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Abstract

Liver cancer is the second leading cause of cancer mortality worldwide, causing more than 700,000 deaths annually. Because of the wide landscape of genomic alterations and limited therapeutic success of targeting tumor cells, a recent focus has been on better understanding and possibly targeting the microenvironment in which liver tumors develop. A unique feature of liver cancer is its close association with liver fibrosis. More than 80% of hepatocellular carcinomas (HCCs) develop in fibrotic or cirrhotic livers, suggesting an important role of liver fibrosis in the premalignant environment (PME) of the liver. Cholangiocarcinoma (CCA), in contrast, is characterized by a strong desmoplasia that typically occurs in response to the tumor, suggesting a key role of cancer-associated fibroblasts (CAFs) and fibrosis in its tumor microenvironment (TME). Here, we discuss the functional contributions of myofibroblasts, CAFs, and fibrosis to the development of HCC and CCA in the hepatic PME and TME, focusing on myofibroblast- and extracellular matrix–associated growth factors, fibrosis-associated immunosuppressive pathways, as well as mechanosensitive signaling cascades that are activated by increased tissue stiffness. Better understanding of the role of myofibroblasts in HCC and CCA development and progression may provide the basis to target these cells for tumor prevention or therapy.

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2017-01-24
2024-03-28
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Literature Cited

  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. 1.  2015. Global cancer statistics, 2012. CA Cancer J. Clin. 65:87–108 [Google Scholar]
  2. Nault JC, Bioulac-Sage P, Zucman-Rossi J. 2.  2013. Hepatocellular benign tumors—from molecular classification to personalized clinical care. Gastroenterology 144:888–902 [Google Scholar]
  3. Ladep NG, Khan SA, Crossey MM, Thillainayagam AV, Taylor-Robinson SD, Toledano MB. 3.  2014. Incidence and mortality of primary liver cancer in England and Wales: changing patterns and ethnic variations. World J. Gastroenterol. 20:1544–53 [Google Scholar]
  4. Taylor-Robinson SD, Toledano MB, Arora S, Keegan TJ, Hargreaves S. 4.  et al. 2001. Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998. Gut 48:816–20 [Google Scholar]
  5. West J, Wood H, Logan RF, Quinn M, Aithal GP. 5.  2006. Trends in the incidence of primary liver and biliary tract cancers in England and Wales 1971–2001. Br. J. Cancer 94:1751–58 [Google Scholar]
  6. El-Serag HB. 6.  2011. Hepatocellular carcinoma. N. Engl. J. Med. 365:1118–27 [Google Scholar]
  7. Rizvi S, Gores GJ. 7.  2013. Pathogenesis, diagnosis, and management of cholangiocarcinoma. Gastroenterology 145:1215–29 [Google Scholar]
  8. Hanahan D, Coussens LM. 8.  2012. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309–22 [Google Scholar]
  9. Hanahan D, Weinberg RA. 9.  2011. Hallmarks of cancer: the next generation. Cell 144:646–74 [Google Scholar]
  10. Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY. 10.  et al. 2008. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N. Engl. J. Med. 359:1995–2004 [Google Scholar]
  11. Sirica AE. 11.  2012. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 9:44–54 [Google Scholar]
  12. Baffy G, Brunt EM, Caldwell SH. 12.  2012. Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace. J. Hepatol. 56:1384–91 [Google Scholar]
  13. Singal AG, El-Serag HB. 13.  2015. Hepatocellular carcinoma from epidemiology to prevention: translating knowledge into practice. Clin. Gastroenterol. Hepatol. 13:2140–51 [Google Scholar]
  14. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. 14.  2013. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann. Intern. Med. 158:329–37 [Google Scholar]
  15. Di Marco V, Calvaruso V, Ferraro D, Bavetta MG, Cabibbo G. 15.  et al. 2016. Effects of viral eradication in patients with HCV and cirrhosis differ with stage of portal hypertension. Gastroenterology 151:130–39.e2 [Google Scholar]
  16. Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM. 16.  2015. Genetic landscape and biomarkers of hepatocellular carcinoma. Gastroenterology 149:1226–39.e4 [Google Scholar]
  17. Mu X, Espanol-Suner R, Mederacke I, Affo S, Manco R. 17.  et al. 2015. Hepatocellular carcinoma originates from hepatocytes and not from the progenitor/biliary compartment. J. Clin. Investig. 125:3891–903 [Google Scholar]
  18. Hernandez-Gea V, Friedman SL. 18.  2011. Pathogenesis of liver fibrosis. Annu. Rev. Pathol. 6:425–56 [Google Scholar]
  19. Hernandez-Gea V, Toffanin S, Friedman SL, Llovet JM. 19.  2013. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology 144:512–27 [Google Scholar]
  20. Bissell MJ, Hines WC. 20.  2011. Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Nat. Med. 17:320–29 [Google Scholar]
  21. Farazi PA, DePinho RA. 21.  2006. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat. Rev. Cancer 6:674–87 [Google Scholar]
  22. Ma C, Kesarwala AH, Eggert T, Medina-Echeverz J, Kleiner DE. 22.  et al. 2016. NAFLD causes selective CD4+ T lymphocyte loss and promotes hepatocarcinogenesis. Nature 531:253–57 [Google Scholar]
  23. Maeda S, Kamata H, Luo JL, Leffert H, Karin M. 23.  2005. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121:977–90 [Google Scholar]
  24. Zhang XF, Tan X, Zeng G, Misse A, Singh S. 24.  et al. 2010. Conditional β-catenin loss in mice promotes chemical hepatocarcinogenesis: role of oxidative stress and platelet-derived growth factor receptor α/phosphoinositide 3-kinase signaling. Hepatology 52:954–65 [Google Scholar]
  25. Seki E, Schwabe RF. 25.  2015. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 61:1066–79 [Google Scholar]
  26. O'Brien AJ, Fullerton JN, Massey KA, Auld G, Sewell G. 26.  et al. 2014. Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2. Nat. Med. 20:518–23 [Google Scholar]
  27. Caviglia JM, Schwabe RF. 27.  2015. Mouse models of liver cancer. Methods Mol. Biol. 1267:165–83 [Google Scholar]
  28. Luedde T, Kaplowitz N, Schwabe RF. 28.  2014. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology 147:765–83.e4 [Google Scholar]
  29. Takehara T, Tatsumi T, Suzuki T, Rucker EB. Hennighausen L. 29.  III, et al. 2004. Hepatocyte-specific disruption of Bcl-xL leads to continuous hepatocyte apoptosis and liver fibrotic responses. Gastroenterology 127:1189–97 [Google Scholar]
  30. Vick B, Weber A, Urbanik T, Maass T, Teufel A. 30.  et al. 2009. Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes. Hepatology 49:627–36 [Google Scholar]
  31. Weber A, Boger R, Vick B, Urbanik T, Haybaeck J. 31.  et al. 2010. Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in mice. Hepatology 51:1226–36 [Google Scholar]
  32. Hikita H, Kodama T, Shimizu S, Li W, Shigekawa M. 32.  et al. 2012. Bak deficiency inhibits liver carcinogenesis: a causal link between apoptosis and carcinogenesis. J. Hepatol. 57:92–100 [Google Scholar]
  33. Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A. 33.  et al. 2007. Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11:119–32 [Google Scholar]
  34. Chen CF, Lee WC, Yang HI, Chang HC, Jen CL. 34.  et al. 2011. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma. Gastroenterology 141:1240–48.e2 [Google Scholar]
  35. Lee MH, Yang HI, Lu SN, Jen CL, Yeh SH. 35.  et al. 2010. Hepatitis C virus seromarkers and subsequent risk of hepatocellular carcinoma: long-term predictors from a community-based cohort study. J. Clin. Oncol. 28:4587–93 [Google Scholar]
  36. Liu X, He Y, Li F, Huang Q, Kato TA. 36.  et al. 2015. Caspase-3 promotes genetic instability and carcinogenesis. Mol. Cell 58:284–96 [Google Scholar]
  37. Ichim G, Lopez J, Ahmed SU, Muthalagu N, Giampazolias E. 37.  et al. 2015. Limited mitochondrial permeabilization causes DNA damage and genomic instability in the absence of cell death. Mol. Cell 57:860–72 [Google Scholar]
  38. Rojkind M, Giambrone MA, Biempica L. 38.  1979. Collagen types in normal and cirrhotic liver. Gastroenterology 76:710–19 [Google Scholar]
  39. Friedman SL. 39.  2015. Extracellular matrix. Signaling Pathways in Liver Diseases J-F Dufour, P-A Clavien 85–96 Chichester, UK: Wiley [Google Scholar]
  40. Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD. 40.  et al. 2013. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19:1617–24 [Google Scholar]
  41. Olaso E, Ikeda K, Eng FJ, Xu L, Wang LH. 41.  et al. 2001. DDR2 receptor promotes MMP-2–mediated proliferation and invasion by hepatic stellate cells. J. Clin. Investig. 108:1369–78 [Google Scholar]
  42. Walsh LA, Nawshad A, Medici D. 42.  2011. Discoidin domain receptor 2 is a critical regulator of epithelial-mesenchymal transition. Matrix Biol. 30:243–47 [Google Scholar]
  43. Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D. 43.  et al. 2013. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nat. Cell Biol. 15:677–87 [Google Scholar]
  44. Mederacke I, Hsu CC, Troeger JS, Huebener P, Mu X. 44.  et al. 2013. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4:2823 [Google Scholar]
  45. Friedman SL. 45.  2008. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88:125–72 [Google Scholar]
  46. Suh B, Park S, Shin DW, Yun JM, Yang HK. 46.  et al. 2015. High liver fibrosis index FIB-4 is highly predictive of hepatocellular carcinoma in chronic hepatitis B carriers. Hepatology 61:1261–68 [Google Scholar]
  47. Kim MN, Kim SU, Kim BK, Park JY, Kim do Y. 47.  et al. 2015. Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography–defined subclinical cirrhosis. Hepatology 61:1851–59 [Google Scholar]
  48. Akima T, Tamano M, Hiraishi H. 48.  2011. Liver stiffness measured by transient elastography is a predictor of hepatocellular carcinoma development in viral hepatitis. Hepatol. Res. 41:965–70 [Google Scholar]
  49. Wang HM, Hung CH, Lu SN, Chen CH, Lee CM. 49.  et al. 2013. Liver stiffness measurement as an alternative to fibrotic stage in risk assessment of hepatocellular carcinoma incidence for chronic hepatitis C patients. Liver Int. 33:756–61 [Google Scholar]
  50. Zhang DY, Goossens N, Guo J, Tsai MC, Chou HI. 50.  et al. 2016. A hepatic stellate cell gene expression signature associated with outcomes in hepatitis C cirrhosis and hepatocellular carcinoma after curative resection. Gut 65:1754–64 [Google Scholar]
  51. Wang Q, Fiel MI, Blank S, Luan W, Kadri H. 51.  et al. 2013. Impact of liver fibrosis on prognosis following liver resection for hepatitis B-associated hepatocellular carcinoma. Br. J. Cancer 109:573–81 [Google Scholar]
  52. Ju MJ, Qiu SJ, Fan J, Xiao YS, Gao Q. 52.  et al. 2009. Peritumoral activated hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma after curative resection. Am. J. Clin. Pathol. 131:498–510 [Google Scholar]
  53. Ji J, Eggert T, Budhu A, Forgues M, Takai A. 53.  et al. 2015. Hepatic stellate cell and monocyte interaction contributes to poor prognosis in hepatocellular carcinoma. Hepatology 62:481–95 [Google Scholar]
  54. Czauderna P, Mackinlay G, Perilongo G, Brown J, Shafford E. 54.  et al. 2002. Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group. J. Clin. Oncol. 20:2798–804 [Google Scholar]
  55. Yang JD, Kim WR, Coelho R, Mettler TA, Benson JT. 55.  et al. 2011. Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin. Gastroenterol. Hepatol. 9:64–70 [Google Scholar]
  56. Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G. 56.  et al. 2013. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed. Res. Int. 2013:187204 [Google Scholar]
  57. Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U. 57.  et al. 2009. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16:295–308 [Google Scholar]
  58. Wilson CL, Jurk D, Fullard N, Banks P, Page A. 58.  et al. 2015. NFκB1 is a suppressor of neutrophil-driven hepatocellular carcinoma. Nat. Commun. 6:6818 [Google Scholar]
  59. Moles A, Murphy L, Wilson CL, Chakraborty JB, Fox C. 59.  et al. 2014. A TLR2/S100A9/CXCL-2 signaling network is necessary for neutrophil recruitment in acute and chronic liver injury in the mouse. J. Hepatol. 60:782–91 [Google Scholar]
  60. Saito JM, Bostick MK, Campe CB, Xu J, Maher JJ. 60.  2003. Infiltrating neutrophils in bile duct-ligated livers do not promote hepatic fibrosis. Hepatol. Res. 25:180–91 [Google Scholar]
  61. Finkin S, Yuan D, Stein I, Taniguchi K, Weber A. 61.  et al. 2015. Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat. Immunol. 16:1235–44 [Google Scholar]
  62. He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H. 62.  et al. 2013. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 155:384–96 [Google Scholar]
  63. Naugler WE, Sakurai T, Kim S, Maeda S, Kim K. 63.  et al. 2007. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–24 [Google Scholar]
  64. Kovalovich K, DeAngelis RA, Li W, Furth EE, Ciliberto G, Taub R. 64.  2000. Increased toxin-induced liver injury and fibrosis in interleukin-6–deficient mice. Hepatology 31:149–59 [Google Scholar]
  65. Streetz KL, Wustefeld T, Klein C, Kallen KJ, Tronche F. 65.  et al. 2003. Lack of gp130 expression in hepatocytes promotes liver injury. Gastroenterology 125:532–43 [Google Scholar]
  66. Pradere JP, Kluwe J, de Minicis S, Jiao JJ, Gwak GY. 66.  et al. 2013. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology 58:1461–73 [Google Scholar]
  67. Miura K, Kodama Y, Inokuchi S, Schnabl B, Aoyama T. 67.  et al. 2010. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1β in mice. Gastroenterology 139:323–34.e7 [Google Scholar]
  68. Sakurai T, He G, Matsuzawa A, Yu GY, Maeda S. 68.  et al. 2008. Hepatocyte necrosis induced by oxidative stress and IL-1α release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell 14:156–65 [Google Scholar]
  69. Seki E, de Minicis S, Osterreicher CH, Kluwe J, Osawa Y. 69.  et al. 2007. TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat. Med. 13:1324–32 [Google Scholar]
  70. Dapito DH, Mencin A, Gwak GY, Pradere JP, Jang MK. 70.  et al. 2012. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21:504–16 [Google Scholar]
  71. Schreiber RD, Old LJ, Smyth MJ. 71.  2011. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 331:1565–70 [Google Scholar]
  72. Sharma P, Allison JP. 72.  2015. The future of immune checkpoint therapy. Science 348:56–61 [Google Scholar]
  73. Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T. 73.  et al. 2011. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479:547–51 [Google Scholar]
  74. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P. 74.  2010. The polarization of immune cells in the tumour environment by TGFβ. Nat. Rev. Immunol. 10:554–67 [Google Scholar]
  75. Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF. 75.  et al. 2013. Non-cell-autonomous tumor suppression by p53. Cell 153:449–60 [Google Scholar]
  76. Lai KK, Shang S, Lohia N, Booth GC, Masse DJ. 76.  et al. 2011. Extracellular matrix dynamics in hepatocarcinogenesis: a comparative proteomics study of PDGFC transgenic and Pten null mouse models. PLOS Genet. 7:e1002147 [Google Scholar]
  77. Calvo F, Ege N, Grande-Garcia A, Hooper S, Jenkins RP. 77.  et al. 2013. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15:637–46 [Google Scholar]
  78. Cieply B, Zeng G, Proverbs-Singh T, Geller DA, Monga SP. 78.  2009. Unique phenotype of hepatocellular cancers with exon-3 mutations in β-catenin gene. Hepatology 49:821–31 [Google Scholar]
  79. Dal Bello B, Rosa L, Campanini N, Tinelli C. Viera F. 79. , Torello et al. 2010. Glutamine synthetase immunostaining correlates with pathologic features of hepatocellular carcinoma and better survival after radiofrequency thermal ablation. Clin. Cancer Res. 16:2157–66 [Google Scholar]
  80. Coulouarn C, Corlu A, Glaise D, Guenon I, Thorgeirsson SS, Clement B. 80.  2012. Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma. Cancer Res. 72:2533–42 [Google Scholar]
  81. Lau EY, Lo J, Cheng BY, Ma MK, Lee JM. 81.  et al. 2016. Cancer-associated fibroblasts regulate tumor-initiating cell plasticity in hepatocellular carcinoma through c-Met/FRA1/HEY1 signaling. Cell Rep. 15:1175–89 [Google Scholar]
  82. Mikula M, Proell V, Fischer AN, Mikulits W. 82.  2006. Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-β dependent fashion. J. Cell Physiol. 209:560–67 [Google Scholar]
  83. Amann T, Bataille F, Spruss T, Muhlbauer M, Gabele E. 83.  et al. 2009. Activated hepatic stellate cells promote tumorigenicity of hepatocellular carcinoma. Cancer Sci. 100:646–53 [Google Scholar]
  84. Zhao W, Zhang L, Yin Z, Su W, Ren G. 84.  et al. 2011. Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice. Int. J. Cancer 129:2651–61 [Google Scholar]
  85. Wang ZM, Zhou LY, Liu BB, Jia QA, Dong YY. 85.  et al. 2014. Rat hepatic stellate cells alter the gene expression profile and promote the growth, migration and invasion of hepatocellular carcinoma cells. Mol. Med. Rep. 10:1725–33 [Google Scholar]
  86. Zhu AX, Duda DG, Sahani DV, Jain RK. 86.  2011. HCC and angiogenesis: possible targets and future directions. Nat. Rev. Clin. Oncol. 8:292–301 [Google Scholar]
  87. van de Veire S, Stalmans I, Heindryckx F, Oura H, Tijeras-Raballand A. 87.  et al. 2010. Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell 141:178–90 [Google Scholar]
  88. Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R. 88.  et al. 2002. Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology 35:834–42 [Google Scholar]
  89. Ding BS, Cao Z, Lis R, Nolan DJ, Guo P. 89.  et al. 2014. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature 505:97–102 [Google Scholar]
  90. Lin N, Chen Z, Lu Y, Li Y, Hu K, Xu R. 90.  2015. Role of activated hepatic stellate cells in proliferation and metastasis of hepatocellular carcinoma. Hepatol. Res. 45:326–36 [Google Scholar]
  91. Taura K, de Minicis S, Seki E, Hatano E, Iwaisako K. 91.  et al. 2008. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135:1729–38 [Google Scholar]
  92. Gordon S, Taylor PR. 92.  2005. Monocyte and macrophage heterogeneity. Nat. Rev. Immunol. 5:953–64 [Google Scholar]
  93. Condeelis J, Pollard JW. 93.  2006. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–66 [Google Scholar]
  94. Noy R, Pollard JW. 94.  2014. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41:49–61 [Google Scholar]
  95. Qian BZ, Pollard JW. 95.  2010. Macrophage diversity enhances tumor progression and metastasis. Cell 141:39–51 [Google Scholar]
  96. Zhu XD, Zhang JB, Zhuang PY, Zhu HG, Zhang W. 96.  et al. 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. 26:2707–16 [Google Scholar]
  97. Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP. 97.  et al. 2009. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206:1327–37 [Google Scholar]
  98. Ding T, Xu J, Wang F, Shi M, Zhang Y. 98.  et al. 2009. High tumor-infiltrating macrophage density predicts poor prognosis in patients with primary hepatocellular carcinoma after resection. Hum. Pathol. 40:381–89 [Google Scholar]
  99. Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M. 99.  et al. 2005. Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Investig. 115:56–65 [Google Scholar]
  100. Ide M, Kuwamura M, Kotani T, Sawamoto O, Yamate J. 100.  2005. Effects of gadolinium chloride (GdCl3) on the appearance of macrophage populations and fibrogenesis in thioacetamide-induced rat hepatic lesions. J. Comp. Pathol. 133:92–102 [Google Scholar]
  101. Li H, Wu K, Tao K, Chen L, Zheng Q. 101.  et al. 2012. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56:1342–51 [Google Scholar]
  102. Wan S, Kuo N, Kryczek I, Zou W, Welling TH. 102.  2015. Myeloid cells in hepatocellular carcinoma. Hepatology 62:1304–12 [Google Scholar]
  103. Kapanadze T, Gamrekelashvili J, Ma C, Chan C, Zhao F. 103.  et al. 2013. Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma. J. Hepatol. 59:1007–13 [Google Scholar]
  104. Hoechst B, Ormandy LA, Ballmaier M, Lehner F, Kruger C. 104.  et al. 2008. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4+CD25+Foxp3+ T cells. Gastroenterology 135:234–43 [Google Scholar]
  105. Kalathil S, Lugade AA, Miller A, Iyer R, Thanavala Y. 105.  2013. Higher frequencies of GARP+CTLA-4+Foxp3+ T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 73:2435–44 [Google Scholar]
  106. Hochst B, Schildberg FA, Sauerborn P, Gabel YA, Gevensleben H. 106.  et al. 2013. Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. J. Hepatol. 59:528–35 [Google Scholar]
  107. Zhao W, Zhang L, Xu Y, Zhang Z, Ren G. 107.  et al. 2014. Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model. Lab. Investig. 94:182–91 [Google Scholar]
  108. Resheq YJ, Li KK, Ward ST, Wilhelm A, Garg A. 108.  et al. 2015. Contact-dependent depletion of hydrogen peroxide by catalase is a novel mechanism of myeloid-derived suppressor cell induction operating in human hepatic stellate cells. J. Immunol. 194:2578–86 [Google Scholar]
  109. Xu Y, Zhao W, Xu J, Li J, Hong Z. 109.  et al. 2016. Activated hepatic stellate cells promote liver cancer by induction of myeloid-derived suppressor cells through cyclooxygenase-2. Oncotarget 7:8866–78 [Google Scholar]
  110. Arihara F, Mizukoshi E, Kitahara M, Takata Y, Arai K. 110.  et al. 2013. Increase in CD14+HLA-DR-/low myeloid-derived suppressor cells in hepatocellular carcinoma patients and its impact on prognosis. Cancer Immunol. Immunother. 62:1421–30 [Google Scholar]
  111. Hynes RO. 111.  2009. The extracellular matrix: not just pretty fibrils. Science 326:1216–19 [Google Scholar]
  112. Rombouts K, Carloni V. 112.  2013. The fibrotic microenvironment as a heterogeneity facet of hepatocellular carcinoma. Fibrogenes. Tissue Repair 6:17 [Google Scholar]
  113. Carloni V, Luong TV, Rombouts K. 113.  2014. Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: more complicated than ever. Liver Int. 34:834–43 [Google Scholar]
  114. Santamato A, Fransvea E, Dituri F, Caligiuri A, Quaranta M. 114.  et al. 2011. Hepatic stellate cells stimulate HCC cell migration via laminin-5 production. Clin. Sci. 121:159–68 [Google Scholar]
  115. Gkretsi V, Mars WM, Bowen WC, Barua L, Yang Y. 115.  et al. 2007. Loss of integrin linked kinase from mouse hepatocytes in vitro and in vivo results in apoptosis and hepatitis. Hepatology 45:1025–34 [Google Scholar]
  116. Begum NA, Mori M, Matsumata T, Takenaka K, Sugimachi K, Barnard GF. 116.  1995. Differential display and integrin α6 messenger RNA overexpression in hepatocellular carcinoma. Hepatology 22:1447–55 [Google Scholar]
  117. Zhao G, Cui J, Qin Q, Zhang J, Liu L. 117.  et al. 2010. Mechanical stiffness of liver tissues in relation to integrin β1 expression may influence the development of hepatic cirrhosis and hepatocellular carcinoma. J. Surg. Oncol. 102:482–89 [Google Scholar]
  118. Lee SK, Kim MH, Cheong JY, Cho SW, Yang SJ, Kwack K. 118.  2009. Integrin αV polymorphisms and haplotypes in a Korean population are associated with susceptibility to chronic hepatitis and hepatocellular carcinoma. Liver Int. 29:187–95 [Google Scholar]
  119. Cox D, Brennan M, Moran N. 119.  2010. Integrins as therapeutic targets: lessons and opportunities. Nat. Rev. Drug Discov. 9:804–20 [Google Scholar]
  120. Zhang DY, Friedman SL. 120.  2012. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology 56:769–75 [Google Scholar]
  121. Shrivastava A, Radziejewski C, Campbell E, Kovac L, McGlynn M. 121.  et al. 1997. An orphan receptor tyrosine kinase family whose members serve as nonintegrin collagen receptors. Mol. Cell 1:25–34 [Google Scholar]
  122. Xie B, Lin W, Ye J, Wang X, Zhang B. 122.  et al. 2015. DDR2 facilitates hepatocellular carcinoma invasion and metastasis via activating ERK signaling and stabilizing SNAIL1. J. Exp. Clin. Cancer Res. 34:101 [Google Scholar]
  123. Park JW, Lee YS, Kim JS, Lee SK, Kim BH. 123.  et al. 2015. Downregulation of discoidin domain receptor 2 decreases tumor growth of hepatocellular carcinoma. J. Cancer Res. Clin. Oncol. 141:1973–83 [Google Scholar]
  124. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M. 124.  et al. 2009. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139:891–906 [Google Scholar]
  125. Lu P, Weaver VM, Werb Z. 125.  2012. The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196:395–406 [Google Scholar]
  126. Samuel MS, Lopez JI, McGhee EJ, Croft DR, Strachan D. 126.  et al. 2011. Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell 19:776–91 [Google Scholar]
  127. Laklai H, Miroshnikova YA, Pickup MW, Collisson EA, Kim GE. 127.  et al. 2016. Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat. Med. 22:497–505 [Google Scholar]
  128. Naba A, Clauser KR, Lamar JM, Carr SA, Hynes RO. 128.  2014. Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters. eLife 3:e01308 [Google Scholar]
  129. Fernandez-Sanchez ME, Barbier S, Whitehead J, Bealle G, Michel A. 129.  et al. 2015. Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure. Nature 523:92–95 [Google Scholar]
  130. Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI. 130.  et al. 2005. Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–54 [Google Scholar]
  131. Schrader J, Gordon-Walker TT, Aucott RL, van Deemter M, Quaas A. 131.  et al. 2011. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 53:1192–205 [Google Scholar]
  132. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S. 132.  et al. 2011. Role of YAP/TAZ in mechanotransduction. Nature 474:179–83 [Google Scholar]
  133. Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN. 133.  et al. 2014. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat. Med. 20:360–67 [Google Scholar]
  134. Lu L, Li Y, Kim SM, Bossuyt W, Liu P. 134.  et al. 2010. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. PNAS 107:1437–42 [Google Scholar]
  135. Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K. 135.  et al. 2004. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J. Clin. Investig. 113:1774–83 [Google Scholar]
  136. Masuzaki R, Tateishi R, Yoshida H, Goto E, Sato T. 136.  et al. 2009. Prospective risk assessment for hepatocellular carcinoma development in patients with chronic hepatitis C by transient elastography. Hepatology 49:1954–61 [Google Scholar]
  137. Williams MJ, Clouston AD, Forbes SJ. 137.  2014. Links between hepatic fibrosis, ductular reaction, and progenitor cell expansion. Gastroenterology 146:349–56 [Google Scholar]
  138. Giannelli G, Bergamini C, Marinosci F, Fransvea E, Quaranta M. 138.  et al. 2002. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int. J. Cancer 97:425–31 [Google Scholar]
  139. Okazaki I. 139.  2012. Novel cancer-targeting agents/application strategies developed from MMP science. Anticancer Agents Med. Chem. 12:687 [Google Scholar]
  140. Jia YL, Shi L, Zhou JN, Fu CJ, Chen L. 140.  et al. 2011. Epimorphin promotes human hepatocellular carcinoma invasion and metastasis through activation of focal adhesion kinase/extracellular signal-regulated kinase/matrix metalloproteinase-9 axis. Hepatology 54:1808–18 [Google Scholar]
  141. Zhao W, Su W, Kuang P, Zhang L, Liu J. 141.  et al. 2012. The role of hepatic stellate cells in the regulation of T-cell function and the promotion of hepatocellular carcinoma. Int. J. Oncol. 41:457–64 [Google Scholar]
  142. Hoechst B, Voigtlaender T, Ormandy L, Gamrekelashvili J, Zhao F. 142.  et al. 2009. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology 50:799–807 [Google Scholar]
  143. Kang N, Gores GJ, Shah VH. 143.  2011. Hepatic stellate cells: partners in crime for liver metastases?. Hepatology 54:707–13 [Google Scholar]
  144. Rosmorduc O, Housset C. 144.  2010. Hypoxia: a link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease. Semin. Liver Dis. 30:258–70 [Google Scholar]
  145. Ankoma-Sey V, Wang Y, Dai Z. 145.  2000. Hypoxic stimulation of vascular endothelial growth factor expression in activated rat hepatic stellate cells. Hepatology 31:141–48 [Google Scholar]
  146. Sanz-Cameno P, Martin-Vilchez S, Lara-Pezzi E, Borque MJ, Salmeron J. 146.  et al. 2006. Hepatitis B virus promotes angiopoietin-2 expression in liver tissue: role of HBV X protein. Am. J. Pathol. 169:1215–22 [Google Scholar]
  147. Torimura T, Ueno T, Kin M, Harada R, Taniguchi E. 147.  et al. 2004. Overexpression of angiopoietin-1 and angiopoietin-2 in hepatocellular carcinoma. J. Hepatol. 40:799–807 [Google Scholar]
  148. Geng ZM, Li QH, Li WZ, Zheng JB, Shah V. 148.  2014. Activated human hepatic stellate cells promote growth of human hepatocellular carcinoma in a subcutaneous xenograft nude mouse model. Cell Biochem. Biophys. 70:337–47 [Google Scholar]
  149. Olaso E, Salado C, Egilegor E, Gutierrez V, Santisteban A. 149.  et al. 2003. Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis. Hepatology 37:674–85 [Google Scholar]
  150. Kang N, Yaqoob U, Geng Z, Bloch K, Liu C. 150.  et al. 2010. Focal adhesion assembly in myofibroblasts fosters a microenvironment that promotes tumor growth. Am. J. Pathol. 177:1888–900 [Google Scholar]
  151. Chen JA, Shi M, Li JQ, Qian CN. 151.  2010. Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration. Hepatol. Int. 4:537–47 [Google Scholar]
  152. Zhang ZL, Liu ZS, Sun Q. 152.  2006. Expression of angiopoietins, Tie2 and vascular endothelial growth factor in angiogenesis and progression of hepatocellular carcinoma. World J. Gastroenterol. 12:4241–45 [Google Scholar]
  153. Wirz W, Antoine M, Tag CG, Gressner AM, Korff T. 153.  et al. 2008. Hepatic stellate cells display a functional vascular smooth muscle cell phenotype in a three-dimensional co-culture model with endothelial cells. Differentiation 76:784–94 [Google Scholar]
  154. Shimizu S, Yamada N, Sawada T, Ikeda K, Kawada N. 154.  et al. 2000. In vivo and in vitro interactions between human colon carcinoma cells and hepatic stellate cells. Jpn. J. Cancer Res. 91:1285–95 [Google Scholar]
  155. Song J, Ge Z, Yang X, Luo Q, Wang C. 155.  et al. 2015. Hepatic stellate cells activated by acidic tumor microenvironment promote the metastasis of hepatocellular carcinoma via osteopontin. Cancer Lett. 356:713–20 [Google Scholar]
  156. Meindl-Beinker NM, Matsuzaki K, Dooley S. 156.  2012. TGF-β signaling in onset and progression of hepatocellular carcinoma. Dig. Dis. 30:514–23 [Google Scholar]
  157. Stover DG, Bierie B, Moses HL. 157.  2007. A delicate balance: TGF-β and the tumor microenvironment. J. Cell. Biochem. 101:851–61 [Google Scholar]
  158. Toyoda H, Komurasaki T, Uchida D, Takayama Y, Isobe T. 158.  et al. 1995. Epiregulin: a novel epidermal growth factor with mitogenic activity for rat primary hepatocytes. J. Biol. Chem. 270:7495–500 [Google Scholar]
  159. Ljubimova JY, Petrovic LM, Wilson SE, Geller SA, Demetriou AA. 159.  1997. Expression of HGF, its receptor c-met, c-myc, and albumin in cirrhotic and neoplastic human liver tissue. J. Histochem. Cytochem. 45:79–87 [Google Scholar]
  160. Neaud V, Faouzi S, Guirouilh J. Bail B, Balabaud C. 160. , Le et al. 1997. Human hepatic myofibroblasts increase invasiveness of hepatocellular carcinoma cells: evidence for a role of hepatocyte growth factor. Hepatology 26:1458–66 [Google Scholar]
  161. Goyal L, Muzumdar MD, Zhu AX. 161.  2013. Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clin. Cancer Res. 19:2310–18 [Google Scholar]
  162. Kaposi-Novak P, Lee JS, Gomez-Quiroz L, Coulouarn C, Factor VM, Thorgeirsson SS. 162.  2006. Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J. Clin. Investig. 116:1582–95 [Google Scholar]
  163. Zhao M, He HW, Sun HX, Ren KH, Shao RG. 163.  2009. Dual knockdown of N-ras and epiregulin synergistically suppressed the growth of human hepatoma cells. Biochem. Biophys. Res. Commun. 387:239–44 [Google Scholar]
  164. Yoshimoto S, Loo TM, Atarashi K, Kanda H, Sato S. 164.  et al. 2013. Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499:97–101 [Google Scholar]
  165. Sia D, Tovar V, Moeini A, Llovet JM. 165.  2013. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene 32:4861–70 [Google Scholar]
  166. Blechacz B, Komuta M, Roskams T, Gores GJ. 166.  2011. Clinical diagnosis and staging of cholangiocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 8:512–22 [Google Scholar]
  167. Everhart JE, Ruhl CE. 167.  2009. Burden of digestive diseases in the United States part III: liver, biliary tract, and pancreas. Gastroenterology 136:1134–44 [Google Scholar]
  168. Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB. 168.  et al. 2016. Expert consensus document: cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat. Rev. Gastroenterol. Hepatol. 13:261–80 [Google Scholar]
  169. Patel T. 169.  2002. Worldwide trends in mortality from biliary tract malignancies. BMC Cancer 2:10 [Google Scholar]
  170. Welzel TM, McGlynn KA, Hsing AW, O'Brien TR, Pfeiffer RM. 170.  2006. Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on the incidence of intra- and extrahepatic cholangiocarcinoma in the United States. J. Natl. Cancer Inst. 98:873–75 [Google Scholar]
  171. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. 171.  2011. Global cancer statistics. CA Cancer J. Clin. 61:69–90 [Google Scholar]
  172. Shin HR, Oh JK, Lim MK, Shin A, Kong HJ. 172.  et al. 2010. Descriptive epidemiology of cholangiocarcinoma and clonorchiasis in Korea. J. Korean Med. Sci. 25:1011–16 [Google Scholar]
  173. Shin HR, Oh JK, Masuyer E, Curado MP, Bouvard V. 173.  et al. 2010. Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci. 101:579–85 [Google Scholar]
  174. Tyson GL, El-Serag HB. 174.  2011. Risk factors for cholangiocarcinoma. Hepatology 54:173–84 [Google Scholar]
  175. Modha K, Navaneethan U. 175.  2015. Diagnosis and management of primary sclerosing cholangitis—perspectives from a therapeutic endoscopist. World J. Hepatol. 7:799–805 [Google Scholar]
  176. Razumilava N, Gores GJ. 176.  2014. Cholangiocarcinoma. Lancet 383:2168–79 [Google Scholar]
  177. Guest RV, Boulter L, Kendall TJ, Minnis-Lyons SE, Walker R. 177.  et al. 2014. Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma. Cancer Res. 74:1005–10 [Google Scholar]
  178. Mu X, Pradere JP, Affo S, Dapito DH, Friedman R. 178.  et al. 2016. Epithelial transforming growth factor-β signaling does not contribute to liver fibrosis but protects mice from cholangiocarcinoma. Gastroenterology 150:720–33 [Google Scholar]
  179. Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N. 179.  et al. 2012. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Investig. 122:2911–15 [Google Scholar]
  180. Sekiya S, Suzuki A. 180.  2012. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J. Clin. Investig. 122:3914–18 [Google Scholar]
  181. Yanger K, Zong Y, Maggs LR, Shapira SN, Maddipati R. 181.  et al. 2013. Robust cellular reprogramming occurs spontaneously during liver regeneration. Genes Dev. 27:719–24 [Google Scholar]
  182. Tarlow BD, Pelz C, Naugler WE, Wakefield L, Wilson EM. 182.  et al. 2014. Bipotential adult liver progenitors are derived from chronically injured mature hepatocytes. Cell Stem Cell 15:605–18 [Google Scholar]
  183. Chan-On W, Nairismagi ML, Ong CK, Lim WK, Dima S. 183.  et al. 2013. Exome sequencing identifies distinct mutational patterns in liver fluke–related and non-infection-related bile duct cancers. Nat. Genet. 45:1474–78 [Google Scholar]
  184. Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM. 184.  et al. 2013. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat. Genet. 45:1470–73 [Google Scholar]
  185. Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A. 185.  et al. 2015. Genomic spectra of biliary tract cancer. Nat. Genet. 47:1003–10 [Google Scholar]
  186. Ong CK, Subimerb C, Pairojkul C, Wongkham S, Cutcutache I. 186.  et al. 2012. Exome sequencing of liver fluke–associated cholangiocarcinoma. Nat. Genet. 44:690–93 [Google Scholar]
  187. Sirica AE, Gores GJ. 187.  2014. Desmoplastic stroma and cholangiocarcinoma: clinical implications and therapeutic targeting. Hepatology 59:2397–402 [Google Scholar]
  188. Kim HJ, Kim JS, Suh SJ, Lee BJ, Park JJ. 188.  et al. 2015. Cholangiocarcinoma risk as long-term outcome after hepatic resection in the hepatolithiasis patients. World J. Surg. 39:1537–42 [Google Scholar]
  189. Kajiyama K, Maeda T, Takenaka K, Sugimachi K, Tsuneyoshi M. 189.  1999. The significance of stromal desmoplasia in intrahepatic cholangiocarcinoma: a special reference of ‘scirrhous-type’ and ‘nonscirrhous-type’ growth. Am. J. Surg. Pathol. 23:892–902 [Google Scholar]
  190. Mertens JC, Fingas CD, Christensen JD, Smoot RL, Bronk SF. 190.  et al. 2013. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res. 73:897–907 [Google Scholar]
  191. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC. 191.  et al. 2014. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25:719–34 [Google Scholar]
  192. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF. 192.  et al. 2014. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735–47 [Google Scholar]
  193. Sia D, Hoshida Y, Villanueva A, Roayaie S, Ferrer J. 193.  et al. 2013. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144:829–40 [Google Scholar]
  194. Hirschfield GM, Karlsen TH, Lindor KD, Adams DH. 194.  2013. Primary sclerosing cholangitis. Lancet 382:1587–99 [Google Scholar]
  195. Sripa B, Kaewkes S, Sithithaworn P, Mairiang E, Laha T. 195.  et al. 2007. Liver fluke induces cholangiocarcinoma. PLOS Med. 4e201
  196. Qian MB, Utzinger J, Keiser J, Zhou XN. 196.  2016. Clonorchiasis. Lancet 387:800–10 [Google Scholar]
  197. Sithithaworn P, Yongvanit P, Duenngai K, Kiatsopit N, Pairojkul C. 197.  2014. Roles of liver fluke infection as risk factor for cholangiocarcinoma. J. Hepatobiliary Pancreat. Sci. 21:301–8 [Google Scholar]
  198. Sripa B, Thinkhamrop B, Mairiang E, Laha T, Kaewkes S. 198.  et al. 2012. Elevated plasma IL-6 associates with increased risk of advanced fibrosis and cholangiocarcinoma in individuals infected by Opisthorchis viverrini. PLOS Negl. Trop. Dis. 6:e1654 [Google Scholar]
  199. Togo S, Polanska UM, Horimoto Y, Orimo A. 199.  2013. Carcinoma-associated fibroblasts are a promising therapeutic target. Cancers 5:149–69 [Google Scholar]
  200. Chuaysri C, Thuwajit P, Paupairoj A, Chau-In S, Suthiphongchai T, Thuwajit C. 200.  2009. α-Smooth muscle actin-positive fibroblasts promote biliary cell proliferation and correlate with poor survival in cholangiocarcinoma. Oncol. Rep. 21:957–69 [Google Scholar]
  201. Okabe H, Beppu T, Hayashi H, Horino K, Masuda T. 201.  et al. 2009. Hepatic stellate cells may relate to progression of intrahepatic cholangiocarcinoma. Ann. Surg. Oncol. 16:2555–64 [Google Scholar]
  202. Utispan K, Thuwajit P, Abiko Y, Charngkaew K, Paupairoj A. 202.  et al. 2010. Gene expression profiling of cholangiocarcinoma-derived fibroblast reveals alterations related to tumor progression and indicates periostin as a poor prognostic marker. Mol. Cancer 9:13 [Google Scholar]
  203. Leyva-Illades D, McMillin M, Quinn M, Demorrow S. 203.  2012. Cholangiocarcinoma pathogenesis: role of the tumor microenvironment. Transl. Gastrointest. Cancer 1:71–80 [Google Scholar]
  204. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D. 204.  et al. 2009. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324:1457–61 [Google Scholar]
  205. Provenzano PP, Cuevas C, Chang AE, Goel VK. Hoff DD, Hingorani SR. 205. , Von 2012. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21:418–29 [Google Scholar]
  206. Brivio S, Cadamuro M, Fabris L, Strazzabosco M. 206.  2015. Epithelial-to-mesenchymal transition and cancer invasiveness: What can we learn from cholangiocarcinoma?. J. Clin. Med. 4:2028–41 [Google Scholar]
  207. Cadamuro M, Nardo G, Indraccolo S, Dall'olmo L, Sambado L. 207.  et al. 2013. Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology 58:1042–53 [Google Scholar]
  208. Hu Q, Tong S, Zhao X, Ding W, Gou Y. 208.  et al. 2015. Periostin mediates TGF-β-induced epithelial mesenchymal transition in prostate cancer cells. Cell Physiol. Biochem. 36:799–809 [Google Scholar]
  209. Kyutoku M, Taniyama Y, Katsuragi N, Shimizu H, Kunugiza Y. 209.  et al. 2011. Role of periostin in cancer progression and metastasis: inhibition of breast cancer progression and metastasis by anti-periostin antibody in a murine model. Int. J. Mol. Med. 28:181–86 [Google Scholar]
  210. Morra L, Moch H. 210.  2011. Periostin expression and epithelial-mesenchymal transition in cancer: a review and an update. Virchows. Arch. 459:465–75 [Google Scholar]
  211. Campbell DJ, Dumur CI, Lamour NF, Dewitt JL, Sirica AE. 211.  2012. Novel organotypic culture model of cholangiocarcinoma progression. Hepatol. Res. 42:1119–30 [Google Scholar]
  212. Dumur CI, Campbell DJ, DeWitt JL, Oyesanya RA, Sirica AE. 212.  2010. Differential gene expression profiling of cultured neu-transformed versus spontaneously-transformed rat cholangiocytes and of corresponding cholangiocarcinomas. Exp. Mol. Pathol. 89:227–35 [Google Scholar]
  213. Midwood KS, Orend G. 213.  2009. The role of tenascin-C in tissue injury and tumorigenesis. J. Cell Commun. Signal. 3:287–310 [Google Scholar]
  214. Yoshida T, Akatsuka T, Imanaka-Yoshida K. 214.  2015. Tenascin-C and integrins in cancer. Cell Adh. Migr. 9:96–104 [Google Scholar]
  215. Aishima S, Taguchi K, Terashi T, Matsuura S, Shimada M, Tsuneyoshi M. 215.  2003. Tenascin expression at the invasive front is associated with poor prognosis in intrahepatic cholangiocarcinoma. Mod. Pathol. 16:1019–27 [Google Scholar]
  216. Prakobwong S, Yongvanit P, Hiraku Y, Pairojkul C, Sithithaworn P. 216.  et al. 2010. Involvement of MMP-9 in peribiliary fibrosis and cholangiocarcinogenesis via Rac1-dependent DNA damage in a hamster model. Int. J. Cancer 127:2576–87 [Google Scholar]
  217. Sirica AE, Dumur CI, Campbell DJ, Almenara JA, Ogunwobi OO, Dewitt JL. 217.  2009. Intrahepatic cholangiocarcinoma progression: prognostic factors and basic mechanisms. Clin. Gastroenterol. Hepatol. 7:S68–78 [Google Scholar]
  218. Terada T, Okada Y, Nakanuma Y. 218.  1996. Expression of immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human normal livers and primary liver tumors. Hepatology 23:1341–44 [Google Scholar]
  219. Ling H, Roux E, Hempel D, Tao J, Smith M. 219.  et al. 2013. Transforming growth factor β neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in thioacetamide-treated rats. PLOS ONE 8e54499
  220. Fingas CD, Bronk SF, Werneburg NW, Mott JL, Guicciardi ME. 220.  et al. 2011. Myofibroblast-derived PDGF-BB promotes Hedgehog survival signaling in cholangiocarcinoma cells. Hepatology 54:2076–88 [Google Scholar]
  221. Erkan M, Reiser-Erkan C, Michalski CW, Deucker S, Sauliunaite D. 221.  et al. 2009. Cancer-stellate cell interactions perpetuate the hypoxia-fibrosis cycle in pancreatic ductal adenocarcinoma. Neoplasia 11:497–508 [Google Scholar]
  222. Sirica AE, Campbell DJ, Dumur CI. 222.  2011. Cancer-associated fibroblasts in intrahepatic cholangiocarcinoma. Curr. Opin. Gastroenterol. 27:276–84 [Google Scholar]
  223. Al-Bahrani R, Nagamori S, Leng R, Petryk A, Sergi C. 223.  2015. Differential expression of Sonic Hedgehog protein in human hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Pathol. Oncol. Res. 21:901–8 [Google Scholar]
  224. Yang L, Wang Y, Mao H, Fleig S, Omenetti A. 224.  et al. 2008. Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. J. Hepatol. 48:98–106 [Google Scholar]
  225. Theunissen JW, de Sauvage FJ. 225.  2009. Paracrine Hedgehog signaling in cancer. Cancer Res. 69:6007–10 [Google Scholar]
  226. Kim Y, Kim MO, Shin JS, Park SH, Kim SB. 226.  et al. 2014. Hedgehog signaling between cancer cells and hepatic stellate cells in promoting cholangiocarcinoma. Ann. Surg. Oncol. 21:2684–98 [Google Scholar]
  227. Boulter L, Guest RV, Kendall TJ, Wilson DH, Wojtacha D. 227.  et al. 2015. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J. Clin. Investig. 125:1269–85 [Google Scholar]
  228. Jung KY, Cho SW, Kim YA, Kim D, Oh BC. 228.  et al. 2015. Cancers with higher density of tumor-associated macrophages were associated with poor survival rates. J. Pathol. Transl. Med. 49:318–24 [Google Scholar]
  229. Hasita H, Komohara Y, Okabe H, Masuda T, Ohnishi K. 229.  et al. 2010. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci. 101:1913–19 [Google Scholar]
  230. Techasen A, Loilome W, Namwat N, Dokduang H, Jongthawin J, Yongvanit P. 230.  2012. Cytokines released from activated human macrophages induce epithelial mesenchymal transition markers of cholangiocarcinoma cells. Asian Pac. J. Cancer Prev. 13:Suppl.115–18 [Google Scholar]
  231. Techasen A, Namwat N, Loilome W, Bungkanjana P, Khuntikeo N. 231.  et al. 2012. Tumor necrosis factor-α (TNF-α) stimulates the epithelial-mesenchymal transition regulator Snail in cholangiocarcinoma. Med. Oncol. 29:3083–91 [Google Scholar]
  232. Xu LB, Liu C, Gao GQ, Yu XH, Zhang R, Wang J. 232.  2010. Nerve growth factor-β expression is associated with lymph node metastasis and nerve infiltration in human hilar cholangiocarcinoma. World J. Surg. 34:1039–45 [Google Scholar]
  233. Ogasawara S, Yano H, Higaki K, Takayama A, Akiba J. 233.  et al. 2001. Expression of angiogenic factors, basic fibroblast growth factor and vascular endothelial growth factor, in human biliary tract carcinoma cell lines. Hepatol. Res. 20:97–113 [Google Scholar]
  234. Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T. 234.  et al. 2008. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br. J. Cancer 98:418–25 [Google Scholar]
  235. Shirabe K, Shimada M, Tsujita E, Aishima S, Maehara S. 235.  et al. 2004. Prognostic factors in node-negative intrahepatic cholangiocarcinoma with special reference to angiogenesis. Am. J. Surg. 187:538–42 [Google Scholar]
  236. Thelen A, Scholz A, Weichert W, Wiedenmann B, Neuhaus P. 236.  et al. 2010. Tumor-associated angiogenesis and lymphangiogenesis correlate with progression of intrahepatic cholangiocarcinoma. Am. J. Gastroenterol. 105:1123–32 [Google Scholar]
  237. Leek RD, Lewis CE, Whitehouse R, Greenall M, Clarke J, Harris AL. 237.  1996. Association of macrophage infiltration with angiogenesis and prognosis in invasive breast carcinoma. Cancer Res. 56:4625–29 [Google Scholar]
  238. Lewis CE, Pollard JW. 238.  2006. Distinct role of macrophages in different tumor microenvironments. Cancer Res. 66:605–12 [Google Scholar]
  239. Claperon A, Mergey M, Aoudjehane L, Ho-Bouldoires TH, Wendum D. 239.  et al. 2013. Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor. Hepatology 58:2001–11 [Google Scholar]
  240. Fingas CD, Mertens JC, Razumilava N, Bronk SF, Sirica AE, Gores GJ. 240.  2012. Targeting PDGFR-β in cholangiocarcinoma. Liver Int. 32:400–9 [Google Scholar]
  241. Wiedmann MW, Mossner J. 241.  2010. Molecular targeted therapy of biliary tract cancer—results of the first clinical studies. Curr. Drug Targets 11:834–50 [Google Scholar]
  242. Riener MO, Fritzsche FR, Soll C, Pestalozzi BC, Probst-Hensch N. 242.  et al. 2010. Expression of the extracellular matrix protein periostin in liver tumours and bile duct carcinomas. Histopathology 56:600–6 [Google Scholar]
  243. Sirica AE, Almenara JA, Li C. 243.  2014. Periostin in intrahepatic cholangiocarcinoma: pathobiological insights and clinical implications. Exp. Mol. Pathol. 97:515–24 [Google Scholar]
  244. Baril P, Gangeswaran R, Mahon PC, Caulee K, Kocher HM. 244.  et al. 2007. Periostin promotes invasiveness and resistance of pancreatic cancer cells to hypoxia-induced cell death: role of the β4 integrin and the PI3k pathway. Oncogene 26:2082–94 [Google Scholar]
  245. Utispan K, Sonongbua J, Thuwajit P, Chau-In S, Pairojkul C. 245.  et al. 2012. Periostin activates integrin α5β1 through a PI3K/AKTdependent pathway in invasion of cholangiocarcinoma. Int. J. Oncol. 41:1110–18 [Google Scholar]
  246. Ruan K, Bao S, Ouyang G. 246.  2009. The multifaceted role of periostin in tumorigenesis. Cell. Mol. Life Sci. 66:2219–30 [Google Scholar]
  247. Kawahara N, Ono M, Taguchi K, Okamoto M, Shimada M. 247.  et al. 1998. Enhanced expression of thrombospondin-1 and hypovascularity in human cholangiocarcinoma. Hepatology 28:1512–17 [Google Scholar]
  248. Tang D, Nagano H, Yamamoto H, Wada H, Nakamura M. 248.  et al. 2006. Angiogenesis in cholangiocellular carcinoma: expression of vascular endothelial growth factor, angiopoietin-1/2, thrombospondin-1 and clinicopathological significance. Oncol. Rep. 15:525–32 [Google Scholar]
  249. Distler JH, Jungel A, Pileckyte M, Zwerina J, Michel BA. 249.  et al. 2007. Hypoxia-induced increase in the production of extracellular matrix proteins in systemic sclerosis. Arthritis Rheum. 56:4203–15 [Google Scholar]
  250. Sargiannidou I, Zhou J, Tuszynski GP. 250.  2001. The role of thrombospondin-1 in tumor progression. Exp. Biol. Med. 226:726–33 [Google Scholar]
  251. Lai GH, Radaeva S, Nakamura T, Sirica AE. 251.  2000. Unique epithelial cell production of hepatocyte growth factor/scatter factor by putative precancerous intestinal metaplasias and associated “intestinal-type” biliary cancer chemically induced in rat liver. Hepatology 31:1257–65 [Google Scholar]
  252. Miyamoto M, Ojima H, Iwasaki M, Shimizu H, Kokubu A. 252.  et al. 2011. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br. J. Cancer 105:131–38 [Google Scholar]
  253. Matsumoto K, Nakamura T. 253.  2006. Hepatocyte growth factor and the Met system as a mediator of tumor-stromal interactions. Int. J. Cancer 119:477–83 [Google Scholar]
  254. Ohira S, Sasaki M, Harada K, Sato Y, Zen Y. 254.  et al. 2006. Possible regulation of migration of intrahepatic cholangiocarcinoma cells by interaction of CXCR4 expressed in carcinoma cells with tumor necrosis factor-α and stromal-derived factor-1 released in stroma. Am. J. Pathol. 168:1155–68 [Google Scholar]
  255. Leelawat K, Leelawat S, Narong S, Hongeng S. 255.  2007. Roles of the MEK1/2 and AKT pathways in CXCL12/CXCR4 induced cholangiocarcinoma cell invasion. World J. Gastroenterol. 13:1561–68 [Google Scholar]
  256. Zhao S, Wang J, Qin C. 256.  2014. Blockade of CXCL12/CXCR4 signaling inhibits intrahepatic cholangiocarcinoma progression and metastasis via inactivation of canonical Wnt pathway. J. Exp. Clin. Cancer Res. 33:103 [Google Scholar]
  257. Liu H, Xue W, Ge G, Luo X, Li Y. 257.  et al. 2010. Hypoxic preconditioning advances CXCR4 and CXCR7 expression by activating HIF-1α in MSCs. Biochem. Biophys. Res. Commun. 401:509–15 [Google Scholar]
  258. Penn MS. 258.  2010. SDF-1:CXCR4 axis is fundamental for tissue preservation and repair. Am. J. Pathol. 177:2166–68 [Google Scholar]
  259. Teicher BA, Fricker SP. 259.  2010. CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin. Cancer. Res. 16:2927–31 [Google Scholar]
  260. Okabe H, Beppu T, Ueda M, Hayashi H, Ishiko T. 260.  et al. 2012. Identification of CXCL5/ENA-78 as a factor involved in the interaction between cholangiocarcinoma cells and cancer-associated fibroblasts. Int. J. Cancer 131:2234–41 [Google Scholar]
  261. Huang L, Xu AM, Liu S, Liu W, Li TJ. 261.  2014. Cancer-associated fibroblasts in digestive tumors. World J. Gastroenterol. 20:17804–18 [Google Scholar]
  262. Li H, Fan X, Houghton J. 262.  2007. Tumor microenvironment: the role of the tumor stroma in cancer. J. Cell Biochem. 101:805–15 [Google Scholar]
  263. Silzle T, Randolph GJ, Kreutz M, Kunz-Schughart LA. 263.  2004. The fibroblast: sentinel cell and local immune modulator in tumor tissue. Int. J. Cancer 108:173–80 [Google Scholar]
  264. Korpos E, Wu C, Sorokin L. 264.  2009. Multiple roles of the extracellular matrix in inflammation. Curr. Pharm. Des. 15:1349–57 [Google Scholar]
  265. Van Lint P, Libert C. 265.  2007. Chemokine and cytokine processing by matrix metalloproteinases and its effect on leukocyte migration and inflammation. J. Leukoc. Biol. 82:1375–81 [Google Scholar]
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