Biochemistry (Moscow)

, Volume 82, Issue 8, pp 861–873 | Cite as

Components of the hepatocellular carcinoma microenvironment and their role in tumor progression

  • M. V. Novikova
  • N. V. Khromova
  • P. B. KopninEmail author


This review summarizes recently published data on the mechanisms of tumor cell interaction with the tumor microenvironment. Tumor stroma influences the processes of hepatocarcinogenesis, epithelial-to-mesenchymal transition, invasion, and metastasis. The tumor microenvironment includes both cellular and noncellular components. Main cellular components of hepatocellular carcinoma (HCC) stroma are tumor-associated fibroblasts, hepatic stellate cells, immune cells, and endothelial cells that produce extracellular components of tumor microenvironment such as extracellular matrix, various proteins, proteolytic enzymes, growth factors, and cytokines. The noncellular components of the stroma modulate signaling pathways in tumor cells and stimulate invasion and metastasis. The tumor microenvironment composition and organization can serve as prognostic factors in HCC pathogenesis. Current approaches in HCC targeted therapy are aimed at creating efficient strategies for interrupting tumor interactions with the stroma. Recent data on the composition and role of the microenvironment in HCC pathogenesis, as well as new developments in antitumor drug design are discussed.


hepatocellular carcinoma tumor microenvironment cytokines hepatic stellate cells Kupffer cells cancer-associated fibroblasts extracellular matrix 



cancer-associated fibroblasts


extracellular matrix


epithelial-to-mesenchymal transition


hepatocellular carcinoma


hepatic stellate cells


matrix metalloproteinases


tumor-associated macrophages


tissue inhibitor of metalloproteinases


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Tang, D-J., Dong, S. S., Ma, N. F., Xie, D., Chen, L., Fu, L., Lau, S. H., Li, Y., and Guan, X. Y. (2010) Overexpression of eukaryotic initiation factor 5A2 enhances cell motility and promotes tumor metastasis in hepatocellular carcinoma, Hepatology, 51, 1255–1263.PubMedCrossRefGoogle Scholar
  2. 2.
    Amann, T., Bataille, F., Spruss, T., Muhlbauer, M., Gabele, E., Scholmerich, J., Kiefer, P., Bosserhoff, A. K., and Hellerbrand, C. (2009) Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma, Cancer Sci., 100, 646–653.PubMedCrossRefGoogle Scholar
  3. 3.
    Nitta, T., Kim, J. S., Mohuczy, D., and Behrns, K. E. (2008) Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways, Hepatology, 48, 909–919.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Wake, K. (1980) Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs, Int. Rev. Cytol., 66, 303–353.PubMedCrossRefGoogle Scholar
  5. 5.
    Friedman, S. L., Roll, F. J., Boyles, J., and Bissell, D. M. (1985) Hepatic lipocytes: the principal collagen-producing cells of normal rat liver, Proc. Natl. Acad. Sci. USA, 82, 8681–8685.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Marra, F. (2002) Chemokines in liver inflammation and fibrosis, Front. Biosci., 7, 1899–1914.CrossRefGoogle Scholar
  7. 7.
    Schwabe, R. F., Bataller, R., and Brenner, D. A. (2003) Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration, Am. J. Physiol. Gastrointest. Liver Physiol., 285, 949–958.CrossRefGoogle Scholar
  8. 8.
    Pinzani, M., Marra, F., and Carloni, V. (1998) Signal transduction in hepatic stellate cells, Liver, 18, 2–13.PubMedCrossRefGoogle Scholar
  9. 9.
    Friedman, S. L. (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver, Physiol. Rev., 88, 125–172.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Kluwe, J., Pradere, J. P., Gwak, G. Y., Mencin, A., De Minicis, S., Osterreicher, C. H., Colmenero, J., Bataller, R., and Schwabe, R. F. (2010) Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition, Gastroenterology, 138, 347–359.PubMedCrossRefGoogle Scholar
  11. 11.
    Adachi, M., and Brenner, D. A. (2008) High molecular weight adiponectin inhibits proliferation of hepatic stellate cells via activation of adenosine monophosphate-activated protein kinase, Hepatology, 47, 677–685.PubMedCrossRefGoogle Scholar
  12. 12.
    Wynn, T. A. (2008) Cellular and molecular mechanisms of fibrosis, J. Pathol., 214, 199–210.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Amann, T., Bataille, F., Spruss, T., Muhlbauer, M., Gabele, E., Scholmerich, J., Kiefer, P., Bosserhoff, A. K., and Hellerbrand, C. (2009) Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma, Cancer Sci., 100, 646–653.PubMedCrossRefGoogle Scholar
  14. 14.
    Sancho-Bru, P., Juez, E., Moreno, M., Khurdayan, V., Morales-Ruiz, M., Colmenero, J., Arroyo, V., Brenner, D. A., Gines, P., and Bataller, R. (2010) Hepatocarcinoma cells stimulate the growth, migration and expression of proangiogenic genes in human hepatic stellate cells, Liver Int., 30, 31–41.PubMedCrossRefGoogle Scholar
  15. 15.
    Santamato, A., Fransvea, E., Dituri, F., Caligiuri, A., Quaranta, M., Niimi, T., Pinzani, M., Antonac, S., and Giannelli, G. (2011) Hepatic stellate cells stimulate HCC cell migration via laminin-5 production, Clin. Sci. (Lond.), 121, 159–168.CrossRefGoogle Scholar
  16. 16.
    Bergers, G., and Song, S. (2005) The role of pericytes in blood-vessel formation and maintenance, Neur. Oncol., 7, 452–464.CrossRefGoogle Scholar
  17. 17.
    Pietras, K., and Ostman, A. (2010) Hallmarks of cancer: interactions with the tumor stroma, Exp. Cell Res., 316, 1324–1331.PubMedCrossRefGoogle Scholar
  18. 18.
    Jia, C. C., Wang, T. T., Liu, W., Fu, B. S., Hua, X., Wang, G. Y., Li, T. J., Li, X., Wu, X. Y., Tai, Y., Zhou, J., Chen, G. H., and Zhang, Q. (2013) Cancer-associated fibroblasts from hepatocellular carcinoma promote malignant cell proliferation by HGF secretion, PLoS One, 8, e63243.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Liu, F., Zhang, W., Yang, F., Feng, T., Zhou, M., Yu, Y., Yu, X., Zhao, W., Yi, F., Tang, W., and Lu, Y. (2016) Interleukin-6-stimulated progranulin expression contributes to the malignancy of hepatocellular carcinoma cells by activating mTOR signaling, Sci. Rep., 6, 21260.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Park, S. Y., Jeong, K. J., Panupinthu, N., Yu, S., Lee, J., Han, J. W., Kim, J. M., Lee, J. S., Kang, J., Park, C. G., Mills, G. B., and Lee, H. Y. (2011) Lysophosphatidic acid augments human hepatocellular carcinoma cell invasion through LPA1 receptor and MMP-9 expression, Oncogene, 30, 1351–1359.PubMedCrossRefGoogle Scholar
  21. 21.
    Infante, J. R., Matsubayashi, H., Sato, N., Tonascia, J., Klein, A. P., Riall, T. A., Yeo, C., Iacobuzio-Donahue, C., and Goggins, M. (2007) Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma, J. Clin. Oncol., 25, 319–325.PubMedCrossRefGoogle Scholar
  22. 22.
    Mazzocca, A., Dituri, F., Lupo, L., Quaranta, M., Antonaci, S., and Giannelli, G. (2011) Tumor-secreted lysophosphatidic acid accelerates hepatocellular carcinoma progression by promoting differentiation of peritumoral fibroblasts in myofibroblasts, Hepatology, 54, 920–930.PubMedCrossRefGoogle Scholar
  23. 23.
    Li, T., Yang, Y., Hua, X., Wang, G., Liu, W., Jia, C., Tai, Y., Zhang, Q., and Chen, G. (2012) Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO, Cancer Lett., 318, 154–161.PubMedCrossRefGoogle Scholar
  24. 24.
    Cheng, J. T., Deng, Y. N., Yi, H. M., Wang, G. Y., Fu, B. S., Chen, W. J., Liu, W., Tai, Y., Peng, Y. W., and Zhang, Q. (2016) Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation, Oncogenesis, 5, e198.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Gaggioli, C., Hooper, S., Hidalgo-Carcedo, C., Grosse, R., Marshall, J. F., Harrington, K., and Sahai, E. (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells, Nat. Cell Biol., 9, 1392–1400.PubMedCrossRefGoogle Scholar
  26. 26.
    Fransvea, E., Mazzocca, A., Antonaci, S., and Giannelli, G. (2009) Targeting transforming growth factor (TGF)-betaRI inhibits activation of beta1 integrin and blocks vascular invasion in hepatocellular carcinoma, Hepatology, 49, 839–850.PubMedCrossRefGoogle Scholar
  27. 27.
    Corpechot, C., Barbu, V., Wendum, D., Kinnman, N., Rey, C., Poupon, R., Housset, C., and Rosmorduc, O. (2002) Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis, Hepatology, 35, 1010–1021.PubMedCrossRefGoogle Scholar
  28. 28.
    Taura, K., De Minicis, S., Seki, E., Hatano, E., Iwaisako, K., Osterreicher, C. H., Kodama, Y., Miura, K., Ikai, I., Uemoto, S., and Brenner, D. A. (2008) Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis, Gastroenterology, 135, 1729–1738.PubMedCrossRefGoogle Scholar
  29. 29.
    Bunt, S. K., Yang, L., Sinha, P., Clements, V. K., Leips, J., and Ostrand-Rosenberg, S. (2007) Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression, Cancer Res., 67, 10019–10026.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Qian, B. Z., and Pollard, J. W. (2010) Macrophage diversity enhances tumor progression and metastasis, Cell, 141, 39–51.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Gordon, S., and Taylor, P. R. (2005) Monocyte and macrophage heterogeneity, Nat. Rev. Immunol., 5, 953–964.PubMedCrossRefGoogle Scholar
  32. 32.
    Solinas, G., Germano, G., Mantovani, A., and Allavena, P. (2009) Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation, J. Leukoc. Biol., 86, 1065–1073.PubMedCrossRefGoogle Scholar
  33. 33.
    Lewis, C. E., and Pollard, J. W. (2006) Distinct role of macrophages in different tumor microenvironments, Cancer Res., 66, 605–612.PubMedCrossRefGoogle Scholar
  34. 34.
    Wu, Y., and Zheng, L. (2012) Dynamic education of macrophages in different areas of human tumors, Cancer Microenviron., 5, 195–201.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Biswas, S. K., and Mantovani, A. (2010) Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm, Nat. Immunol., 11, 889–896.PubMedCrossRefGoogle Scholar
  36. 36.
    Pietras, K., Pahler, J., Bergers, G., and Hanahan, D. (2008) Functions of paracrine PDGF signaling in the proangiogenic tumor stroma revealed by pharmacological targeting, PLoS Med., 5, e19.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    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., and Sun, H. C. (2008) High expression of macrophage colony-stimulating factor in peritumoral liver tissue is associated with poor survival after curative resection of hepatocellular carcinoma, J. Clin. Oncol., 26, 2707–2716.PubMedCrossRefGoogle Scholar
  38. 38.
    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., and Alessandri, G. (2008) Transforming growth factorbeta1 and CD105 promote the migration of hepatocellular carcinoma-derived endothelium, Cancer Res., 68, 8626–8634.PubMedCrossRefGoogle Scholar
  39. 39.
    Mantovani, A., Sica, A., Allavena, P., Garlanda, C., and Locati, M. (2009) Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation, Hum. Immunol., 70, 325–330.PubMedCrossRefGoogle Scholar
  40. 40.
    Chen, T. A., Wang, J. L., Hung, S. W., Chu, C. L., Cheng, Y. C., and Liang, S. M. (2011) Recombinant VP1, an Akt inhibitor, suppresses progression of hepatocellular carcinoma by inducing apoptosis and modulation of CCL2 production, PLoS One, 6, e23317.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Kuang, D. M., Peng, C., Zhao, Q., Wu, Y., Chen, M. S., and Zheng, L. (2010) Activated monocytes in peritumoral stroma of hepatocellular carcinoma promote expansion of memory T helper 17 cells, Hepatology, 51, 154–164.PubMedCrossRefGoogle Scholar
  42. 42.
    Wu, K., Kryczek, I., Chen, L., Zou, W., and Welling, T. H. (2009) Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions, Cancer Res., 69, 8067–8075.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Fujii, H., and Kawada, N. (2014) Fibrogenesis in alcoholic liver disease, World J. Gastroenterol., 20, 8048–8054.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Chen, W., Jin, W., Hardegen, N., Lei, K. J., Li, L., Marinos, N., McGrady, G., and Wahl, S. M. (2003) Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3, J. Exp. Med., 198, 1875–1886.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    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., and Wang, F. S. (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients, Gastroenterology, 132, 2328–2339.PubMedCrossRefGoogle Scholar
  46. 46.
    Gao, Q., Qiu, S. J., Fan, J., Zhou, J., Wang, X. Y., Xiao, Y. S., Xu, Y., Li, Y. W., and Tang, Z. Y. (2007) Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection, J. Clin. Oncol., 25, 2586–2593.PubMedCrossRefGoogle Scholar
  47. 47.
    Baluk, P., Morikawa, S., Haskell, A., Mancuso, M., and McDonald, D. M. (2003) Abnormalities of basement membrane on blood vessels and endothelial sprouts in tumors, Am. J. Pathol., 163, 1801–1815.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    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., and Alessandri, G. (2008) Transforming growth factorbeta1 and CD105 promote the migration of hepatocellular carcinoma-derived endothelium, Cancer Res., 68, 8626–8634.PubMedCrossRefGoogle Scholar
  49. 49.
    Knipe, L., Meli, A., Hewlett, L., Bierings, R., Dempster, J., Skehel, P., Hannah, M. J., and Carter, T. (2010) A revised model for the secretion of tPA and cytokines from cultured endothelial cells, Blood, 116, 2183–2191.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    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., and Fausto, N. (2005) Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma, Proc. Natl. Acad. Sci. USA, 102, 3389–3394.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Uchimura, K., Morimoto-Tomita, M., Bistrup, A., Li, J., Lyon, M., Gallagher, J., Werb, Z., and Rosen, S. D. (2006) hSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1, BMC Biochem., 7, 2.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Lai, J. P., Chien, J. R., Moser, D. R., Staub, J. K., Aderca, I., Montoya, D. P., Matthews, T. A., Nagorney, D. M., Cunningham, J. M., Smith, D. I., Greene, E. L., Shridhar, V., and Roberts, L. R. (2004) hSulf1 sulfatase promotes apoptosis of hepatocellular cancer cells by decreasing heparin-binding growth factor signaling, Gastroenterology, 126, 231–248.PubMedCrossRefGoogle Scholar
  53. 53.
    Faouzi, S., Le Bail, B., Neaud, V., Boussarie, L., Saric, J., Bioulac-Sage, P., Balabaud, C., and Rosenbaum, J. (1999) Myofibroblasts are responsible for collagen synthesis in the stroma of human hepatocellular carcinoma: an in vivo and in vitro study, J. Hepatol., 30, 275–284.PubMedCrossRefGoogle Scholar
  54. 54.
    Ji, J., Zhao, L., Budhu, A., Forgues, M., Jia, H. L., Qin, L. X., Ye, Q. H., Yu, J., Shi, X., Tang, Z. Y., and Wang, X. W. (2010) Let-7g targets collagen type I alpha2 and inhibits cell migration in hepatocellular carcinoma, J. Hepatol., 52, 690–697.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Miner, J. H. (2008) Laminins and their roles in mammals, Microsc. Res. Tech., 71, 349–356.PubMedCrossRefGoogle Scholar
  56. 56.
    Giannelli, G., Fransvea, E., Bergamini, C., Marinosci, F., and Antonaci, S. (2003) Laminin-5 chains are expressed differentially in metastatic and nonmetastatic hepatocellular carcinoma, Clin. Cancer Res., 9, 3684–3691.PubMedGoogle Scholar
  57. 57.
    Giannelli, G., Bergamini, C., Fransvea, E., Sgarra, C., and Antonaci, S. (2005) Laminin-5 with transforming growth factor-beta1 induces epithelial to mesenchymal transition in hepatocellular carcinoma, Gastroenterology, 129, 1375–1383.PubMedCrossRefGoogle Scholar
  58. 58.
    Silva, R., D’Amico, G., Hodivala-Dilke, K. M., and Reynolds, L. E. (2008) Integrins: the keys to unlocking angiogenesis, Arterioscler. Thromb. Vasc. Biol., 28, 1703–1713.PubMedCrossRefGoogle Scholar
  59. 59.
    Fu, Y., Fang, Z., Liang, Y., Zhu, X., Prins, P., Li, Z., Wang, L., Sun, L., Jin, J., Yang, Y., and Zha, X. (2007) Overexpression of integrin beta1 inhibits proliferation of hepatocellular carcinoma cell SMMC-7721 through preventing Skp2-dependent degradation of p27 via PI3K pathway, J. Cell. Biochem., 102, 704–718.PubMedCrossRefGoogle Scholar
  60. 60.
    Mizuno, H., Ogura, M., Saito, Y., Sekine, W., Sano, R., Gotou, T., Oku, T., Itoh, S., Katabami, K., and Tsuji, T. (2008) Changes in adhesive and migratory characteristics of hepatocellular carcinoma (HCC) cells induced by expression of alpha3beta1 integrin, Biochim. Biophys. Acta, 1780, 564–570.PubMedCrossRefGoogle Scholar
  61. 61.
    Liang, C. M., Chen, L., Hu, H., Ma, H. Y., Gao, L. L., Qin, J., and Zhong, C. P. (2015) Chemokines and their receptors play important roles in the development of hepatocellular carcinoma, World J. Hepatol., 7, 1390–1402.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Akira, S., Uematsu, S., and Takeuchi, O. (2006) Pathogen recognition and innate immunity, Cell, 124, 783–801.PubMedCrossRefGoogle Scholar
  63. 63.
    Han, Y. P., Zhou, L., Wang, J., Xiong, S., Garner, W. L., French, S. W., and Tsukamoto, H. (2004) Essential role of matrix metalloproteinases in interleukin-1-induced myofibroblastic activation of hepatic stellate cell in collagen, J. Biol. Chem., 279, 4820–4828.PubMedCrossRefGoogle Scholar
  64. 64.
    Shiraki, K., Yamanaka, T., Inoue, H., Kawakita, T., Enokimura, N., Okano, H., Sugimoto, K., Murata, K., and Nakano, T. (2005) Expression of TNF-related apoptosis-inducing ligand in human hepatocellular carcinoma, Int. J. Oncol., 26, 1273–1281.PubMedGoogle Scholar
  65. 65.
    Huang, Y. S., Hwang, S. J., Chan, C. Y., Wu, J. C., Chao, Y., Chang, F. Y., and Lee, S. D. (1999) Serum levels of cytokines in hepatitis C-related liver disease: a longitudinal study, Zhonghua Yi Xue Za Zhi (Taipei), 62, 327–333.Google Scholar
  66. 66.
    Bortolami, M., Venturi, C., Giacomelli, L., Scalerta, R., Bacchetti, S., Marino, F., Floreani, A., Lise, M., Naccarato, R., and Farinati, F. (2002) Cytokine, infiltrating macrophage and T cell-mediated response to development of primary and secondary human liver cancer, Dig. Liver Dis., 34, 794–801.PubMedCrossRefGoogle Scholar
  67. 67.
    Hirankarn, N., Kimkong, I., Kummee, P., Tangkijvanich, P., and Poovorawan, Y. (2006) Interleukin-1beta gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection, World J. Gastroenterol., 12, 776–779.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Cressman, D. E., Greenbaum, L. E., DeAngelis, R. A., Ciliberto, G., Furt, E. E., Poli, V., and Taub, R. (1996) Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice, Science, 274, 1379–1383.PubMedCrossRefGoogle Scholar
  69. 69.
    Wong, V. W., Yu, J., Cheng, A. S., Wong, G. L., Chan, H. Y., Chu, E. S., Ng, E. K., Chan, F. K., Sung, J. J., and Chan, H. L. (2009) High serum interleukin-6 level predicts future hepatocellular carcinoma development in patients with chronic hepatitis B, Int. J. Cancer, 124, 2766–2770.PubMedCrossRefGoogle Scholar
  70. 70.
    Yu, H., Pardoll, D., and Jove, R. (2009) STATs in cancer inflammation and immunity: a leading role for STAT3, Nat. Rev. Cancer, 9, 798–809.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Littman, D. R., and Rudensky, A. Y. (2010) Th17 and regulatory T cells in mediating and restraining inflammation, Cell, 140, 845–858.PubMedCrossRefGoogle Scholar
  72. 72.
    Reichner, J. S., Mulligan, J. A., Spisni, R., Sotomayor, E. A., Albina, J. E., and Bland, K. I. (1998) Effect of IL-6 overexpression on the metastatic potential of rat hepatocellular carcinoma cells, Ann. Surg. Oncol., 5, 279–286.PubMedCrossRefGoogle Scholar
  73. 73.
    Kakumu, S., Okumura, A., Ishikawa, T., Yano, M., Enomoto, A., Nishimura, H., Yoshioka, K., and Yoshika, Y. (1997) Serum levels of IL-10, IL-15 and soluble tumour necrosis factor-alpha (TNF-alpha) receptors in type C chronic liver disease, Clin. Exp. Immunol., 109, 458–463.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Chau, G. Y., Wu, C. W., Lui, W. Y., Chang, T. J., Kao, H. L., Wu, L. H., King, K. L., Loong, C. C., Hsia, C. Y., and Chi, C. W. (2000) Serum interleukin-10 but not interleukin-6 is related to clinical outcome in patients with resectable hepatocellular carcinoma, Ann. Surg., 231, 552–558.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Trinchieri, G. (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity, Nat. Rev. Immunol., 3, 133–146.PubMedCrossRefGoogle Scholar
  76. 76.
    Kitaoka, S., Shiota, G., and Kawasaki, H. (2003) Serum levels of interleukin-10, interleukin-12 and soluble interleukin-2 receptor in chronic liver disease type C, Hepatogastroenterology, 50, 1569–1574.PubMedGoogle Scholar
  77. 77.
    Barajas, M., Mazzolini, G., Genove, G., Bilbao, R., Narvaiza, I., Schmitz, V., Sangro, B., Melero, I., Qian, C., and Prieto, J. (2001) Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12, Hepatology, 33, 52–61.PubMedCrossRefGoogle Scholar
  78. 78.
    Sangro, B., Mazzolini, G., Ruiz, J., Herraiz, M., Quiroga, J., Herrero, I., Benito, A., Larrache, J., Pueyo, J., Subtil, J. C., Olague, C., Sola, J., Sadaba, B., Lacasa, C., Melero, I., Qian, C., and Prieto, J. J. (2004) Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors, Clin. Oncol., 22, 1389–1397.CrossRefGoogle Scholar
  79. 79.
    Zhang, J. P., Yan, J., Xu, J., Pang, X. H., Chen, M. S., Li, L., Wu, C., Li, S. P., and Zheng, L. J. (2009) Increased intratumoral IL-17-producing cells correlate with poor survival in hepatocellular carcinoma patients, J. Hepatol., 50, 980–989.PubMedCrossRefGoogle Scholar
  80. 80.
    Gu, F. M., Li, Q. L., Gao, Q., Jiang, J. H., Zhu, K., Huang, X. Y., Pan, J. F., Yan, J., Hu, J. H., Wang, Z., Dai, Z., Fan, J., and Zhou, J. (2011) IL-17 induces AKT-dependent IL-6/JAK2/STAT3 activation and tumor progression in hepatocellular carcinoma, J. Mol. Cancer, 10, 150.CrossRefGoogle Scholar
  81. 81.
    Karin, M. (2006) Nuclear factor-kappaB in cancer development and progression, Nature, 441, 431–436.PubMedCrossRefGoogle Scholar
  82. 82.
    Wheelhouse, N. M., Chan, Y. S., Gillies, S. E., Caldwell, H., Ross, J. A., Harrison, D. J., and Prost, S. (2003) TNF-alpha induced DNA damage in primary murine hepatocyte, Int. J. Mol. Med., 12, 889–894.PubMedGoogle Scholar
  83. 83.
    Talaat, R. M., Esmail, A. A., Elwakil, R., Gurgis, A. A., and Nasr, M. I. (2012) Tumor necrosis factor-alpha -308G/A polymorphism and risk of hepatocellular carcinoma in hepatitis C virus-infected patients, Chin. J. Cancer, 31, 29–35.PubMedPubMedCentralGoogle Scholar
  84. 84.
    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., and Wang, X. W. (2006) Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment, Cancer Cell, 10, 99–111.PubMedCrossRefGoogle Scholar
  85. 85.
    Massague, J. (2008) TGFbeta in cancer, Cell, 134, 215–230.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Yamazaki, K., Masugi, Y., and Sakamoto, M. (2011) Molecular pathogenesis of hepatocellular carcinoma: altering transforming growth factor-β signaling in hepatocarcinogenesis, Dig. Dis., 29, 284–288.PubMedCrossRefGoogle Scholar
  87. 87.
    Murata, T., Ohshima, T., Yamaji, M., Hosaka, M., Miyanari, Y., Hijikata, M., and Shimotohno, K. (2005) Suppression of hepatitis C virus replicon by TGF-beta, Virology, 331, 407–417.PubMedCrossRefGoogle Scholar
  88. 88.
    Murata, M., Matsuzaki, K., Yoshida, K., Sekimoto, G., Tahashi, Y., Mori, S., Uemura, Y., Sakaida, N., Fujisawa, J., Seki, T., Kobayashi, K., Yokote, K., Koike, K., and Okazaki, K. (2009) Hepatitis B virus X protein shifts human hepatic transforming growth factor (TGF)-beta signaling from tumor suppression to oncogenesis in early chronic hepatitis B, Hepatology, 49, 1203–1217.PubMedCrossRefGoogle Scholar
  89. 89.
    Sohn, B. H., Park, I. Y., Lee, J. J., Yang, S. J., Jang, Y. J., Park, K. C., Kim, D. J., Lee, D. C., Sohn, H. A., Kim, T. W., Yoo, H. S., Choi, J. Y., Bae, Y. S., and Yeom, Y. I. (2010) Functional switching of TGF-beta1 signaling in liver cancer via epigenetic modulation of a single CpG site in TTP promoter, Gastroenterology, 138, 1898–1908.PubMedCrossRefGoogle Scholar
  90. 90.
    Wang, B., Hsu, S. H., Majumder, S., Kutay, H., Huang, W., Jacob, S. T., and Ghoshal, K. (2010) TGFbeta-mediated upregulation of hepatic miR-181b promotes hepatocarcinogenesis by targeting TIMP3, Oncogene, 29, 1787–1797.PubMedCrossRefGoogle Scholar
  91. 91.
    Okumoto, K., Hattori, E., Tamura, K., Kiso, S., Watanabe, H., Saito, K., Saito, T., Togashi, H., and Kawata, S. (2004) Possible contribution of circulating transforming growth factor-beta1 to immunity and prognosis in unresectable hepatocellular carcinoma, Liver Int., 24, 21–28.PubMedCrossRefGoogle Scholar
  92. 92.
    Gurtner, G. C., Werner, S., Barrandon, Y., and Longaker, M. T. (2008) Wound repair and regeneration, Nature, 453, 314–321.PubMedCrossRefGoogle Scholar
  93. 93.
    Amann, T., Bataille, F., Spruss, T., Dettmer, K., Wild, P., Liedtke, C., Muhlbauer, M., Kiefer, P., Oefner, P. J., Trautwein, C., Bosserhoff, A. K., and Hellerbrand, C. (2010) Reduced expression of fibroblast growth factor receptor 2IIIb in hepatocellular carcinoma induces a more aggressive growth, Am. J. Pathol., 176, 1433–1442.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Neaud, V., Faouzi, S., Guirouilh, J., Le Bail, B., Balabaud, C., Bioulac-Sage, P., and Rosenbaum, J. (1997) Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: evidence for a role of hepatocyte growth factor, Hepatology, 26, 1458–1466.PubMedCrossRefGoogle Scholar
  95. 95.
    Tavian, D., De Petro, G., Benetti, A., Portolani, N., Giulini, S. M., and Barlati, S. (2000) u-PA and c-MET mRNA expression is co-ordinately enhanced while hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma, Int. J. Cancer, 87, 644–649.PubMedCrossRefGoogle Scholar
  96. 96.
    Kaposi-Novak, P., Lee, J. S., Gomez-Quiroz, L., Coulouarn, C., Factor, V. M., and Thorgeirsson, S. S. (2006) Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype, J. Clin. Invest., 116, 1582–1595.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Semela, D., and Dufour, J. F. (2004) Angiogenesis and hepatocellular carcinoma, J. Hepatol., 41, 864–880.PubMedCrossRefGoogle Scholar
  98. 98.
    Bangoura, G., Liu, Z. S., Qian, Q., Jiang, C. Q., Yang, G. F., and Jing, S. (2007) Prognostic significance of HIF-2alpha/EPAS1 expression in hepatocellular carcinoma, World J. Gastroenterol., 13, 3176–3182.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Liu, L., Liang, H. F., Chen, X. P., Zhang, W. G., Yang, S. L., Xu, T., and Ren, L. (2010) The role of NF-kappaB in hepatitis B virus X protein-mediated upregulation of VEGF and MMPs, Cancer Invest., 28, 443–451.PubMedCrossRefGoogle Scholar
  100. 100.
    Poon, R. T., Ho, J. W., Tong, C. S., Lau, C., Ng, I. O., and Fan, S. T. (2004) Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma, Br. J. Surg., 91, 1354–1360.PubMedCrossRefGoogle Scholar
  101. 101.
    Poon, R. T., Lau, C., Yu, W. C., Fan, S. T., and Wong, J. (2004) High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: a prospective study, Oncol. Rep., 11, 1077–1084.PubMedGoogle Scholar
  102. 102.
    Castellano, G., Malaponte, G., Mazzarino, M. C., Figini, M., Marchese, F., Gangemi, P., Travali, S., Stivala, F., Canevari, S., and Libra, M. (2008) Activation of the osteopontin/matrix metalloproteinase-9 pathway correlates with prostate cancer progression, Clin. Cancer Res., 14, 7470–7480.PubMedCrossRefGoogle Scholar
  103. 103.
    Bourboulia, D., and Stetler-Stevenson, W. G. (2010) Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): positive and negative regulators in tumor cell adhesion, Semin. Cancer Biol., 20, 161–168.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Zhao, X., Sun, T., Che, N., Sun, D., Zhao, N., Dong, X. Y., Gu, Q., Yao, Z., and Sun, B. C. (2011) Promotion of hepatocellular carcinoma metastasis through matrix metalloproteinase activation by epithelial-mesenchymal transition regulator Twist1, J. Cell. Mol. Med., 15, 691–700.PubMedCrossRefGoogle Scholar
  105. 105.
    Mitsiades, N., Yu, W. H., Poulaki, V., Tsokos, M., and Stamenkovic, I. (2001) Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity, Cancer Res., 61, 577–581.PubMedGoogle Scholar
  106. 106.
    Manicone, A. M., and McGuire, J. K. (2008) Matrix metalloproteinases as modulators of inflammation, Semin. Cell Dev. Biol., 19, 34–41.PubMedCrossRefGoogle Scholar
  107. 107.
    Yu, Q., and Stamenkovic, I. (1999) Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD44-mediated tumor invasion, Genes Dev., 13, 35–48.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Chen, J. S., Wang, Q., Fu, X. H., Huang, X. H., Chen, X. L., Cao, L. Q., Chen, L. Z., Tan, H. X., Li, W., Bi, J., and Zhang, L. J. (2009) Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: association with MMP-9, Hepatol. Res., 39, 177–186.PubMedCrossRefGoogle Scholar
  109. 109.
    Takafuji, V., Forgues, M., Unsworth, E., Goldsmith, P., and Wang, X. W. (2007) An osteopontin fragment is essential for tumor cell invasion in hepatocellular carcinoma, Oncogene, 26, 6361–6371.PubMedCrossRefGoogle Scholar
  110. 110.
    Xia, D., Yan, L. N., Xie, J. G., Tong, Y., Yan, M. L., Wang, X. P., Zhang, M. M., and Zhao, L. Y. (2006) Overexpression of TIMP-1 mediated by recombinant adenovirus in hepatocellular carcinoma cells inhibits proliferation and invasion in vitro, Hepatobiliary Pancreat. Dis. Int., 5, 409–415.PubMedGoogle Scholar
  111. 111.
    Zhang, H., Wang, Y. S., Han, G., and Shi, Y. (2007) TIMP-3 gene transfection suppresses invasive and metastatic capacity of human hepatocarcinoma cell line HCC-7721, Hepatobiliary Pancreat. Dis. Int., 6, 487–491.PubMedGoogle Scholar
  112. 112.
    Wu, X. Z., Xie, G. R., and Chen, D. J. (2007) Hypoxia and hepatocellular carcinoma: the therapeutic target for hepatocellular carcinoma, Gastroenterol. Hepatol., 22, 1178–1182.CrossRefGoogle Scholar
  113. 113.
    Hamaguchi, T., Iizuka, N., Tsunedomi, R., Hamamoto, Y., Miyamoto, T., Iida, M., Tokuhisa, Y., Sakamoto, K., Takashima, M., Tamesa, T., and Oka, M. (2008) Glycolysis module activated by hypoxia-inducible factor 1alpha is related to the aggressive phenotype of hepatocellular carcinoma, Int. J. Oncol., 33, 725–731.PubMedGoogle Scholar
  114. 114.
    Liu, L., Zhu, X. D., Wang, W. Q., Shen, Y., Qin, Y., Ren, Z. G., Sun, H. C., and Tang, Z. Y. (2010) Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis, Clin. Cancer Res., 16, 2740–2750.PubMedCrossRefGoogle Scholar
  115. 115.
    Fiaschi, T., and Chiarugi, P. (2012) Oxidative stress, tumor microenvironment, and metabolic reprogramming: a diabolic liaison, Int. J. Cell Biol., 762825.Google Scholar
  116. 116.
    Guichard, C., Amaddeo, G., Imbeaud, S., Ladeiro, Y., Pelletier, L., Maad, I. B., Calderaro, J., Bioulac-Sage, P., Letexier, M., Degos, F., Clement, B., Balabaud, C., Chevet, E., Laurent, A., Couchy, G., Letouze E., Calvo, F., and Zucman-Rossi, J. (2012) Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma, Nat. Genet., 44, 694–698.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Whittaker, S., Marais, R., and Zhu, A. X. (2010) The role of signaling pathways in the development and treatment of hepatocellular carcinoma, Oncogene, 29, 4989–5005.PubMedCrossRefGoogle Scholar
  118. 118.
    Li, L., Zhao, G. D., Shi, Z., Qi, L. L., Zhou, L. Y., and Fu, Z. X. (2016) The Ras/Raf/MEK/ERK signaling pathway and its role in the occurrence and development of HCC, Oncol. Lett., 12, 3045–3050.PubMedPubMedCentralGoogle Scholar
  119. 119.
    Hwang, Y. H., Choi, J. Y., Kim, S., Chung, E. S., Kim, T., Koh, S. S., Lee, B., Bae, S. H., Kim, J., and Park, Y. M. (2004) Overexpression of c-raf-1 proto-oncogene in liver cirrhosis and hepatocellular carcinoma, Hepatol. Res., 29, 113–121.PubMedCrossRefGoogle Scholar
  120. 120.
    Gu, Y. J., Sun, W. Y., Zhang, S., Li, X. R., and Wei, W. (2016) Targeted blockade of JAK/STAT3 signaling inhibits proliferation, migration and collagen production as well as inducing the apoptosis of hepatic stellate cells, Int. J. Mol. Med., 38, 903–911.PubMedGoogle Scholar
  121. 121.
    Gollob, J. A., Wilhelm, S., Carter, C., and Kelley, S. L. (2006) Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway, Semin. Oncol., 33, 392–406.PubMedCrossRefGoogle Scholar
  122. 122.
    Leicht, D. T., Balan, V., Kaplun, A., Singh-Gupta, V., Kaplun, L., Dobson, M., and Tzivion, G. (2007) Raf kinases: function, regulation and role in human cancer, Biochim. Biophys. Acta, 1773, 1196–1212.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    De La Coste, A., Romagnolo, B., Billuart, P., Renard, C. A., Buendia, M. A., Soubrane, O., Fabre, M., Chelly, J., Beldjord, C., Kahn, A., and Perret, C. (1998) Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas, Proc. Natl. Acad. Sci. USA, 95, 8847–8851.PubMedCentralCrossRefGoogle Scholar
  124. 124.
    Giles, R. H., Van Es, J. H., and Clevers, H. (2003) Caught up in a Wnt storm: Wnt signaling in cancer, Biochim. Biophys. Acta, 1653, 1–24.PubMedGoogle Scholar
  125. 125.
    Hoshida, Y., Nijman, S. M., Kobayashi, M., Chan, J. A., Brunet, J. P., Chiang, D. Y., Villanueva, A., Newell, P., Ikeda, K., Hashimoto, M., Watanabe, G., Gabriel, S., Friedman, S. L., Kumada, H., Llovet, J. M., and Golub, T. R. (2009) Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma, Cancer Res., 69, 7385–7392.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Bansal, R., Van Baarlen, J., Storm, G., and Prakash, J. (2015) The interplay of the Notch signaling in hepatic stellate cells and macrophages determines the fate of liver fibrogenesis, Sci. Rep., 5, 18272.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Morell, C. M., Fiorotto, R., Fabris, L., and Strazzabosco, M. (2013) Notch signalling beyond liver development: emerging concepts in liver repair and oncogenesis, Clin. Res. Hepatol. Gastroenterol., 37, 447–454.PubMedCrossRefGoogle Scholar
  128. 128.
    Zhang, K., Zhang, Y. Q., Ai, W. B., Hu, Q. T., Zhang, Q. J., Wan, L. Y., Wang, X. L., Liu, C. B., and Wu, J. F. (2015) Hes1, an important gene for activation of hepatic stellate cells, is regulated by Notch1 and TGF-β/BMP signaling, World J. Gastroenterol., 21, 878–887.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Wang, M., Xue, L., Cao, Q., Lin, Y., Ding, Y., Yang, P., and Che, L. (2009) Expression of Notch1, Jagged1 and beta-catenin and their clinicopathological significance in hepatocellular carcinoma, Neoplasma, 56, 533–541.PubMedCrossRefGoogle Scholar
  130. 130.
    Wan, X., Cheng, C., Shao, Q., Lin, Z., Lu, S., and Chen, Y. (2015) CD24 promotes HCC progression via triggering Notch-related EMT and modulation of tumor microenvironment, Tumor Biol., 37, 6073–6084.CrossRefGoogle Scholar
  131. 131.
    Shen, Z., Liu, Y., Dewidar, B., Hu, J., Park, O., Feng, T., Xu, C., Yu, C., Li, Q., Meyer, C., Ilkavets, I., Muller, A., Stump-Guthier, C., Munker, S., Liebe, R., Zimmer, V., Lammert, F., Mertens, P. R., Li, H., Ten Dijke, P., Augustin, H. G., Li, J., Gao, B., Ebert, M. P., Dooley, S., Li, Y., and Weng, H. L. (2016) Delta-like ligand 4 modulates liver damage by down-regulating chemokine expression, Am. J. Pathol., 86, 1874–1889.CrossRefGoogle Scholar
  132. 132.
    Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J. F., De Oliveira, A. C., Santoro, A., Raoul, J. L., and Forner, A. N. (2008) Sorafenib in advanced hepatocellular carcinoma, N. Engl. J. Med., 359, 378–390.PubMedCrossRefGoogle Scholar
  133. 133.
    Melisi, D., Ishiyama, S., Sclabas, G. M., Fleming, J. B., Xia, Q., Tortora, G., Abbruzzese, J. L., and Chiao, P. J. (2008) LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis, Mol. Cancer Ther., 7, 829–840.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Tahmasebi, B. M., and Carloni, V. (2017) Tumor microenvironment, a paradigm in hepatocellular carcinoma progression and therapy, Int. J. Mol. Sci., 18, 405.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2017

Authors and Affiliations

  • M. V. Novikova
    • 1
  • N. V. Khromova
    • 1
  • P. B. Kopnin
    • 1
    Email author
  1. 1.Blokhin Russian Cancer Research CenterMinistry of Health of RussiaMoscowRussia

Personalised recommendations