The inflammatory microenvironment in hepatocellular carcinoma: A pivotal role for tumor-associated macrophages

BioMed Research International

Volumn 2013, Issue , 2013, Pages

  Capece, Daria ^a   Fischietti, Mariafausta ^a   Verzella, Daniela ^a   Gaggiano, Agata ^a   Cicciarelli, Germana ^a   Tessitore, Alessandra ^a   Zazzeroni, Francesca ^a   Alesse, Edoardo ^a  

^a UNIVERSITY OF L'AQUILA   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

ARGINASE 1; CD163 ANTIGEN; CHEMOKINE RECEPTOR CCR6; CHEMOKINE RECEPTOR CXCR4; COLONY STIMULATING FACTOR 1; CYCLOOXYGENASE 2; EOTAXIN 2; GELATINASE A; GELATINASE B; GLYPICAN 3; HLA DR ANTIGEN; HYPOXIA INDUCIBLE FACTOR 1; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IMMUNOGLOBULIN FC FRAGMENT; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 13; INTERLEUKIN 1BETA; INTERLEUKIN 23; INTERLEUKIN 4; INTERLEUKIN 6; MACROPHAGE DERIVED CHEMOKINE; MESSENGER RNA; MONOCYTE CHEMOTACTIC PROTEIN 1; PLATELET DERIVED GROWTH FACTOR BETA RECEPTOR; STAT3 PROTEIN; THYMUS AND ACTIVATION REGULATED CHEMOKINE; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR ALPHA; CYTOKINE;

ADAPTIVE IMMUNITY; ANGIOGENESIS; CANCER GROWTH; CANCER PROGNOSIS; CELL CYCLE PROGRESSION; CELL DIFFERENTIATION; CELL INVASION; CELL MIGRATION; CELL PROLIFERATION; CYTOKINE PRODUCTION; GENE EXPRESSION PROFILING; GENE OVEREXPRESSION; HUMAN; INTRACELLULAR SIGNALING; LIVER CELL CARCINOMA; NONHUMAN; OXIDATIVE STRESS; PHENOTYPE; PROTEIN EXPRESSION; REVIEW; TUMOR ASSOCIATED LEUKOCYTE; TUMOR GROWTH; TUMOR MICROENVIRONMENT; DISEASE COURSE; GENETICS; INFLAMMATION; LEUKOCYTE; LIVER TUMOR; MACROPHAGE; METABOLISM; PATHOLOGY; SIGNAL TRANSDUCTION;

CARCINOMA, HEPATOCELLULAR; CYTOKINES; DISEASE PROGRESSION; HUMANS; INFLAMMATION; LEUKOCYTES; LIVER NEOPLASMS; MACROPHAGES; NF-KAPPA B; SIGNAL TRANSDUCTION; TUMOR MICROENVIRONMENT;

EID: 84874642641     PISSN: 23146133     EISSN: 23146141     Source Type: Journal    
DOI: 10.1155/2013/187204     Document Type: Review

References (172)

1. Yang J. D., Nakamura I., Roberts L. R., The tumor microenvironment in hepatocellular carcinoma: current status and therapeutic targets. Seminars in Cancer Biology 2011 21 1 35 43 2-s2.0-79952038728 10.1016/j.semcancer.2010.10. 007
2. Bruix J., Boix L., Sala M., Llovet J. M., Focus on hepatocellular carcinoma. Cancer Cell 2004 5 3 215 219 2-s2.0-1642544603 10.1016/S1535-6108(04) 00058-3 (Pubitemid 38402113)
3. Berasain C., Castillo J., Perugorria M. J., Latasa M. U., Prieto J., Avila M. A., Inflammation and liver cancer: new molecular links. Annals of the New York Academy of Sciences 2009 1155 206 221 2-s2.0-61649106928 10.1111/j.1749-6632.2009.03704.x
4. Porta C., Riboldi E., Sica A., Mechanisms linking pathogens-associated inflammation and cancer. Cancer Letters 2011 305 2 250 262 2-s2.0-79955465043 10.1016/j.canlet.2010.10.012
5. Budhu A., Xin W. W., The role of cytokines in hepatocellular carcinoma. Journal of Leukocyte Biology 2006 80 6 1197 1213 2-s2.0-33845420396 10.1189/jlb.0506297 (Pubitemid 44904957)
6. Leonardi G. C., Candido S., Cervello M., The tumor microenvironment in hepatocellular carcinoma. International Journal of Oncology 2012 40 6 1733 1747 2-s2.0-84865044419 10.3892/ijo.2012.1408
7. Pikarsky E., Porat R. M., Stein I., Abramovitch R., Amit S., Kasem S., Gutkovich-Pyest E., Uriell-Shoval S., Galun E., Ben-Neriah Y., NF- B functions as a tumour promoter in inflammation-associated cancer. Nature 2004 431 7007 461 466 2-s2.0-4644324186 10.1038/nature02924 (Pubitemid 39329586)
8. Luedde T., Schwabe R. F., NF- B in the liver-linking injury, fibrosis and hepatocellular carcinoma. Nature Reviews Gastroenterology and Hepatology 2011 8 2 108 118 2-s2.0-79751492851 10.1038/nrgastro.2010.213
9. Mantovani A., Germano G., Marchesi F., Locatelli M., Biswas S. K., Cancer-promoting tumor-associated macrophages: new vistas and open questions. European Journal of Immunology 2011 41 9 2522 2525 2-s2.0-80052138920 10.1002/eji.201141894
10. Solinas G., Germano G., Mantovani A., Allavena P., Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. Journal of Leukocyte Biology 2009 86 5 1065 1073 2-s2.0-70350728931 10.1189/jlb.0609385
11. Porta C., Larghi P., Rimoldi M., Grazia Totaro M., Allavena P., Mantovani A., Sica A., Cellular and molecular pathways linking inflammation and cancer. Immunobiology 2009 214 9-10 761 777 2-s2.0-68349121579 10.1016/j.imbio.2009.06. 014
12. Mantovani A., Sica A., Macrophages, innate immunity and cancer: balance, tolerance, and diversity. Current Opinion in Immunology 2010 22 2 231 237 2-s2.0-77950944395 10.1016/j.coi.2010.01.009
13. Qian B. Z., Pollard J. W., Macrophage diversity enhances tumor progression and metastasis. Cell 2010 141 1 39 51 2-s2.0-77950950894 10.1016/j.cell.2010.03.014
14. Mantovani A., Sozzani S., Locati M., Allavena P., Sica A., Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in Immunology 2002 23 11 549 555 2-s2.0-0036839143 10.1016/S1471-4906(02)02302-5 (Pubitemid 35223554)
15. Gordon S., Taylor P. R., Monocyte and macrophage heterogeneity. Nature Reviews Immunology 2005 5 12 953 964 2-s2.0-28544446111 10.1038/nri1733 (Pubitemid 41746764)
16. Biswas S. K., Mantovani A., Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunology 2010 11 10 889 896 2-s2.0-77956976681 10.1038/ni.1937
17. Movahedi K., Laoui D., Gysemans C., Baeten M., Stangé G., Van Bossche J. D., Mack M., Pipeleers D., In't Veld P., De Baetselier P., Van Ginderachter J. A., Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Research 2010 70 14 5728 5739 2-s2.0-77955038532 10.1158/0008-5472.CAN-09-4672
18. Stout R. D., Jiang C., Matta B., Tietzel I., Watkins S. K., Suttles J., Macrophages sequentially change their functional phenotype in response to changes in microenvironmental influences. The Journal of Immunology 2005 175 1 342 349 2-s2.0-21244443731 (Pubitemid 40884337)
19. Gabrilovich D. I., Nagaraj S., Myeloid-derived suppressor cells as regulators of the immune system. Nature Reviews Immunology 2009 9 3 162 174 2-s2.0-61349100687 10.1038/nri2506
20. Chang C. I., Liao J. C., Kuo L., Macrophage arginase promotes tumor cell growth and suppresses nitric oxide-mediated tumor cytotoxicity. Cancer Research 2001 61 3 1100 1106 2-s2.0-0035113742 (Pubitemid 32174431)
21. Davel L. E., Jasnis M. A., De la Torre E., Gotoh T., Diament M., Magenta G., Sacerdote de Lustig E., Sales M. E., Arginine metabolic pathways involved in the modulation of tumor-induced angiogenesis by macrophages. FEBS Letters 2002 532 1-2 216 220 2-s2.0-0037021412 10.1016/S0014-5793(02)03682-7 (Pubitemid 35375892)
22. Pollard J. W., Tumour-educated macrophages promote tumour progression and metastasis. Nature Reviews Cancer 2004 4 1 71 78 2-s2.0-0347123433 (Pubitemid 38082155)
23. Lewis C. E., Pollard J. W., Distinct role of macrophages in different tumor microenvironments. Cancer Research 2006 66 2 605 612 2-s2.0-31544441610 10.1158/0008-5472.CAN-05-4005 (Pubitemid 43165918)
24. Sica A., Bronte V., Altered macrophage differentiation and immune dysfunction in tumor development. The Journal of Clinical Investigation 2007 117 5 1155 1166 2-s2.0-34248172324 10.1172/JCI31422 (Pubitemid 46718400)
25. Kusmartsev S., Gabrilovich D. I., STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. The Journal of Immunology 2005 174 8 4880 4891 2-s2.0-17044366637
26. Tsai C. S., Chen F. H., Wang C. C., Huang H. L., Jung S. M., Wu C. J., Lee C. C., McBride W. H., Chiang C. S., Hong J. H., Macrophages from irradiated tumors express higher levels of iNOS, arginase-I and COX-2, and promote tumor growth. International Journal of Radiation Oncology Biology Physics 2007 68 2 499 507 2-s2.0-34247844643 10.1016/j.ijrobp.2007.01.041 (Pubitemid 46694184)
27. Sugai H., Kono K., Takahashi A., Ichihara F., Kawaida H., Fujii H., Matsumoto Y., Characteristic alteration of monocytes with increased intracellular IL-10 and IL-12 in patients with advanced-stage gastric cancer. Journal of Surgical Research 2004 116 2 277 287 2-s2.0-0842285547 10.1016/j.jss.2003.10.008 (Pubitemid 38175318)
28. Hagemann T., Wilson J., Burke F., Kulbe H., Li N. F., Plüddemann A., Charles K., Gordon S., Balkwill F. R., Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. The Journal of Immunology 2006 176 8 5023 5032 2-s2.0-33645760428
29. Biswas S. K., Gangi L., Paul S., Schioppa T., Saccani A., Sironi M., Bottazzi B., Doni A., Vincenzo B., Pasqualini F., Vago L., Nebuloni M., Mantovani A., Sica A., A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF- B and enhanced IRF-3/STAT1 activation). Blood 2006 107 5 2112 2122 2-s2.0-33344460032 10.1182/blood-2005- 01-0428 (Pubitemid 43289397)
30. Kuang D. M., Wu Y., Chen N., Cheng J., Zhuang S. M., Zheng L., Tumor-derived hyaluronan induces formation of immunosuppressive macrophages through transient early activation of monocytes. Blood 2007 110 2 587 595 2-s2.0-34547113798 10.1182/blood-2007-01-068031 (Pubitemid 47105397)
31. Wu Y., Zheng L., Dynamic education of macrophages in different areas of human tumors. Cancer Microenvironment. In press 2-s2.0-84861980743 10.1007/s12307-012-0113-z
32. Kuang D. M., Peng C., Zhao Q., Wu Y., Chen M. S., Zheng L., Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells. Hepatology 2010 51 1 154 164 2-s2.0-73449111925 10.1002/hep.23291
33. Pietras K., Pahler J., Bergers G., Hanahan D., Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting. PLoS Medicine 2008 5 1, article e19 2-s2.0-38849202330 10.1371/journal.pmed.0050019 (Pubitemid 351198267)
34. Zhu X. D., Zhang J. B., Zhuang P. Y., Zhu H. G., Zhang W., Xiong Y. Q., Wu W. Z., Wang L., Tang Z. Y., Sun H. C., High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma. Journal of Clinical Oncology 2008 26 16 2707 2716 2-s2.0-45749137283 10.1200/JCO.2007.15. 6521
35. Benetti A., Berenzi A., Gambarotti M., Garrafa E., Gelati M., Dessy E., Portolani N., Piardi T., Giulini S. M., Caruso A., Invernici G., Parati E. A., Nicosia R., Alessandri G., Transforming growth factor- β 1 and CD105 promote the migration of hepatocellular carcinoma-derived endothelium. Cancer Research 2008 68 20 8626 8634 2-s2.0-54249139202 10.1158/0008-5472.CAN-08-1218
36. Takai H., Kato A., Kato C., Watanabe T., Matsubara K., Suzuki M., Kataoka H., The expression profile of glypican-3 and its relation to macrophage population in human hepatocellular carcinoma. Liver International 2009 29 7 1056 1064 2-s2.0-67650474215 10.1111/j.1478-3231.2008.01968.x
37. Jia J. B., Wang W. Q., Sun H. C., Zhu X. D., Liu L., Zhuang P. Y., Zhang J. B., Zhang W., Xu H. X., Kong L. Q., Lu L., Wu W. Z., Wang L., Tang Z. Y., High expression of macrophage colony-stimulating factor-1 receptor in peritumoral liver tissue is associated with poor outcome in hepatocellular carcinoma after curative resection. Oncologist 2010 15 7 732 743 2-s2.0-77956097076 10.1634/theoncologist.2009-0170
38. Haybaeck J., Zeller N., Wolf M. J., Weber A., Wagner U., Kurrer M. O., Bremer J., Iezzi G., Graf R., Clavien P. A., Thimme R., Blum H., Nedospasov S. A., Zatloukal K., Ramzan M., Ciesek S., Pietschmann T., Marche P. N., Karin M., Kopf M., Browning J. L., Aguzzi A., Heikenwalder M., A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 2009 16 4 295 308 2-s2.0-70349568358 10.1016/j.ccr.2009.08.021
39. Chen T. A., Wang J. L., Hung S. W., Chu C. L., Cheng Y. C., Liang S. M., Recombinant VP1, an akt inhibitor, suppresses progression of hepatocellular carcinoma by inducing apoptosis and modulation of CCL2 production. PLoS ONE 2011 6 8 2-s2.0-79961053391 10.1371/journal.pone.0023317 e23317
40. Sakai Y., Honda M., Fujinaga H., Tatsumi I., Mizukoshi E., Nakamoto Y., Kaneko S., Common transcriptional signature of tumor-infiltrating mononuclear inflammatory cells and peripheral blood mononuclear cells in hepatocellular carcinoma patients. Cancer Research 2008 68 24 10267 10279 2-s2.0-57749116168 10.1158/0008-5472.CAN-08-0911
41. Budhu A., Forgues M., Ye Q. H., Jia H. L., He P., Zanetti K. A., Kammula U. S., Chen Y., Qin L. X., Tang Z. Y., Wang X. W., Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 2006 10 2 99 111 2-s2.0-33747029250 10.1016/j.ccr.2006.06.016 (Pubitemid 44202603)
42. Zhou J., Ding T., Pan W., Zhu L. Y., Li A., Zheng L., Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. International Journal of Cancer 2009 125 7 1640 1648 2-s2.0-68549136586 10.1002/ijc.24556
43. Kuang D. M., Zhao Q., Peng C., Xu J., Zhang J. P., Wu C., Zheng L., Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. The Journal of Experimental Medicine 2009 206 6 1327 1337 2-s2.0-67449110979 10.1084/jem.20082173
44. Ding T., Xu J., Wang F., Shi M., Zhang Y., Li S. P., Zheng L., High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Human Pathology 2009 40 3 381 389 2-s2.0-59049106749 10.1016/j.humpath.2008.08.011
45. Li Y. W., Qiu S. J., Fan J., Gao Q., Zhou J., Xiao Y. S., Xu Y., Wang X. Y., Sun J., Huang X. W., Tumor-infiltrating macrophages can predict favorable prognosis in hepatocellular carcinoma after resection. Journal of Cancer Research and Clinical Oncology 2009 135 3 439 449 2-s2.0-59449106245 10.1007/s00432-008-0469-0
46. Chew V., Tow C., Teo M., Wong H. L., Chan J., Gehring A., Loh M., Bolze A., Quek R., Lee V. K. M., Lee K. H., Abastado J. P., Toh H. C., Nardin A., Inflammatory tumour microenvironment is associated with superior survival in hepatocellular carcinoma patients. Journal of Hepatology 2010 52 3 370 379 2-s2.0-77549084467 10.1016/j.jhep.2009.07.013
47. Wyckoff J. B., Wang Y., Lin E. Y., Li J. F., Goswami S., Stanley E. R., Segall J. E., Pollard J. W., Condeelis J., Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Research 2007 67 6 2649 2656 2-s2.0-34047246527 10.1158/0008-5472.CAN-06-1823 (Pubitemid 46548952)
48. Lee J. S., Heo J., Libbrecht L., Chu I. S., Kaposi-Novak P., Calvisi D. F., Mikaelyan A., Roberts L. R., Demetris A. J., Sun Z., Nevens F., Roskams T., Thorgeirsson S. S., A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nature Medicine 2006 12 4 410 416 2-s2.0-33645742425 10.1038/nm1377
49. Hoshida Y., Villanueva A., Kobayashi M., Peix J., Chiang D. Y., Camargo A., Gupta S., Moore J., Wrobel M. J., Lerner J., Reich M., Chan J. A., Glickman J. N., Ikeda K., Hashimoto M., Watanabe G., Daidone M. G., Roayaie S., Schwartz M., Thung S., Salvesen H. B., Gabriel S., Mazzaferro V., Bruix J., Friedman S. L., Kumada H., Llovet J. M., Golub T. R., Gene expression in fixed tissues and outcome in hepatocellular carcinoma. The New England Journal of Medicine 2008 359 19 1995 2004 2-s2.0-57349090407 10.1056/NEJMoa0804525
50. Maeda S., Kamata H., Luo J. L., Leffert H., Karin M., IKK β couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005 121 7 977 990 2-s2.0-21244472975 10.1016/j.cell.2005.04.014 (Pubitemid 40884391)
51. Naugler W. E., Sakurai T., Kim S., Maeda S., Kim K., Elsharkawy A. M., Karin M., Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 2007 317 5834 121 124 2-s2.0-34447327216 10.1126/science.1140485 (Pubitemid 47056470)
52. Park E. J., Lee J. H., Yu G. Y., He G., Ali S. R., Holzer R. G., Österreicher C. H., Takahashi H., Karin M., Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010 140 2 197 208 2-s2.0-74549167737 10.1016/j.cell.2009.12. 052
53. Wong V. W. S., Yu J., Cheng A. S. L., Wong G. L. H., Chan H. Y., Chu E. S. H., Ng E. K. O., Chan F. K. L., Sung J. J. Y., Chan H. L. Y., High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B. International Journal of Cancer 2009 124 12 2766 2770 2-s2.0-65649111667 10.1002/ijc.24281
54. Nakagawa H., Maeda S., Yoshida H., Tateishi R., Masuzaki R., Ohki T., Hayakawa Y., Kinoshita H., Yamakado M., Kato N., Shiina S., Omata M., Serum IL-6 levels and the risk for hepatocarcinogenesis in chronic hepatitis C patients: an analysis based on gender differences. International Journal of Cancer 2009 125 10 2264 2269 2-s2.0-70349849505 10.1002/ijc.24720
55. Hsia C. Y., Huo T. I., Chiang S. Y., Lu M. F., Sun C. L., Wu J. C., Lee P. C., Chi C. W., Lui W. Y., Lee S. D., Evaluation of interleukin-6, interleukin-10 and human hepatocyte growth factor as tumor markers for hepatocellular carcinoma. European Journal of Surgical Oncology 2007 33 2 208 212 2-s2.0-33847344307 10.1016/j.ejso.2006.10.036 (Pubitemid 46336558)
56. Reichner J. S., Mulligan J. A., Spisni R., Sotomayor E. A., Albina J. E., Bland K. I., Effect of IL-6 overexpression on the metastatic potential of rat hepatocellular carcinoma cells. Annals of Surgical Oncology 1998 5 3 279 286 2-s2.0-0031811737 10.1007/BF02303786 (Pubitemid 28249321)
57. Coskun U., Bukan N., Sancak B., Günel N., Ozenirler S., Unal A., Yucel A., Serum hepatocyte growth factor and interleukin-6 levels can distinguish patients with primary or metastatic liver tumors from those with benign liver lesions. Neoplasma 2004 51 3 209 213 2-s2.0-3042575159 (Pubitemid 38821501)
58. Tang Y., Kitisin K., Jogunoori W., Li C., Deng C. X., Mueller S. C., Ressom H. W., Rashid A., He A. R., Mendelson J. S., Jessup J. M., Shetty K., Zasloff M., Mishra B., Reddy E. P., Johnson L., Mishra L., Progenitor/stem cells give rise to liver cancer due to aberrant TGF- β and IL-6 signaling. Proceedings of the National Academy of Sciences of the United States of America 2008 105 7 2445 2450 2-s2.0-40649116943 10.1073/pnas.0705395105 (Pubitemid 351520533)
59. Werno C., Menrad H., Weigert A., Dehne N., Goerdt S., Schledzewski K., Kzhyshkowska J., Brüne B., Knockout of HIF-1 α in tumor-associated macrophages enhances M2 polarization and attenuates their pro-angiogenic responses. Carcinogenesis 2010 31 10 1863 1872 2-s2.0-77957808350 10.1093/carcin/bgq088
60. Littman D. R., Rudensky A. Y., Th17 and regulatory T cells in mediating and restraining inflammation. Cell 2010 140 6 845 858 2-s2.0-77950349016 10.1016/j.cell.2010.02.021
61. Zhang J. P., Yan J., Xu J., Pang X. H., Chen M. S., Li L., Wu C., Li S. P., Zheng L., Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients. Journal of Hepatology 2009 50 5 980 989 2-s2.0-64549108462 10.1016/j.jhep.2008.12.033
62. Fausto N., Campbell J. S., Riehle K. J., Liver regeneration. Hepatology 2006 43 1 S45 S53 2-s2.0-32044436238 10.1002/hep.20969
63. Gallucci R. M., Simeonova P. P., Toriumi W., Luster M. I., TNF- α regulates transforming growth factor- α expression in regenerating murine liver and isolated hepatocytes. The Journal of Immunology 2000 164 2 872 878 2-s2.0-0034650820 (Pubitemid 30043712)
64. Cosgrove B. D., Cheng C., Pritchard J. R., Stolz D. B., Lauffenburger D. A., Griffith L. G., An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor- α Hepatology 2008 48 1 276 288 2-s2.0-47149092247 10.1002/hep.22335 (Pubitemid 351975552)
65. Wheelhouse N. M., Chan Y. S., Gillies S. E., Caldwell H., Ross J. A., Harrison D. J., Prost S., TNF-alpha induced DNA damage in primary murine hepatocytes. International Journal of Molecular Medicine 2003 12 6 889 894
66. Wang Y., Wang W., Wang L., Wang X., Xia J., Regulatory mechanisms of interleukin-8 production induced by tumour necrosis factor- α in human hepatocellular carcinoma cells. Journal of Cellular and Molecular Medicine 2012 16 3 496 506 2-s2.0-0030984057 10.1111/j.1582-4934.2011.01337.x
67. Mueller L., Goumas F. A., Affeldt M., Sandtner S., Gehling U. M., Brilloff S., Walter J., Karnatz N., Lamszus K., Rogiers X., Broering D. C., Stromal fibroblasts in colorectal liver metastases originate from resident fibroblasts and generate an inflammatory microenvironment. American Journal of Pathology 2007 171 5 1608 1618 2-s2.0-36349034540 10.2353/ajpath.2007.060661 (Pubitemid 350158321)
68. Shiraki K., Yamanaka T., Inoue H., Kawakita T., Enokimura N., Okano H., Sugimoto K., Murata K., Nakano T., Expression of TNF-related apoptosis-inducing ligand in human hepatocellular carcinoma. International Journal of Oncology 2005 26 5 1273 1281 2-s2.0-21444450865
69. + T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Research 2009 69 20 8067 8075 2-s2.0-70350234729 10.1158/0008-5472.CAN-09-0901
70. Talaat R. M., Esmail A. A., Elwakil R., Gurgis A. A., Nasr M. I., Tumor necrosis factor-alpha -308G/A polymorphism and risk of hepatocellular carcinoma in hepatitis C virus-infected patients. Chinese Journal of Cancer 2012 31 1 29 35 2-s2.0-84856173209 10.5732/cjc.011.10258
71. Chen J., Li G., Meng H., Upregulation of B7-H1 expression is associated with macrophage infiltration in hepatocellular carcinomas. Cancer Immunology, Immunotherapy 2012 61 1 101 108 2-s2.0-84856747778 10.1007/s00262-011-1094-3
72. Ju M. J., Qiu S. J., Fan J., Xiao Y. S., Gao Q., Zhou J., Li Y. W., Tang Z. Y., Peritumoral activated hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma after curative resection. American Journal of Clinical Pathology 2009 131 4 498 510 2-s2.0-65349160340 10.1309/ AJCP86PPBNGOHNNL
73. Gao Q., Qiu S. J., Fan J., Zhou J., Wang X. Y., Xiao Y. S., Xu Y., Li Y. W., Tang Z. Y., Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. Journal of Clinical Oncology 2007 25 18 2586 2593 2-s2.0-34447277894 10.1200/JCO.2006.09.4565 (Pubitemid 47041232)
74. Fu J., Xu D., Liu Z., Shi M., Zhao P., Fu B., Zhang Z., Yang H., Zhang H., Zhou C., Yao J., Jin L., Wang H., Yang Y., Fu Y. X., Wang F. S., Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 2007 132 7 2328 2339 2-s2.0-34250005419 10.1053/j.gastro.2007.03.102 (Pubitemid 46890865)
75. Shen X., Li N., Li H., Zhang T., Wang F., Li Q., Increased prevalence of regulatory T cells in the tumor microenvironment and its correlation with TNM stage of hepatocellular carcinoma. Journal of Cancer Research and Clinical Oncology 2010 136 11 1745 1754 2-s2.0-77957607351 10.1007/s00432-010-0833-8
76. Ryschich E., Lizdenis P., Ittrich C., Benner A., Stahl S., Hamann A., Schmidt J., Knolle P., Arnold B., Hämmerling G. J., Ganss R., Molecular fingerprinting and autocrine growth regulation of endothelial cells in a murine model of hepatocellular carcinoma. Cancer Research 2006 66 1 198 211 2-s2.0-31544467539 10.1158/0008-5472.CAN-05-1636 (Pubitemid 43166026)
77. Zhao Q., Xiao X., Wu Y., Wei Y., Zhu L. Y., Zhou J., Kuang D. M., Interleukin-17-educated monocytes suppress cytotoxic T-cell function through B7-H1 in hepatocellular carcinoma patients. European Journal of Immunology 2011 41 8 2314 2322 2-s2.0-79960735970 10.1002/eji.201041282
78. + T cells in hepatocellular carcinoma patients. The Journal of Immunology 2010 185 3 1544 1549 2-s2.0-77956397098 10.4049/jimmunol.0904094
79. Uchida H., Iwashita Y., Sasaki A., Shibata K., Matsumoto T., Ohta M., Kitano S., Chemokine receptor CCR6 as a prognostic factor after hepatic resection for hepatocellular carcinoma. Journal of Gastroenterology and Hepatology 2006 21 1 161 168 2-s2.0-33645235093 10.1111/j.1440-1746.2005.04157.x
80. Shih Y.-T., Wang M.-C., Peng H.-H., Modulation of chemotactic and pro-inflammatory activities of endothelial progenitor cells by hepatocellular carcinoma. Cellular Signalling 2012 24 3 779 793 2-s2.0-84855571033 10.1016/j.cellsig.2011.11.013
81. Sutton A., Friand V., Brulé-Donneger S., Chaigneau T., Ziol M., Sainte-Catherine O., Poiré A., Saffar L., Kraemer M., Vassy J., Nahon P., Salzmann J. L., Gattegno L., Charnaux N., Stromal cell-derived factor-1/chemokine (C-X-C motif) ligand 12 stimulates human hepatoma cell growth, migration, and invasion. Molecular Cancer Research 2007 5 1 21 33 2-s2.0-33846985321 10.1158/1541-7786.MCR-06-0103
82. Liu H., Pan Z., Li A., Fu S., Lei Y., Sun H., Wu M., Zhou W., Roles of chemokine receptor 4 (CXCR4) and chemokine ligand 12 (CXCL12) in metastasis of hepatocellular carcinoma cells. Cellular and Molecular Immunology 2008 5 5 373 378 2-s2.0-63849150544 10.1038/cmi.2008.46
83. Chu H., Zhou H., Liu Y., Liu X., Hu Y., Zhang J., Functional expression of CXC chemokine recepter-4 mediates the secretion of matrix metalloproteinases from mouse hepatocarcinoma cell lines with different lymphatic metastasis ability. International Journal of Biochemistry and Cell Biology 2007 39 1 197 205 2-s2.0-33749832089 10.1016/j.biocel.2006.07.008 (Pubitemid 44559773)
84. Schimanski C. C., Bahre R., Gockel I., Müller A., Frerichs K., Hörner V., Teufel A., Simiantonaki N., Biesterfeld S., Wehler T., Schuler M., Achenbach T., Junginger T., Galle P. R., Moehler M., Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4. British Journal of Cancer 2006 95 2 210 217 2-s2.0-33745888428 10.1038/sj.bjc.6603251 (Pubitemid 44050921)
85. Liu Z., Yang L., Xu J., Zhang X., Wang B., Enhanced expression and clinical significance of chemokine receptor CXCR2 in hepatocellular carcinoma. Journal of Surgical Research 2011 166 2 241 246 2-s2.0-79952484341 10.1016/j.jss.2009.07.014
86. Breuhahn K., Longerich T., Schirmacher P., Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006 25 27 3787 3800 2-s2.0-33745552897 10.1038/sj.onc.1209556 (Pubitemid 43980474)
87. Peng S. H., Deng H., Yang J. F., Xie P. P., Li C., Li H., Feng D. Y., Significance and relationship between infiltrating inflammatory cell and tumor angiogenesis in hepatocellular carcinoma tissues. World Journal of Gastroenterology 2005 11 41 6521 6524 2-s2.0-31344466042 (Pubitemid 43136892)
88. Drucker C., Parzefall W., Teufelhofer O., Grusch M., Ellinger A., Schulte-Hermann R., Grasl-Kraupp B., Non-parenchymal liver cells support the growth advantage in the first stages of hepatocarcinogenesis. Carcinogenesis 2006 27 1 152 161 2-s2.0-29744455074 10.1093/carcin/bgi202 (Pubitemid 43025256)
89. Giannelli G., Mazzocca A., Fransvea E., Lahn M., Antonaci S., Inhibiting TGF- β signaling in hepatocellular carcinoma. Biochimica et Biophysica Acta 2011 1815 2 214 223 2-s2.0-79251633236 10.1016/j.bbcan.2010.11.004
90. Zamarron B. F., Chen W., Dual roles of immune cells and their factors in cancer development and progression. International Journal of Biological Sciences 2011 7 5 651 658 2-s2.0-79960122931
91. Volpe E., Servant N., Zollinger R., Bogiatzi S. I., Hupé P., Barillot E., Soumelis V., A critical function for transforming growth factor- β interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses. Nature Immunology 2008 9 6 650 657 2-s2.0-44049102724 10.1038/ni.1613 (Pubitemid 351712635)
92. Manel N., Unutmaz D., Littman D. R., The differentiation of human TH-17 cells requires transforming growth factor- β and induction of the nuclear receptor ROR γ t. Nature Immunology 2008 9 6 641 649 2-s2.0-44049104564 10.1038/ni.1610 (Pubitemid 351714729)
93. Fransvea E., Mazzocca A., Antonaci S., Giannelli G., Targeting transforming growth factor (TGF)- β RI inhibits activation of β 1 integrin and blocks vascular invasion in hepatocellular carcinoma. Hepatology 2009 49 3 839 850 2-s2.0-63349088695 10.1002/hep.22731
94. Giannelli G., Fransvea E., Marinosci F., Bergamini C., Colucci S., Schiraldi O., Antonaci S., Transforming growth factor- β 1 triggers hepatocellular carcinoma invasiveness via α 3 β 1 integrin. American Journal of Pathology 2002 161 1 183 193 2-s2.0-0036317838 (Pubitemid 34760784)
95. Mazzocca A., Fransvea E., Lavezzari G., Antonaci S., Giannelli G., Inhibition of transforming growth factor β receptor I kinase blocks hepatocellular carcinoma growth through neo-angiogenesis regulation. Hepatology 2009 50 4 1140 1151 2-s2.0-70350059078 10.1002/hep.23118
96. Fransvea E., Mazzocca A., Santamato A., Azzariti A., Antonaci S., Giannelli G., Kinase activation profile associated with TGF- β -dependent migration of HCC cells: a preclinical study. Cancer Chemotherapy and Pharmacology 2011 68 1 79 86 2-s2.0-79959599396 10.1007/s00280-010-1459-x
97. Giannelli G., Bergamini C., Fransvea E., Sgarra C., Antonaci S., Laminin-5 with transforming growth factor- β 1 induces epithelial to mesenchymal transition in hepatocellular carcinoma. Gastroenterology 2005 129 5 1375 1383 2-s2.0-27744527762 10.1053/j.gastro.2005.09.055 (Pubitemid 41597379)
98. Van Zijl F., Mair M., Csiszar A., Schneller D., Zulehner G., Huber H., Eferl R., Beug H., Dolznig H., Mikulits W., Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge. Oncogene 2009 28 45 4022 4033 2-s2.0-70449636444 10.1038/onc.2009.253
99. Wu J., Ru N. Y., Zhang Y., Li Y., Wei D., Ren Z., Huang X. F., Chen Z. N., Bian H., HAb18G/CD147 promotes epithelial-mesenchymal transition through TGF- β signaling and is transcriptionally regulated by Slug. Oncogene 2011 30 43 4410 4427 2-s2.0-79955455590 10.1038/onc.2011.149
100. Wang B., Hsu S. H., Majumder S., Kutay H., Huang W., Jacob S. T., Ghoshal K., TGF β -mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3. Oncogene 2010 29 12 1787 1797 2-s2.0-77950095763 10.1038/onc.2009.468
101. Huang S., He X., Ding J., Liang L., Zhao Y., Zhang Z., Yao X., Pan Z., Zhang P., Li J., Wan D., Gu J., Upregulation of miR-23a 27a 24 decreases transforming growth factor-beta-induced tumor-suppressive activities in human hepatocellular carcinoma cells. International Journal of Cancer 2008 123 4 972 978 2-s2.0-47049125858 10.1002/ijc.23580 (Pubitemid 352032429)
102. Bedossa P., Peltier E., Terris B., Franco D., Poynard T., Transforming growth factor-beta 1 (TGF- β 1) and TGF- β 1 receptors in normal, cirrhotic, and neoplastic human livers. Hepatology 1995 21 3 760 766 2-s2.0-0028959114
103. Shirai Y., Kawata S., Tamura S., Ito N., Tsushima H., Takaishi K., Kiso S., Matsuzawa Y., Plasma transforming growth factor- β 1 in patients with hepatocellular carcinoma: comparison with chronic liver diseases. Cancer 1994 73 9 2275 2279 2-s2.0-0028301747 (Pubitemid 24129108)
104. Okumoto K., Hattori E., Tamura K., Kiso S., Watanabe H., Saito K., Saito T., Togashi H., Kawata S., Possible contribution of circulating transforming growth factor- β 1 to immunity and prognosis in unresectable hepatocellular carcinoma. Liver International 2004 24 1 21 28 2-s2.0-1542709590 (Pubitemid 38351210)
105. Mamiya T., Yamazaki K., Masugi Y., Mori T., Effendi K., Du W., Hibi T., Tanabe M., Ueda M., Takayama T., Sakamoto M., Reduced transforming growth factor- β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis. Laboratory Investigation 2010 90 9 1339 1345 2-s2.0-77956100350 10.1038/labinvest.2010.105
106. Hirschi K. K., D'Amore P. A., Control of angiogenesis by the pericyte: molecular mechanisms and significance. EXS 1997 79 419 428 2-s2.0-0030639167
107. Campbell J. S., Hughes S. D., Gilbertson D. G., Palmer T. E., Holdren M. S., Haran A. C., Odell M. M., Bauer R. L., Ren H. P., Haugen H. S., Yeh M. M., Fausto N., Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Proceedings of the National Academy of Sciences of the United States of America 2005 102 9 3389 3394 2-s2.0-20044385758 10.1073/pnas.0409722102 (Pubitemid 40328055)
108. Perugorria M. J., Latasa M. U., Nicou A., Cartagena-Lirola H., Castillo J., Goñi S., Vespasiani-Gentilucci U., Zagami M. G., Lotersztajn S., Prieto J., Berasain C., Avila M. A., The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis. Hepatology 2008 48 4 1251 1261 2-s2.0-54449093971 10.1002/hep.22437
109. Berasain C., Castillo J., Prieto J., Avila M. A., New molecular targets for hepatocellular carcinoma: the ErbB1 signaling system. Liver International 2007 27 2 174 185 2-s2.0-34247598862 10.1111/j.1478-3231.2006.01424.x (Pubitemid 46680720)
110. Schiffer E., Housset C., Cacheux W., Wendum D., Desbois-Mouthon C., Rey C., Clergue F., Poupon R., Barbu V., Rosmorduc O., Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology 2005 41 2 307 314 2-s2.0-19944432263 10.1002/hep.20538 (Pubitemid 40165374)
111. Tabernero J., The role of VEGF and EGFR inhibition: implications for combining Anti-VEGF and Anti-EGFR Agents. Molecular Cancer Research 2007 5 3 203 220 2-s2.0-34147130694 10.1158/1541-7786.MCR-06-0404 (Pubitemid 46569773)
112. Yang J. C., Teng C. F., Wu H. C., Tsai H. W., Chuang H. C., Tsai T. F., Hsu Y. H., Huang W., Wu L. W., Su I. J., Enhanced expression of vascular endothelial growth factor-A in ground glass hepatocytes and its implication in hepatitis B virus hepatocarcinogenesis. Hepatology 2009 49 6 1962 1971 2-s2.0-68949091981 10.1002/hep.22889
113. Zhu A. X., Duda D. G., Ancukiewicz M., Di Tomaso E., Clark J. W., Miksad R., Fuchs C. S., Ryan D. P., Jain R. K., Exploratory analysis of early toxicity of sunitinib in advanced hepatocellular carcinoma patients: kinetics and potential biomarker value. Clinical Cancer Research 2011 17 4 918 927 2-s2.0-79951818748 10.1158/1078-0432.CCR-10-0515
114. Wu S.-D., Ma Y.-S., Fang Y., Liu L.-L., Fu D., Shen X.-Z., Role of the microenvironment in hepatocellular carcinoma development and progression. Cancer Treatment Reviews 2012 38 3 218 225 2-s2.0-84857652096 10.1016/j.ctrv.2011.06. 010
115. Arii S., Mise M., Harada T., Furutani M., Ishigami S. I., Niwano M., Mizumoto M., Fukumoto M., Imamura M., Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology 1996 24 2 316 322 2-s2.0-0029741786 10.1053/jhep.1996.v24.pm0008690399 (Pubitemid 26260026)
116. Maatta M., Soini Y., Liakka A., Autio-Harmainen H., Differential expression of matrix metalloproteinase (MMP)-2, MMP-9, and membrane type 1-MMP in hepatocellular and pancreatic adenocarcinoma: implications for tumor progression and clinical prognosis. Clinical Cancer Research 2000 6 7 2726 2734 2-s2.0-0033910993 (Pubitemid 30482111)
117. Cheng J. C. H., Chou C. H., Kuo M. L., Hsieh C. Y., Radiation-enhanced hepatocellular carcinoma cell invasion with MMP-9 expression through PI3K/Akt/NF- B signal transduction pathway. Oncogene 2006 25 53 7009 7018 2-s2.0-33750890673 10.1038/sj.onc.1209706 (Pubitemid 44722069)
118. Sakamoto Y., Mafune K., Mori M., Shiraishi T., Imamura H., Mori M., Takayama T., Makuuchi M., Overexpression of MMP-9 correlates with growth of small hepatocellular carcinoma. International Journal of Oncology 2000 17 2 237 243 2-s2.0-0034241817
119. Roderfeld M., Rath T., Lammert F., Dierkes C., Graf J., Roeb E., Innovative immunohistochemistry identifies MMP-9 expressing macrophages at the invasive front of murine HCC. World Journal of Hepatology 2010 2 5 175 179
120. Kohga K., Tatsumi T., Takehara T., Tsunematsu H., Shimizu S., Yamamoto M., Sasakawa A., Miyagi T., Hayashi N., Expression of CD133 confers malignant potential by regulating metalloproteinases in human hepatocellular carcinoma. Journal of Hepatology 2010 52 6 872 879 2-s2.0-77952429537 10.1016/j.jhep.2009. 12.030
121. Littlepage L. E., Sternlicht M. D., Rougier N., Phillips J., Gallo E., Yu Y., Williams K., Brenot A., Gordon J. I., Werb Z., Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Research 2010 70 6 2224 2234 2-s2.0-77950266184 10.1158/0008-5472.CAN-09-3515
122. Yu Q., Stamenkovic I., Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion. Genes and Development 1999 13 1 35 48 2-s2.0-0032926177 (Pubitemid 29045114)
123. Takafuji V., Forgues M., Unsworth E., Goldsmith P., Wang X. W., An osteopontin fragment is essential for tumor cell invasion in hepatocellular carcinoma. Oncogene 2007 26 44 6361 6371 2-s2.0-34547885530 10.1038/sj.onc. 1210463 (Pubitemid 47494216)
124. Zhang H., Ye Q. H., Ren N., Zhao L., Wang Y. F., Wu X., Sun H. C., Wang L., Zhang B. H., Liu Y. K., Tang Z. Y., Qin L. X., The prognostic significance of preoperative plasma levels of osteopontin in patients with hepatocellular carcinoma. Journal of Cancer Research and Clinical Oncology 2006 132 11 709 717 2-s2.0-33748369659 10.1007/s00432-006-0119-3 (Pubitemid 44337931)
125. Ramaiah S. K., Rittling S., Reviews: pathophysiological role of osteopontin in hepatic inflammation, toxicity, and cancer. Toxicological Sciences 2008 103 1 4 13 2-s2.0-42149085600 10.1093/toxsci/kfm246 (Pubitemid 351524472)
126. Kim J., Ki S. S., Lee S. D., Han C. J., Kim Y. C., Park S. H., Cho S. Y., Hong Y. J., Park H. Y., Lee M., Jung H. H., Lee K. H., Jeong S. H., Elevated plasma osteopontin levels in patients with hepatocellular carcinoma. American Journal of Gastroenterology 2006 101 9 2051 2059 2-s2.0-33748371845 10.1111/j.1572-0241.2006.00679.x (Pubitemid 44337631)
127. Ye Q. H., Qin L. X., Forgues M., He P., Kim J. W., Peng A. C., Simon R., Li Y., Robles A. I., Chen Y., Ma Z. C., Wu Z. Q., Ye S. L., Liu Y. K., Tang Z. Y., Wang X. W., Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nature Medicine 2003 9 4 416 423 2-s2.0-0037391756 10.1038/nm843 (Pubitemid 36460075)
128. Leng J., Han C., Demetris A. J., Michalopoulos G. K., Wu T., Cyclooxygenase-2 promotes hepatocellular carcinoma cell growth through Akt activation: evidence for Akt inhibition in celecoxib-induced apoptosis. Hepatology 2003 38 3 756 768 2-s2.0-0041822007 10.1053/jhep.2003.50380 (Pubitemid 37052162)
129. Cervello M., Foderà D., Florena A. M., Soresi M., Tripodo C., D'Alessandro N., Montalto G., Correlation between expression of cyclooxygenase-2 and the presence of inflammatory cells in human primary hepatocellular carcinoma: possible role in tumor promotion and angiogenesis. World Journal of Gastroenterology 2005 11 30 4638 4643 2-s2.0-23844462029 (Pubitemid 41179515)
130. Zheng Q., Tang Z. Y., Xue Q., Shi D. R., Song H. Y., Tang H. B., Invasion and metastasis of hepatocellular carcinoma in relation to urokinase-type plasminogen activator, its receptor and inhibitor. Journal of Cancer Research and Clinical Oncology 2000 126 11 641 646 2-s2.0-0033784038
131. Mantovani A., Allavena P., Sica A., Balkwill F., Cancer-related inflammation. Nature 2008 454 7203 436 444 2-s2.0-47949096781 10.1038/nature07205
132. Karin M., Nuclear factor- B in cancer development and progression. Nature 2006 441 7092 431 436 2-s2.0-33745298519 10.1038/nature04870 (Pubitemid 44050137)
133. Bonizzi G., Karin M., The two NF- B activation pathways and their role in innate and adaptive immunity. Trends in Immunology 2004 25 6 280 288 2-s2.0-2342464085 10.1016/j.it.2004.03.008 (Pubitemid 38610351)
134. Luedde T., Beraza N., Kotsikoris V., van Loo G., Nenci A., De Vos R., Roskams T., Trautwein C., Pasparakis M., Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 2007 11 2 119 132 2-s2.0-33846839443 10.1016/j.ccr.2006.12.016 (Pubitemid 46209851)
135. Sakurai T., He G., Matsuzawa A., Yu G. Y., Maeda S., Hardiman G., Karin M., Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 2008 14 2 156 165 2-s2.0-48649109203 10.1016/j.ccr.2008.06.016
136. Saccani A., Schioppa T., Porta C., Biswas S. K., Nebuloni M., Vago L., Bottazzi B., Colombo M. P., Mantovani A., Sica A., p50 nuclear factor- B overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor resistance. Cancer Research 2006 66 23 11432 11440 2-s2.0-33845752914 10.1158/0008-5472.CAN-06-1867 (Pubitemid 46009975)
137. Guiducci C., Vicari A. P., Sangaletti S., Trinchieri G., Colombo M. P., Redirecting in vivo elicited tumor infiltrating macrophages and dendritic cells towards tumor rejection. Cancer Research 2005 65 8 3437 3446 2-s2.0-17144398046 (Pubitemid 40524630)
138. Hagemann T., Lawrence T., McNeish I., Charles K. A., Kulbe H., Thompson R. G., Robinson S. C., Balkwill F. R., "Re-educating" tumor-associated macrophages by targeting NF- B. The Journal of Experimental Medicine 2008 205 6 1261 1268 2-s2.0-45149134605 10.1084/jem.20080108 (Pubitemid 351831483)
139. Hagemann T., Biswas S. K., Lawrence T., Sica A., Lewis C. E., Regulation of macrophage function in tumors: the multifaceted role of NF- B. Blood 2009 113 14 3139 3146 2-s2.0-63149160727 10.1182/blood-2008-12-172825
140. Balkwill F., Mantovani A., Inflammation and cancer: back to Virchow? The Lancet 2001 357 9255 539 545 2-s2.0-0035901090 10.1016/S0140-6736(00)04046-0 (Pubitemid 32173595)
141. Mantovani A., Sica A., Locati M., New vistas on macrophage differentiation and activation. European Journal of Immunology 2007 37 1 14 16 2-s2.0-33846352854 10.1002/eji.200636910 (Pubitemid 46128780)
142. Sica A., Allavena P., Mantovani A., Cancer related inflammation: the macrophage connection. Cancer Letters 2008 267 2 204 215 2-s2.0-47749155653 10.1016/j.canlet.2008.03.028
143. Calvisi D. F., Dr. Jekyll and Mr. Hyde: a paradoxical oncogenic and tumor suppressive role of signal transducer and activator of transcription 3 in liver cancer. Hepatology 2011 54 1 9 12 2-s2.0-79959538616 10.1002/hep.24435
144. Dalwadi H., Krysan K., Heuze-Vourc'h N., Dohadwala M., Elashoff D., Sharma S., Cacalano N., Lichtenstein A., Dubinett S., Cyclooxygenase-2-dependent activation of signal transducer and activator of transcription 3 by interleukin-6 in non-small cell lung cancer. Clinical Cancer Research 2005 11 21 7674 7682 2-s2.0-27744468499 10.1158/1078-0432.CCR-05-1205 (Pubitemid 41611609)
145. Kortylewski M., Kujawski M., Wang T., Wei S., Zhang S., Pilon-Thomas S., Niu G., Kay H., Mulé J., Kerr W. G., Jove R., Pardoll D., Yu H., Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity. Nature Medicine 2005 11 12 1314 1321 2-s2.0-28644445445 10.1038/nm1325 (Pubitemid 41752912)
146. Kortylewski M., Xin H., Kujawski M., Lee H., Liu Y., Harris T., Drake C., Pardoll D., Yu H., Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment. Cancer Cell 2009 15 2 114 123 2-s2.0-58649119388 10.1016/j.ccr.2008.12.018
147. Yu H., Kortylewski M., Pardoll D., Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nature Reviews Immunology 2007 7 1 41 51 2-s2.0-33845865825 10.1038/nri1995 (Pubitemid 46020826)
148. He G., Karin M., NF- B and STAT3- key players in liver inflammation and cancer. Cell Research 2011 21 1 159 168 2-s2.0-78650859531 10.1038/cr.2010.183
149. Calvisi D. F., Ladu S., Gorden A., Farina M., Conner E. A., Lee J. S., Factor V. M., Thorgeirsson S. S., Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006 130 4 1117 1128 2-s2.0-33645976174 10.1053/j.gastro.2006.01.006
150. Wurmbach E., Chen Y. B., Khitrov G., Zhang W., Roayaie S., Schwartz M., Fiel I., Thung S., Mazzaferro V., Bruix J., Bottinger E., Friedman S., Waxman S., Llovet J. M., Genome-wide molecular profiles of HCV-induced dysplasia and hepatocellular carcinoma. Hepatology 2007 45 4 938 947 2-s2.0-34247549347 10.1002/hep.21622 (Pubitemid 46646500)
151. He G., Yu G. Y., Temkin V., Ogata H., Kuntzen C., Sakurai T., Sieghart W., Peck-Radosavljevic M., Leffert H. L., Karin M., Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation. Cancer Cell 2010 17 3 286 297 2-s2.0-74549217325 10.1016/j.ccr.2009.12.048
152. Yoshida T., Ogata H., Kamio M., Joo A., Shiraishi H., Tokunaga Y., Sata M., Nagai H., Yoshimura A., SOCS1 is a suppressor of liver fibrosis and hepatitis-induced carcinogenesis. The Journal of Experimental Medicine 2004 199 12 1701 1707 2-s2.0-3042592451 10.1084/jem.20031675 (Pubitemid 38822003)
153. Riehle K. J., Campbell J. S., McMahan R. S., Johnson M. M., Beyer R. P., Bammler T. K., Fausto N., Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3. The Journal of Experimental Medicine 2008 205 1 91 103 2-s2.0-38749084203 10.1084/jem.20070820 (Pubitemid 351185718)
154. Ogata H., Kobayashi T., Chinen T., Takaki H., Sanada T., Minoda Y., Koga K., Takaesu G., Maehara Y., Iida M., Yoshimura A., Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology 2006 131 1 179 193 2-s2.0-33745750797 10.1053/j.gastro.2006.04. 025 (Pubitemid 44015756)
155. Liu Y., Liu A., Xu Z., Yu W., Wang H., Li C., Lin J., XZH-5 inhibits STAT3 phosphorylation and causes apoptosis in human hepatocellular carcinoma cells. Apoptosis 2011 16 5 502 510 2-s2.0-79955839265 10.1007/s10495-011-0578-0
156. Li W. C., Ye S. L., Sun R. X., Liu Y. K., Tang Z. Y., Kim Y., Karras J. G., Zhang H., Inhibition of growth and metastasis of human hepatocellular carcinoma by antisense oligonucleotide targeting signal transducer and activator of transcription 3. Clinical Cancer Research 2006 12 23 7140 7148 2-s2.0-33845771270 10.1158/1078-0432.CCR-06-0484 (Pubitemid 44974515)
157. Yan W., Chang Y., Liang X., High-mobility group box 1 activates caspase-1 and promotes hepatocellular carcinoma invasiveness and metastases. Hepatology 2012 55 6 1863 1875 2-s2.0-84861536618 10.1002/hep.25572
158. Murdoch C., Muthana M., Coffelt S. B., Lewis C. E., The role of myeloid cells in the promotion of tumour angiogenesis. Nature Reviews Cancer 2008 8 8 618 631 2-s2.0-47949090079 10.1038/nrc2444
159. Weigert A., Brüne B., Nitric oxide, apoptosis and macrophage polarization during tumor progression. Nitric Oxide-Biology and Chemistry 2008 19 2 95 102 2-s2.0-47049089532 10.1016/j.niox.2008.04.021
160. Rius J., Guma M., Schachtrup C., Akassoglou K., Zinkernagel A. S., Nizet V., Johnson R. S., Haddad G. G., Karin M., NF- B links innate immunity to the hypoxic response through transcriptional regulation of HIF-1 α Nature 2008 453 7196 807 811 2-s2.0-44849100198 10.1038/nature06905 (Pubitemid 351793778)
161. Murdoch C., Giannoudis A., Lewis C. E., Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood 2004 104 8 2224 2234 2-s2.0-4944244259 10.1182/blood-2004-03-1109 (Pubitemid 39331817)
162. Knowles H. J., Mole D. R., Ratcliffe P. J., Harris A. L., Normoxic stabilization of hypoxia-inducible factor-1 α by modulation of the labile iron pool in differentiating U937 macrophages: effect of natural resistance-associated macrophage protein 1. Cancer Research 2006 66 5 2600 2607 2-s2.0-33645080666 10.1158/0008-5472.CAN-05-2351
163. Schioppa T., Uranchimeg B., Saccani A., Biswas S. K., Doni A., Rapisarda A., Bernasconi S., Saccani S., Nebuloni M., Vago L., Mantovani A., Melillo G., Sica A., Regulation of the chemokine receptor CXCR4 by hypoxia. The Journal of Experimental Medicine 2003 198 9 1391 1402 2-s2.0-10744219598 10.1084/jem.20030267 (Pubitemid 37392484)
164. Ceradini D. J., Kulkarni A. R., Callaghan M. J., Tepper O. M., Bastidas N., Kleinman M. E., Capla J. M., Galiano R. D., Levine J. P., Gurtner G. C., Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nature Medicine 2004 10 8 858 864 2-s2.0-4043184065 10.1038/nm1075 (Pubitemid 39070860)
165. Cramer T., Yamanishi Y., Clausen B. E., Förster I., Pawlinski R., Mackman N., Haase V. H., Jaenisch R., Corr M., Nizet V., Firestein G. S., Gerber H. P., Ferrara N., Johnson R. S., HIF-1 α is essential for myeloid cell-mediated inflammation. Cell 2003 112 5 645 657 2-s2.0-0037423948 10.1016/S0092-8674(03)00154-5 (Pubitemid 36331777)
166. Doedens A. L., Stockmann C., Rubinstein M. P., Liao D., Zhang N., DeNardo D. G., Coussens L. M., Karin M., Goldrath A. W., Johnson R. S., Macrophage expression of hypoxia-inducible factor-1 α suppresses T-cell function and promotes tumor progression. Cancer Research 2010 70 19 7465 7475 2-s2.0-77957350018 10.1158/0008-5472.CAN-10-1439
167. Imtiyaz H. Z., Williams E. P., Hickey M. M., Patel S. A., Durham A. C., Yuan L. J., Hammond R., Gimotty P. A., Keith B., Simon M. C., Hypoxia-inducible factor 2 α regulates macrophage function in mouse models of acute and tumor inflammation. The Journal of Clinical Investigation 2010 120 8 2699 2714 2-s2.0-77955295091 10.1172/JCI39506
168. WeiXing C., Tiantian H., Qun N., Chaohui Y., Ping X., Inhibitory effect of Hypoxia inducible factor-1 antisense oligonucleotide on growth of human hepatocellular carcinoma cells. Medical Oncology 2008 25 1 88 92 2-s2.0-42949088151 10.1007/s12032-007-0050-8
169. Liu F., Wang P., Jiang X., Tan G., Qiao H., Jiang H., Krissansen G. W., Sun X., Antisense hypoxia-inducible factor 1 α gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinoma. Cancer Science 2008 99 10 2055 2061 2-s2.0-54949123005 10.1111/j.1349-7006.2008.00905.x
170. Cheng A. L., Kang Y. K., Chen Z., Tsao C. J., Qin S., Kim J. S., Luo R., Feng J., Ye S., Yang T. S., Xu J., Sun Y., Liang H., Liu J., Wang J., Tak W. Y., Pan H., Burock K., Zou J., Voliotis D., Guan Z., Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. The Lancet Oncology 2009 10 1 25 34 2-s2.0-57749189578 10.1016/S1470-2045(08)70285-7
171. Cheng A.-L., Guan Z., Chen Z., Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III Sorafenib Asia-Pacific trial. European Journal of Cancer 2012 48 10 1452 1465 2-s2.0-84863574234 10.1016/j.ejca.2011.12.006
172. Zhang W., Zhu X. D., Sun H. C., Xiong Y. Q., Zhuang P. Y., Xu H. X., Kong L. Q., Wang L., Wu W. Z., Tang Z. Y., Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clinical Cancer Research 2010 16 13 3420 3430 2-s2.0-77954229219 10.1158/1078-0432.CCR-09-2904