
59. Bandeira-Melo, C., M. Phoofolo, and R.F. Weller, Extranuclear lipid bodies, elicited by CCR3-mediated signaling pathways, are the sites of chemokine-enhanced leukotriene C4 production in eosinophils and basophils. J Biol Chem,2001.276(25):p.22779-87.
60. Yamamura, K., T. Adachi, T. Masuda, et al., Intracellular protein phosphorylation in eosinophils and the functional relevance in cytokine production. Int Arch Allergy Immunol,2009.149 Suppl 1:p.45-50.
1. Mackay, C.R., Chemokines:immunology's high impact factors. Nature Immunology,2001.2(2):p.95-101.
2. Kulbe, H., N.R. Levinson, F. Balkwill, et al., The chemokine network in cancer-much more than directing cell movement. International Journal of Developmental Biology,2004.48(5-6):p.489-496.
3. Olson, T.S. and K. Ley, Chemokines and chemokine receptors in leukocyte trafficking. American Journal of Physiology-Regulatory Integrative and Comparative Physiology,2002.283(1):p. R7-R28.
4. O'Hayre, M., C.L. Salanga, T.M. Handel, et al., Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochemical Journal,2008.409:p.635-649.
5. Balkwill, F., Cancer and the chemokine network. Nature Reviews Cancer, 2004.4(7):p.540-550.
6. Kakinuma, T. and S.T. Hwang, Chemokines, chemokine receptors, and cancer metastasis. J Leukoc Biol,2006.79(4):p.639-51.
7. Strieter, R.M., J.A. Belperio, R.J. Phillips, et al., CXC chemokines in angiogenesis of cancer. Seminars in Cancer Biology,2004.14(3):p.195-200.
8. Vandercappellen, J., J. Van Damme, and S. Struyf, The role of CXC chemokines and their receptors in cancer. Cancer Lett,2008.267(2):p. 226-44.
9. Singh, S., A. Sadanandam, and R.K. Singh, Chemokines in tumor angiogenesis and metastasis. Cancer and Metastasis Reviews,2007.26(3-4):p. 453-467.
10. Raman, D., P.J. Baugher, Y.M. Thu, et al., Role of chemokines in tumor growth. Cancer Letters,2007.256(2):p.137-165.
11. Kryczek, I., S. Wei, E. Keller, et al., Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol,2007.292(3):p. C987-95.
12. Busillo, J.M. and J.L. Benovic, Regulation of CXCR4 signaling. Biochimica Et Biophysica Acta-Biomembranes,2007.1768(4):p.952-963.
13. Strieter, R.M., M.D. Burdick, B.N. Gomperts, et al., CXC chemokines in angiogenesis. Cytokine & Growth Factor Reviews,2005.16(6):p.593-609.
14. Mantovani, A., S. Sozzani, M. Locati, et al., Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in Immunology,2002.23(11):p.549-555.
15. Porta, C., B.S. Kumar, P. Larghi, et al., Tumor promotion by tumor-associated macrophages, in Advances in Molecular Oncology.2007. p.67-86.
16. Milliken, D., C. Scotton, S. Raju, et al., Analysis of chemokines and chemokine receptor expression in ovarian cancer ascites. Clin Cancer Res, 2002.8(4):p.1108-14.
17. Balkwill, F. and A. Mantovani, Inflammation and cancer:back to Virchow? Lancet,2001.357(9255):p.539-545.
18. Skinnider, B.F. and T.W. Mak, The role of cytokines in classical Hodgkin lymphoma. Blood,2002.99(12):p.4283-97.
19. Wilson, J. and F. Balkwill, The role of cytokines in the epithelial cancer microenvironment. Semin Cancer Biol,2002.12(2):p.113-20.
20. Holland, J.D., M. Kochetkova, C. Akekawatchai, et al., Differential functional activation of chemokine receptor CXCR4 is mediated by G proteins in breast cancer cells. Cancer Res,2006.66(8):p.4117-24.
21. Mori, T., R. Doi, M. Koizumi, et al., CXCR4 antagonist inhibits stromal cell-derived factor I-induced migration and invasion of human pancreatic cancer. Mol Cancer Ther,2004.3(1):p.29-37.
22. Sun, Y.X., A. Schneider, Y. Jung, et al., Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. J Bone Miner Res,2005.20(2):p.318-29.
23. Chu, H., H. Zhou, Y. Liu, et al., Functional expression of CXC chemokine recepter-4 mediates the secretion of matrix metalloproteinases from mouse hepatocarcinoma cell lines with different lymphatic metastasis ability. Int J Biochem Cell Biol,2007.39(1):p.197-205.
24. Sutton, A., V. Friand, S. Brule-Donneger, et al., Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Mol Cancer Res,2007.5(1):p.21-33.
25. Schimanski, C.C., R. Bahre, I. Gockel, et al., Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4. Br J Cancer,2006. 95(2):p.210-7.
26. Koizumi, K., S. Hojo, T. Akashi, et al., Chemokine receptors in cancer metastasis and cancer cell-derived chemokines in host immune response. Cancer Science,2007.98(11):p.1652-1658.
27. Bromley, S.K., S.Y. Thomas, and A.D. Luster, Chemokine receptor CCR7 guides T cell exit from peripheral tissues and entry into afferent lymphatics. Nat Immunol,2005.6(9):p.895-901.
28. Sancho, M., J.M. Vieira, C. Casalou, et al., Expression and function of the chemokine receptor CCR7 in thyroid carcinomas. J Endocrinol,2006.191(1): p.229-38.
29. Mburu, Y.K., J. Wang, M.A. Wood, et al., CCR7 mediates inflammation-associated tumor progression. Immunol Res,2006.36(1-3):p. 61-72.
30. Mashino, K., N. Sadanaga, H. Yamaguchi, et al., Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res,2002.62(10):p.2937-41.
31. Ishigami, S., S. Natsugoe, A. Nakajo, et al., Prognostic value of CCR7 expression in gastric cancer. Hepatogastroenterology,2007.54(76):p.1025-8.
32. Li, A., M.L. Varney, J. Valasek, et al., Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis,2005.8(1):p.63-71.
33. Addison, C.L., T.O. Daniel, M.D. Burdick, et al., The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+CXC chemokine-induced angiogenic activity. J Immunol,2000.165(9):p.5269-77.
34. De Larco, J.E., B.R. Wuertz, K.A. Rosner, et al., A potential role for interleukin-8 in the metastatic phenotype of breast carcinoma cells. Am J Pathol,2001.158(2):p.639-46.
35. Akiba, J., H. Yano, S. Ogasawara, et al., Expression and function of interleukin-8 in human hepatocellular carcinoma. Int J Oncol,2001.18(2):p. 257-64.
36. Haraguchi, M., K. Komuta, A. Akashi, et al., Elevated IL-8 levels in the drainage vein of resectable Dukes'C colorectal cancer indicate high risk for developing hepatic metastasis. Oncol Rep,2002.9(1):p.159-65.
37. Lu, P.R., Y. Nakamoto, Y. Nemoto-Sasaki, et al., Potential interaction between CCR1 and its ligand, CCL3, induced by endogenously produced interleukin-1 in human hepatomas. American Journal of Pathology,2003.162(4):p. 1249-1258.
38. Wu, X.F., J. Fan, X.Y Wang, et al., Downregulation of CCR1 inhibits human hepatocellular carcinoma cell invasion. Biochemical and Biophysical Research Communications,2007.355(4):p.866-871.
39. Rubie, C., V.O. Frick, M. Wagner, et al., Enhanced expression and clinical significance of CC-chemokine MIP-3 alpha in hepatocellular carcinoma. Scand J Immunol,2006.63(6):p.468-77.
40. Uchida, H., Y. Iwashita, A. Sasaki, et al., Chemokine receptor CCR6 as a prognostic factor after hepatic resection for hepatocellular carcinoma. Journal of Gastroenterology and Hepatology,2006.21(1):p.161-168.