1932

Abstract

Cholangiocarcinoma (CCA) encompasses a group of malignancies that can arise at any point in the biliary tree. Although considered a rare cancer, the incidence of CCA is increasing globally. The silent and asymptomatic nature of these tumors, particularly in their early stages, in combination with their high aggressiveness, intra- and intertumor heterogeneity, and chemoresistance, significantly compromises the efficacy of current therapeutic options, contributing to a dismal prognosis. During the last few years, increasing efforts have been made to unveil the etiologies and pathogenesis of these tumors and to develop more effective therapies. In this review, we summarize current findings in the field of CCA, mainly focusing on the mechanisms of pathogenesis, cells of origin, genomic and epigenetic abnormalities, molecular alterations, chemoresistance, and therapies.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pathol-030220-020455
2021-01-24
2024-12-03
Loading full text...

Full text loading...

/deliver/fulltext/pathmechdis/16/1/annurev-pathol-030220-020455.html?itemId=/content/journals/10.1146/annurev-pathol-030220-020455&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Banales JM, Cardinale V, Carpino G, Marzioni M, Andersen JB et al. 2016. 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]
  2. 2. 
    Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ 2018. Cholangiocarcinoma—evolving concepts and therapeutic strategies. Nat. Rev. Clin. Oncol. 15:95–111
    [Google Scholar]
  3. 3. 
    Sia D, Villanueva A, Friedman SL, Llovet JM 2017. Liver cancer cell of origin, molecular class, and effects on patient prognosis. Gastroenterology 152:745–61
    [Google Scholar]
  4. 4. 
    Khan SA, Tavolari S, Brandi G 2019. Cholangiocarcinoma: epidemiology and risk factors. Liver Int 39:Suppl. 119–31
    [Google Scholar]
  5. 5. 
    Shaib YH, Davila JA, McGlynn K, El-Serag HB 2004. Rising incidence of intrahepatic cholangiocarcinoma in the United States: a true increase. J. Hepatol. 40:472–77
    [Google Scholar]
  6. 6. 
    Bertuccio P, Malvezzi M, Carioli G, Hashim D, Boffetta P et al. 2019. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J. Hepatol. 71:104–14
    [Google Scholar]
  7. 7. 
    Clements O, Eliahoo J, Kim JU, Taylor-Robinson SD, Khan SA 2020. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J. Hepatol. 72:95–103
    [Google Scholar]
  8. 8. 
    Farioli A, Straif K, Brandi G, Curti S, Kjaerheim K et al. 2018. Occupational exposure to asbestos and risk of cholangiocarcinoma: a population-based case-control study in four Nordic countries. Occup. Environ. Med. 75:191–98
    [Google Scholar]
  9. 9. 
    Brandi G, Di Girolamo S, Farioli A, de Rosa F, Curti S et al. 2013. Asbestos: a hidden player behind the cholangiocarcinoma increase? Findings from a case-control analysis. Cancer Causes Control 24:911–18
    [Google Scholar]
  10. 10. 
    Petrick JL, Yang B, Altekruse SF, Van Dyke AL, Koshiol J et al. 2017. Risk factors for intrahepatic and extrahepatic cholangiocarcinoma in the United States: a population-based study in SEER-Medicare. PLOS ONE 12:e0186643
    [Google Scholar]
  11. 11. 
    Shin HR, Oh JK, Masuyer E, Curado MP, Bouvard V et al. 2010. Epidemiology of cholangiocarcinoma: an update focusing on risk factors. Cancer Sci 101:579–85
    [Google Scholar]
  12. 12. 
    Kato I, Kido C. 1987. Increased risk of death in thorotrast-exposed patients during the late follow-up period. Jpn. J. Cancer Res. 78:1187–92
    [Google Scholar]
  13. 13. 
    Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA et al. 1996. Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. Ann. Surg. 224:463–73; discussion 473–75
    [Google Scholar]
  14. 14. 
    Cardinale V, Carpino G, Reid L, Gaudio E, Alvaro D 2012. Multiple cells of origin in cholangiocarcinoma underlie biological, epidemiological and clinical heterogeneity. World J. Gastrointest. Oncol. 4:94–102
    [Google Scholar]
  15. 15. 
    Bridgewater J, Galle PR, Khan SA, Llovet JM, Park JW et al. 2014. Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma. J. Hepatol. 60:1268–89
    [Google Scholar]
  16. 16. 
    Yamasaki S. 2003. Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. J. Hepatobiliary Pancreat. Surg. 10:288–91
    [Google Scholar]
  17. 17. 
    Vijgen S, Terris B, Rubbia-Brandt L 2017. Pathology of intrahepatic cholangiocarcinoma. Hepatobiliary Surg. Nutr. 6:22–34
    [Google Scholar]
  18. 18. 
    Aishima S, Oda Y. 2015. Pathogenesis and classification of intrahepatic cholangiocarcinoma: different characters of perihilar large duct type versus peripheral small duct type. J. Hepatobiliary Pancreat. Sci. 22:94–100
    [Google Scholar]
  19. 19. 
    Blechacz B, Komuta M, Roskams T, Gores GJ 2011. Clinical diagnosis and staging of cholangiocarcinoma. Nat. Rev. Gastroenterol. Hepatol. 8:512–22
    [Google Scholar]
  20. 20. 
    Sato Y, Harada K, Sasaki M, Nakanuma Y 2013. Histological characteristics of biliary intraepithelial neoplasia-3 and intraepithelial spread of cholangiocarcinoma. Virchows Arch 462:421–27
    [Google Scholar]
  21. 21. 
    Krasinskas AM. 2018. Cholangiocarcinoma. Surg. Pathol. Clin. 11:403–29
    [Google Scholar]
  22. 22. 
    Banales JM, Marin JJG, Lamarca A, Rodrigues PM, Khan AS et al. 2020. Cholangiocarcinoma 2020: the next horizon in mechanisms and management. Nat. Rev. Gastroenterol. Hepatol. 17:557–88
    [Google Scholar]
  23. 23. 
    Kendall T, Verheij J, Gaudio E, Evert M, Guido M et al. 2019. Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver Int 39:Suppl. 17–18
    [Google Scholar]
  24. 24. 
    Akita M, Fujikura K, Ajiki T, Fukumoto T, Otani K et al. 2017. Dichotomy in intrahepatic cholangiocarcinomas based on histologic similarities to hilar cholangiocarcinomas. Mod. Pathol. 30:986–97
    [Google Scholar]
  25. 25. 
    Nakanishi Y, Nakanuma Y, Ohara M, Iwao T, Kimura N et al. 2011. Intraductal papillary neoplasm arising from peribiliary glands connecting with the inferior branch of the bile duct of the anterior segment of the liver. Pathol. Int. 61:773–77
    [Google Scholar]
  26. 26. 
    Komuta M, Govaere O, Vandecaveye V, Akiba J, Van Steenbergen W et al. 2012. Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes. Hepatology 55:1876–88
    [Google Scholar]
  27. 27. 
    Cardinale V, Wang Y, Carpino G, Reid LM, Gaudio E, Alvaro D 2012. Mucin-producing cholangiocarcinoma might derive from biliary tree stem/progenitor cells located in peribiliary glands. Hepatology 55:2041–42
    [Google Scholar]
  28. 28. 
    Komuta M, Spee B, Vander Borght S, De Vos R, Verslype C et al. 2008. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology 47:1544–56
    [Google Scholar]
  29. 29. 
    Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N et al. 2012. Cholangiocarcinomas can originate from hepatocytes in mice. J. Clin. Investig. 122:2911–15
    [Google Scholar]
  30. 30. 
    Font-Burgada J, Shalapour S, Ramaswamy S, Hsueh B, Rossell D et al. 2015. Hybrid periportal hepatocytes regenerate the injured liver without giving rise to cancer. Cell 162:766–79
    [Google Scholar]
  31. 31. 
    Wang B, Zhao L, Fish M, Logan CY, Nusse R 2015. Self-renewing diploid Axin2+ cells fuel homeostatic renewal of the liver. Nature 524:180–85
    [Google Scholar]
  32. 32. 
    Holczbauer A, Factor VM, Andersen JB, Marquardt JU, Kleiner DE et al. 2013. Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology 145:221–31
    [Google Scholar]
  33. 33. 
    Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A et al. 2015. Genomic spectra of biliary tract cancer. Nat. Genet. 47:1003–10
    [Google Scholar]
  34. 34. 
    Simbolo M, Fassan M, Ruzzenente A, Mafficini A, Wood LD et al. 2014. Multigene mutational profiling of cholangiocarcinomas identifies actionable molecular subgroups. Oncotarget 5:2839–52
    [Google Scholar]
  35. 35. 
    Arai Y, Totoki Y, Hosoda F, Shirota T, Hama N et al. 2014. Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma. Hepatology 59:1427–34
    [Google Scholar]
  36. 36. 
    Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M et al. 2012. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology 142:1021–31.e15
    [Google Scholar]
  37. 37. 
    Sia D, Hoshida Y, Villanueva A, Roayaie S, Ferrer J et al. 2013. Integrative molecular analysis of intrahepatic cholangiocarcinoma reveals 2 classes that have different outcomes. Gastroenterology 144:829–40
    [Google Scholar]
  38. 38. 
    Nepal C, O'Rourke CJ, Oliveira D, Taranta A, Shema S et al. 2018. Genomic perturbations reveal distinct regulatory networks in intrahepatic cholangiocarcinoma. Hepatology 68:949–63
    [Google Scholar]
  39. 39. 
    Lin J, Shi J, Guo H, Yang X, Jiang Y et al. 2019. Alterations in DNA damage repair genes in primary liver cancer. Clin. Cancer Res. 25:4701–11
    [Google Scholar]
  40. 40. 
    Maynard H, Stadler ZK, Berger MF, Solit DB, Ly M et al. 2020. Germline alterations in patients with biliary tract cancers: a spectrum of significant and previously underappreciated findings. Cancer 126:1995–2002
    [Google Scholar]
  41. 41. 
    Jusakul A, Cutcutache I, Yong CH, Lim JQ, Huang MN et al. 2017. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma. Cancer Discov 7:1116–35
    [Google Scholar]
  42. 42. 
    Chan-On W, Nairismagi ML, Ong CK, Lim WK, Dima S 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]
  43. 43. 
    Ong CK, Subimerb C, Pairojkul C, Wongkham S, Cutcutache I et al. 2012. Exome sequencing of liver fluke-associated cholangiocarcinoma. Nat. Genet. 44:690–93
    [Google Scholar]
  44. 44. 
    O'Rourke CJ, Munoz-Garrido P, Aguayo EL, Andersen JB 2018. Epigenome dysregulation in cholangiocarcinoma. Biochim. Biophys. Acta Mol. Basis Dis. 1864:1423–34
    [Google Scholar]
  45. 45. 
    Losman JA, Kaelin WG Jr 2013. What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer. Genes Dev 27:836–52
    [Google Scholar]
  46. 46. 
    Morine Y, Shimada M, Iwahashi S, Utsunomiya T, Imura S et al. 2012. Role of histone deacetylase expression in intrahepatic cholangiocarcinoma. Surgery 151:412–19
    [Google Scholar]
  47. 47. 
    Mizuguchi Y, Specht S, Lunz JG 3rd, Isse K, Corbitt N et al. 2012. SPRR2A enhances p53 deacetylation through HDAC1 and down regulates p21 promoter activity. BMC Mol. Biol. 13:20
    [Google Scholar]
  48. 48. 
    Wang B, Yang R, Wu Y, Li H, Hu Z et al. 2013. Sodium valproate inhibits the growth of human cholangiocarcinoma in vitro and in vivo. Gastroenterol. Res. Pract. 2013:374593
    [Google Scholar]
  49. 49. 
    Iwahashi S, Utsunomiya T, Imura S, Morine Y, Ikemoto T et al. 2014. Effects of valproic acid in combination with S-1 on advanced pancreatobiliary tract cancers: clinical study phases I/II. Anticancer Res 34:5187–91
    [Google Scholar]
  50. 50. 
    Nakagawa S, Sakamoto Y, Okabe H, Hayashi H, Hashimoto D et al. 2014. Epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A inhibits the growth of cholangiocarcinoma cells. Oncol. Rep. 31:983–88
    [Google Scholar]
  51. 51. 
    Salati M, Braconi C. 2019. Noncoding RNA in cholangiocarcinoma. Semin. Liver Dis. 39:13–25
    [Google Scholar]
  52. 52. 
    An F, Olaru AV, Mezey E, Xie Q, Li L et al. 2015. MicroRNA-224 induces G1/S checkpoint release in liver cancer. J. Clin. Med. 4:1713–28
    [Google Scholar]
  53. 53. 
    Han Y, Meng F, Venter J, Wu N, Wan Y et al. 2016. miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth. J. Hepatol. 64:1295–304
    [Google Scholar]
  54. 54. 
    Deng Y, Yao L, Chau L, Ng SS, Peng Y et al. 2003. N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation. Int. J. Cancer 106:342–47
    [Google Scholar]
  55. 55. 
    Zhu H, Mi Y, Jiang X, Zhou X, Li R et al. 2016. Hepatocyte nuclear factor 6 inhibits the growth and metastasis of cholangiocarcinoma cells by regulating miR-122. J. Cancer Res. Clin. Oncol. 142:969–80
    [Google Scholar]
  56. 56. 
    Li J, Tian F, Li D, Chen J, Jiang P et al. 2014. MiR-605 represses PSMD10/gankyrin and inhibits intrahepatic cholangiocarcinoma cell progression. FEBS Lett 588:3491–500
    [Google Scholar]
  57. 57. 
    Jiang F, Ling X. 2019. The advancement of long non-coding RNAs in cholangiocarcinoma development. J. Cancer 10:2407–14
    [Google Scholar]
  58. 58. 
    Xu Y, Yao Y, Leng K, Li Z, Qin W et al. 2017. Long non-coding RNA UCA1 indicates an unfavorable prognosis and promotes tumorigenesis via regulating AKT/GSK-3β signaling pathway in cholangiocarcinoma. Oncotarget 8:96203–14
    [Google Scholar]
  59. 59. 
    Zhang F, Wan M, Xu Y, Li Z, Leng K et al. 2017. Long noncoding RNA PCAT1 regulates extrahepatic cholangiocarcinoma progression via the Wnt/β-catenin-signaling pathway. Biomed. Pharmacother. 94:55–62
    [Google Scholar]
  60. 60. 
    Carotenuto P, Fassan M, Pandolfo R, Lampis A, Vicentini C et al. 2017. Wnt signalling modulates transcribed-ultraconserved regions in hepatobiliary cancers. Gut 66:1268–77
    [Google Scholar]
  61. 61. 
    Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ 2000. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res 60:184–90
    [Google Scholar]
  62. 62. 
    Han C, Wu T. 2005. Cyclooxygenase-2-derived prostaglandin E2 promotes human cholangiocarcinoma cell growth and invasion through EP1 receptor-mediated activation of the epidermal growth factor receptor and Akt. J. Biol. Chem. 280:24053–63
    [Google Scholar]
  63. 63. 
    Zhang Z, Lai GH, Sirica AE 2004. Celecoxib-induced apoptosis in rat cholangiocarcinoma cells mediated by Akt inactivation and Bax translocation. Hepatology 39:1028–37
    [Google Scholar]
  64. 64. 
    Han C, Leng J, Demetris AJ, Wu T 2004. Cyclooxygenase-2 promotes human cholangiocarcinoma growth: evidence for cyclooxygenase-2-independent mechanism in celecoxib-mediated induction of p21waf1/cip1 and p27kip1 and cell cycle arrest. Cancer Res 64:1369–76
    [Google Scholar]
  65. 65. 
    Cheon YK, Cho YD, Moon JH, Jang JY, Kim YS et al. 2007. Diagnostic utility of interleukin-6 (IL-6) for primary bile duct cancer and changes in serum IL-6 levels following photodynamic therapy. Am. J. Gastroenterol. 102:2164–70
    [Google Scholar]
  66. 66. 
    Sia D, Tovar V, Moeini A, Llovet JM 2013. Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene 32:4861–70
    [Google Scholar]
  67. 67. 
    Kobayashi S, Werneburg NW, Bronk SF, Kaufmann SH, Gores GJ 2005. Interleukin-6 contributes to Mcl-1 up-regulation and TRAIL resistance via an Akt-signaling pathway in cholangiocarcinoma cells. Gastroenterology 128:2054–65
    [Google Scholar]
  68. 68. 
    Yamagiwa Y, Meng F, Patel T 2006. Interleukin-6 decreases senescence and increases telomerase activity in malignant human cholangiocytes. Life Sci 78:2494–502
    [Google Scholar]
  69. 69. 
    Frampton G, Invernizzi P, Bernuzzi F, Pae HY, Quinn M et al. 2012. Interleukin-6-driven progranulin expression increases cholangiocarcinoma growth by an Akt-dependent mechanism. Gut 61:268–77
    [Google Scholar]
  70. 70. 
    Tadlock L, Patel T. 2001. Involvement of p38 mitogen-activated protein kinase signaling in transformed growth of a cholangiocarcinoma cell line. Hepatology 33:43–51
    [Google Scholar]
  71. 71. 
    Braconi C, Huang N, Patel T 2010. MicroRNA-dependent regulation of DNA methyltransferase-1 and tumor suppressor gene expression by interleukin-6 in human malignant cholangiocytes. Hepatology 51:881–90
    [Google Scholar]
  72. 72. 
    Isomoto H, Mott JL, Kobayashi S, Werneburg NW, Bronk SF et al. 2007. Sustained IL-6/STAT-3 signaling in cholangiocarcinoma cells due to SOCS-3 epigenetic silencing. Gastroenterology 132:384–96
    [Google Scholar]
  73. 73. 
    Li Y, Deuring J, Peppelenbosch MP, Kuipers EJ, de Haar C, van der Woude CJ 2012. IL-6-induced DNMT1 activity mediates SOCS3 promoter hypermethylation in ulcerative colitis-related colorectal cancer. Carcinogenesis 33:1889–96
    [Google Scholar]
  74. 74. 
    Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ 2019. Cholangiocyte pathobiology. Nat. Rev. Gastroenterol. Hepatol. 16:269–81
    [Google Scholar]
  75. 75. 
    Gil-Garcia B, Baladron V. 2016. The complex role of NOTCH receptors and their ligands in the development of hepatoblastoma, cholangiocarcinoma and hepatocellular carcinoma. Biol. Cell 108:29–40
    [Google Scholar]
  76. 76. 
    Wu WR, Shi XD, Zhang R, Zhu MS, Xu LB et al. 2014. Clinicopathological significance of aberrant Notch receptors in intrahepatic cholangiocarcinoma. Int. J. Clin. Exp. Pathol. 7:3272–79
    [Google Scholar]
  77. 77. 
    Guest RV, Boulter L, Dwyer BJ, Kendall TJ, Man TY et al. 2016. Notch3 drives development and progression of cholangiocarcinoma. PNAS 113:12250–55
    [Google Scholar]
  78. 78. 
    Sekiya S, Suzuki A. 2012. Intrahepatic cholangiocarcinoma can arise from Notch-mediated conversion of hepatocytes. J. Clin. Investig. 122:3914–18
    [Google Scholar]
  79. 79. 
    Aoki S, Mizuma M, Takahashi Y, Haji Y, Okada R et al. 2016. Aberrant activation of Notch signaling in extrahepatic cholangiocarcinoma: clinicopathological features and therapeutic potential for cancer stem cell-like properties. BMC Cancer 16:854
    [Google Scholar]
  80. 80. 
    Zender S, Nickeleit I, Wuestefeld T, Sorensen I, Dauch D et al. 2013. A critical role for Notch signaling in the formation of cholangiocellular carcinomas. Cancer Cell 23:784–95
    [Google Scholar]
  81. 81. 
    Huntzicker EG, Hotzel K, Choy L, Che L, Ross J et al. 2015. Differential effects of targeting Notch receptors in a mouse model of liver cancer. Hepatology 61:942–52
    [Google Scholar]
  82. 82. 
    Perugorria MJ, Olaizola P, Labiano I, Esparza-Baquer A, Marzioni M et al. 2019. Wnt-β-catenin signalling in liver development, health and disease. Nat. Rev. Gastroenterol. Hepatol. 16:121–36
    [Google Scholar]
  83. 83. 
    Okabe H, Yang J, Sylakowski K, Yovchev M, Miyagawa Y et al. 2016. Wnt signaling regulates hepatobiliary repair following cholestatic liver injury in mice. Hepatology 64:1652–66
    [Google Scholar]
  84. 84. 
    Chen T, Lei S, Zeng Z, Pan S, Zhang J et al. 2020. MicroRNA137 suppresses the proliferation, migration and invasion of cholangiocarcinoma cells by targeting WNT2B. Int. J. Mol. Med. 45:886–96
    [Google Scholar]
  85. 85. 
    Goeppert B, Konermann C, Schmidt CR, Bogatyrova O, Geiselhart L et al. 2014. Global alterations of DNA methylation in cholangiocarcinoma target the Wnt signaling pathway. Hepatology 59:544–54
    [Google Scholar]
  86. 86. 
    Merino-Azpitarte M, Lozano E, Perugorria MJ, Esparza-Baquer A, Erice O et al. 2017. SOX17 regulates cholangiocyte differentiation and acts as a tumor suppressor in cholangiocarcinoma. J. Hepatol. 67:72–83
    [Google Scholar]
  87. 87. 
    Boulter L, Guest RV, Kendall TJ, Wilson DH, Wojtacha D et al. 2015. WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited. J. Clin. Investig. 125:1269–85
    [Google Scholar]
  88. 88. 
    Salaritabar A, Berindan-Neagoe I, Darvish B, Hadjiakhoondi F, Manayi A et al. 2019. Targeting Hedgehog signaling pathway: paving the road for cancer therapy. Pharmacol. Res. 141:466–80
    [Google Scholar]
  89. 89. 
    Tang L, Tan YX, Jiang BG, Pan YF, Li SX et al. 2013. The prognostic significance and therapeutic potential of hedgehog signaling in intrahepatic cholangiocellular carcinoma. Clin. Cancer Res. 19:2014–24
    [Google Scholar]
  90. 90. 
    El Khatib M, Kalnytska A, Palagani V, Kossatz U, Manns MP et al. 2013. Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma. Hepatology 57:1035–45
    [Google Scholar]
  91. 91. 
    Pan D. 2007. Hippo signaling in organ size control. Genes Dev 21:886–97
    [Google Scholar]
  92. 92. 
    Tao J, Calvisi DF, Ranganathan S, Cigliano A, Zhou L et al. 2014. Activation of β-catenin and Yap1 in human hepatoblastoma and induction of hepatocarcinogenesis in mice. Gastroenterology 147:690–701
    [Google Scholar]
  93. 93. 
    Pei T, Li Y, Wang J, Wang H, Liang Y et al. 2015. YAP is a critical oncogene in human cholangiocarcinoma. Oncotarget 6:17206–20
    [Google Scholar]
  94. 94. 
    Moeini A, Sia D, Bardeesy N, Mazzaferro V, Llovet JM 2016. Molecular pathogenesis and targeted therapies for intrahepatic cholangiocarcinoma. Clin. Cancer Res. 22:291–300
    [Google Scholar]
  95. 95. 
    Sugihara T, Isomoto H, Gores G, Smoot R 2019. YAP and the Hippo pathway in cholangiocarcinoma. J. Gastroenterol. 54:485–91
    [Google Scholar]
  96. 96. 
    Sirica AE. 2008. Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma. World J. Gastroenterol. 14:7033–58
    [Google Scholar]
  97. 97. 
    Endo K, Yoon BI, Pairojkul C, Demetris AJ, Sirica AE 2002. ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditions. Hepatology 36:439–50
    [Google Scholar]
  98. 98. 
    Voss JS, Holtegaard LM, Kerr SE, Fritcher EG, Roberts LR et al. 2013. Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions. Hum. Pathol. 44:1216–22
    [Google Scholar]
  99. 99. 
    Graham RP, Barr Fritcher EG, Pestova E, Schulz J, Sitailo LA et al. 2014. Fibroblast growth factor receptor 2 translocations in intrahepatic cholangiocarcinoma. Hum. Pathol. 45:1630–38
    [Google Scholar]
  100. 100. 
    Leone F, Cavalloni G, Pignochino Y, Sarotto I, Ferraris R et al. 2006. Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin. Cancer Res. 12:1680–85
    [Google Scholar]
  101. 101. 
    Borad MJ, Champion MD, Egan JB, Liang WS, Fonseca R et al. 2014. Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma. PLOS Genet 10:e1004135
    [Google Scholar]
  102. 102. 
    Jimeno A, Rubio-Viqueira B, Amador ML, Oppenheimer D, Bouraoud N et al. 2005. Epidermal growth factor receptor dynamics influences response to epidermal growth factor receptor targeted agents. Cancer Res 65:3003–10
    [Google Scholar]
  103. 103. 
    Zhang C, Xu H, Zhou Z, Tian Y, Cao X et al. 2018. Blocking of the EGFR-STAT3 signaling pathway through afatinib treatment inhibited the intrahepatic cholangiocarcinoma. Exp. Ther. Med. 15:4995–5000
    [Google Scholar]
  104. 104. 
    Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC et al. 2006. Phase II study of erlotinib in patients with advanced biliary cancer. J. Clin. Oncol. 24:3069–74
    [Google Scholar]
  105. 105. 
    Zhang Z, Oyesanya RA, Campbell DJ, Almenara JA, Dewitt JL, Sirica AE 2010. Preclinical assessment of simultaneous targeting of epidermal growth factor receptor (ErbB1) and ErbB2 as a strategy for cholangiocarcinoma therapy. Hepatology 52:975–86
    [Google Scholar]
  106. 106. 
    Gruenberger B, Schueller J, Heubrandtner U, Wrba F, Tamandl D et al. 2010. Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study. Lancet Oncol 11:1142–48
    [Google Scholar]
  107. 107. 
    Lee J, Park SH, Chang HM, Kim JS, Choi HJ et al. 2012. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol 13:181–88
    [Google Scholar]
  108. 108. 
    Yoshikawa D, Ojima H, Iwasaki M, Hiraoka N, Kosuge T et al. 2008. Clinicopathological and prognostic significance of EGFR, VEGF, and HER2 expression in cholangiocarcinoma. Br. J. Cancer 98:418–25
    [Google Scholar]
  109. 109. 
    Tabernero J. 2007. The role of VEGF and EGFR inhibition: implications for combining anti-VEGF and anti-EGFR agents. Mol. Cancer Res. 5:203–20
    [Google Scholar]
  110. 110. 
    Sugiyama H, Onuki K, Ishige K, Baba N, Ueda T et al. 2011. Potent in vitro and in vivo antitumor activity of sorafenib against human intrahepatic cholangiocarcinoma cells. J. Gastroenterol. 46:779–89
    [Google Scholar]
  111. 111. 
    Bengala C, Bertolini F, Malavasi N, Boni C, Aitini E et al. 2010. Sorafenib in patients with advanced biliary tract carcinoma: a phase II trial. Br. J. Cancer 102:68–72
    [Google Scholar]
  112. 112. 
    Lubner SJ, Mahoney MR, Kolesar JL, Loconte NK, Kim GP et al. 2010. Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II consortium study. J. Clin. Oncol. 28:3491–97
    [Google Scholar]
  113. 113. 
    Prager BC, Xie Q, Bao S, Rich JN 2019. Cancer stem cells: the architects of the tumor ecosystem. Cell Stem Cell 24:41–53
    [Google Scholar]
  114. 114. 
    Valent P, Bonnet D, De Maria R, Lapidot T, Copland M et al. 2012. Cancer stem cell definitions and terminology: The devil is in the details. Nat. Rev. Cancer 12:767–75
    [Google Scholar]
  115. 115. 
    Thiery JP, Acloque H, Huang RY, Nieto MA 2009. Epithelial-mesenchymal transitions in development and disease. Cell 139:871–90
    [Google Scholar]
  116. 116. 
    Shuang ZY, Wu WC, Xu J, Lin G, Liu YC et al. 2014. Transforming growth factor-β1-induced epithelial-mesenchymal transition generates ALDH-positive cells with stem cell properties in cholangiocarcinoma. Cancer Lett 354:320–28
    [Google Scholar]
  117. 117. 
    Wellner U, Schubert J, Burk UC, Schmalhofer O, Zhu F et al. 2009. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat. Cell Biol. 11:1487–95
    [Google Scholar]
  118. 118. 
    Oishi N, Kumar MR, Roessler S, Ji J, Forgues M et al. 2012. Transcriptomic profiling reveals hepatic stem-like gene signatures and interplay of miR-200c and epithelial-mesenchymal transition in intrahepatic cholangiocarcinoma. Hepatology 56:1792–803
    [Google Scholar]
  119. 119. 
    Raggi C, Invernizzi P, Andersen JB 2015. Impact of microenvironment and stem-like plasticity in cholangiocarcinoma: molecular networks and biological concepts. J. Hepatol. 62:198–207
    [Google Scholar]
  120. 120. 
    Chuaysri C, Thuwajit P, Paupairoj A, Chau-In S, Suthiphongchai T, Thuwajit C 2009. Alpha-smooth muscle actin-positive fibroblasts promote biliary cell proliferation and correlate with poor survival in cholangiocarcinoma. Oncol. Rep. 21:957–69
    [Google Scholar]
  121. 121. 
    Terada T, Okada Y, Nakanuma Y 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]
  122. 122. 
    Mertens JC, Fingas CD, Christensen JD, Smoot RL, Bronk SF et al. 2013. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res 73:897–907
    [Google Scholar]
  123. 123. 
    Cadamuro M, Brivio S, Mertens J, Vismara M, Moncsek A et al. 2019. Platelet-derived growth factor-D enables liver myofibroblasts to promote tumor lymphangiogenesis in cholangiocarcinoma. J. Hepatol. 70:700–9
    [Google Scholar]
  124. 124. 
    Pradere JP, Kluwe J, De Minicis S, Jiao JJ, Gwak GY 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]
  125. 125. 
    Hasita H, Komohara Y, Okabe H, Masuda T, Ohnishi K et al. 2010. Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma. Cancer Sci 101:1913–19
    [Google Scholar]
  126. 126. 
    Atanasov G, Hau HM, Dietel C, Benzing C, Krenzien F et al. 2016. Prognostic significance of TIE2-expressing monocytes in hilar cholangiocarcinoma. J. Surg. Oncol. 114:91–98
    [Google Scholar]
  127. 127. 
    Mao ZY, Zhu GQ, Xiong M, Ren L, Bai L 2015. Prognostic value of neutrophil distribution in cholangiocarcinoma. World J. Gastroenterol. 21:4961–68
    [Google Scholar]
  128. 128. 
    Budzynska A, Nowakowska-Dulawa E, Marek T, Boldys H, Nowak A, Hartleb M 2013. Differentiation of pancreatobiliary cancer from benign biliary strictures using neutrophil gelatinase-associated lipocalin. J. Physiol. Pharmacol. 64:109–14
    [Google Scholar]
  129. 129. 
    Zhou SL, Dai Z, Zhou ZJ, Chen Q, Wang Z et al. 2014. CXCL5 contributes to tumor metastasis and recurrence of intrahepatic cholangiocarcinoma by recruiting infiltrative intratumoral neutrophils. Carcinogenesis 35:597–605
    [Google Scholar]
  130. 130. 
    Bjorkstrom NK, Ljunggren HG, Michaelsson J 2016. Emerging insights into natural killer cells in human peripheral tissues. Nat. Rev. Immunol. 16:310–20
    [Google Scholar]
  131. 131. 
    Morisaki T, Umebayashi M, Kiyota A, Koya N, Tanaka H et al. 2012. Combining cetuximab with killer lymphocytes synergistically inhibits human cholangiocarcinoma cells in vitro. Anticancer Res 32:2249–56
    [Google Scholar]
  132. 132. 
    Jung IH, Kim DH, Yoo DK, Baek SY, Jeong SH et al. 2018. In vivo study of natural killer (NK) cell cytotoxicity against cholangiocarcinoma in a nude mouse model. In Vivo 32:771–81
    [Google Scholar]
  133. 133. 
    Goeppert B, Frauenschuh L, Zucknick M, Stenzinger A, Andrulis M et al. 2013. Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer. Br. J. Cancer 109:2665–74
    [Google Scholar]
  134. 134. 
    Kitano Y, Okabe H, Yamashita YI, Nakagawa S, Saito Y et al. 2018. Tumour-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. Br. J. Cancer 118:171–80
    [Google Scholar]
  135. 135. 
    Ghidini M, Cascione L, Carotenuto P, Lampis A, Trevisani F et al. 2017. Characterisation of the immune-related transcriptome in resected biliary tract cancers. Eur. J. Cancer 86:158–65
    [Google Scholar]
  136. 136. 
    Takagi S, Miyagawa S, Ichikawa E, Soeda J, Miwa S et al. 2004. Dendritic cells, T-cell infiltration, and Grp94 expression in cholangiocellular carcinoma. Hum. Pathol. 35:881–86
    [Google Scholar]
  137. 137. 
    Marin JJG, Lozano E, Herraez E, Asensio M, Di Giacomo S et al. 2018. Chemoresistance and chemosensitization in cholangiocarcinoma. Biochim. Biophys. Acta Mol. Basis Dis. 1864:1444–53
    [Google Scholar]
  138. 138. 
    Pan ST, Li ZL, He ZX, Qiu JX, Zhou SF 2016. Molecular mechanisms for tumour resistance to chemotherapy. Clin. Exp. Pharmacol. Physiol. 43:723–37
    [Google Scholar]
  139. 139. 
    Marin JJG, Briz O, Herraez E, Lozano E, Asensio M et al. 2018. Molecular bases of the poor response of liver cancer to chemotherapy. Clin. Res. Hepatol. Gastroenterol. 42:182–92
    [Google Scholar]
  140. 140. 
    Wlcek K, Svoboda M, Riha J, Zakaria S, Olszewski U et al. 2011. The analysis of organic anion transporting polypeptide (OATP) mRNA and protein patterns in primary and metastatic liver cancer. Cancer Biol. Ther. 11:801–11
    [Google Scholar]
  141. 141. 
    Cadamuro M, Brivio S, Spirli C, Joplin RE, Strazzabosco M, Fabris L 2017. Autocrine and paracrine mechanisms promoting chemoresistance in cholangiocarcinoma. Int. J. Mol. Sci. 18:149
    [Google Scholar]
  142. 142. 
    Lozano E, Macias RIR, Monte MJ, Asensio M, Del Carmen S et al. 2019. Causes of hOCT1-dependent cholangiocarcinoma resistance to sorafenib and sensitization by tumor-selective gene therapy. Hepatology 70:1246–61
    [Google Scholar]
  143. 143. 
    Srimunta U, Sawanyawisuth K, Kraiklang R, Pairojkul C, Puapairoj A et al. 2012. High expression of ABCC1 indicates poor prognosis in intrahepatic cholangiocarcinoma. Asian Pac. J. Cancer Prev. 13:Suppl.125–30
    [Google Scholar]
  144. 144. 
    Nakajima T, Takayama T, Miyanishi K, Nobuoka A, Hayashi T et al. 2003. Reversal of multiple drug resistance in cholangiocarcinoma by the glutathione S-transferase-π-specific inhibitor O1-hexadecyl-γ-glutamyl-S-benzylcysteinyl-d-phenylglycine ethylester. J. Pharmacol. Exp. Ther. 306:861–69
    [Google Scholar]
  145. 145. 
    Hwang IG, Jang JS, Do JH, Kang JH, Lee GW et al. 2011. Different relation between ERCC1 overexpression and treatment outcomes of two platinum agents in advanced biliary tract adenocarcinoma patients. Cancer Chemother. Pharmacol. 68:935–44
    [Google Scholar]
  146. 146. 
    Morton SD, Cadamuro M, Brivio S, Vismara M, Stecca T et al. 2015. Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation. Oncotarget 6:26052–64
    [Google Scholar]
  147. 147. 
    Chiang KC, Yeh TS, Wu RC, Pang JS, Cheng CT et al. 2016. Lipocalin 2 (LCN2) is a promising target for cholangiocarcinoma treatment and bile LCN2 level is a potential cholangiocarcinoma diagnostic marker. Sci. Rep. 6:36138
    [Google Scholar]
  148. 148. 
    Radtke A, Konigsrainer A. 2016. Surgical therapy of cholangiocarcinoma. Visc. Med. 32:422–26
    [Google Scholar]
  149. 149. 
    Choi SB, Kim KS, Choi JY, Park SW, Choi JS et al. 2009. The prognosis and survival outcome of intrahepatic cholangiocarcinoma following surgical resection: association of lymph node metastasis and lymph node dissection with survival. Ann. Surg. Oncol. 16:3048–56
    [Google Scholar]
  150. 150. 
    Kizy S, Altman AM, Marmor S, Wirth K, Ching Hui JY et al. 2019. Surgical resection of lymph node positive intrahepatic cholangiocarcinoma may not improve survival. HPB 21:235–41
    [Google Scholar]
  151. 151. 
    Valle JW, Borbath I, Khan SA, Huguet F, Gruenberger T et al. 2016. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 27:v28–37
    [Google Scholar]
  152. 152. 
    Buettner S, Ten Cate DWG, Bagante F, Alexandrescu S, Marques HP et al. 2019. Survival after resection of multiple tumor foci of intrahepatic cholangiocarcinoma. J. Gastrointest. Surg. 23:2239–46
    [Google Scholar]
  153. 153. 
    Ebata T, Hirano S, Konishi M, Uesaka K, Tsuchiya Y et al. 2018. Randomized clinical trial of adjuvant gemcitabine chemotherapy versus observation in resected bile duct cancer. Br. J. Surg. 105:192–202
    [Google Scholar]
  154. 154. 
    Shroff RT, Kennedy EB, Bachini M, Bekaii-Saab T, Crane C et al. 2019. Adjuvant therapy for resected biliary tract cancer: ASCO clinical practice guideline. J. Clin. Oncol. 37:1015–27
    [Google Scholar]
  155. 155. 
    Darwish Murad S, Kim WR, Harnois DM, Douglas DD, Burton J et al. 2012. Efficacy of neoadjuvant chemoradiation, followed by liver transplantation, for perihilar cholangiocarcinoma at 12 US centers. Gastroenterology 143:88–98.e3
    [Google Scholar]
  156. 156. 
    Ethun CG, Lopez-Aguiar AG, Anderson DJ, Adams AB, Fields RC et al. 2018. Transplantation versus resection for hilar cholangiocarcinoma: an argument for shifting treatment paradigms for resectable disease. Ann. Surg. 267:797–805
    [Google Scholar]
  157. 157. 
    Sapisochin G, Facciuto M, Rubbia-Brandt L, Marti J, Mehta N et al. 2016. Liver transplantation for “very early” intrahepatic cholangiocarcinoma: international retrospective study supporting a prospective assessment. Hepatology 64:1178–88
    [Google Scholar]
  158. 158. 
    Sapisochin G, de Lope CR, Gastaca M, de Urbina JO, Lopez-Andujar R et al. 2014. Intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma in patients undergoing liver transplantation: a Spanish matched cohort multicenter study. Ann. Surg. 259:944–52
    [Google Scholar]
  159. 159. 
    Lunsford KE, Javle M, Heyne K, Shroff RT, Abdel-Wahab R et al. 2018. Liver transplantation for locally advanced intrahepatic cholangiocarcinoma treated with neoadjuvant therapy: a prospective case-series. Lancet Gastroenterol. Hepatol 3:337–48 Erratum. 2018 Lancet Gastroenterol. Hepatol3:e3
    [Google Scholar]
  160. 160. 
    Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A et al. 2010. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N. Engl. J. Med. 362:1273–81
    [Google Scholar]
  161. 161. 
    Shroff RT, Javle MM, Xiao L, Kaseb AO, Varadhachary GR et al. 2019. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol 5:824–30
    [Google Scholar]
  162. 162. 
    Valle JW, Wasan H, Lopes A, Backen AC, Palmer DH et al. 2015. Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial. Lancet Oncol 16:967–78
    [Google Scholar]
  163. 163. 
    Lamarca A, Palmer DH, Wasan HS, Ross PJ, Ma YT et al. 2019. ABC-06 | A randomised phase III, multi-centre, open-label study of active symptom control (ASC) alone or ASC with oxaliplatin/5-FU chemotherapy (ASC+mFOLFOX) for patients (pts) with locally advanced/metastatic biliary tract cancers (ABC) previously-treated with cisplatin/gemcitabine (CisGem) chemotherapy. J. Clin. Oncol. 37:4003
    [Google Scholar]
  164. 164. 
    Park SY, Kim JH, Yoon HJ, Lee IS, Yoon HK, Kim KP 2011. Transarterial chemoembolization versus supportive therapy in the palliative treatment of unresectable intrahepatic cholangiocarcinoma. Clin. Radiol. 66:322–28
    [Google Scholar]
  165. 165. 
    Hyder O, Marsh JW, Salem R, Petre EN, Kalva S et al. 2013. Intra-arterial therapy for advanced intrahepatic cholangiocarcinoma: a multi-institutional analysis. Ann. Surg. Oncol. 20:3779–86
    [Google Scholar]
  166. 166. 
    Hong TS, Wo JY, Yeap BY, Ben-Josef E, McDonnell EI et al. 2016. Multi-institutional phase II study of high-dose hypofractionated proton beam therapy in patients with localized, unresectable hepatocellular carcinoma and intrahepatic cholangiocarcinoma. J. Clin. Oncol. 34:460–68
    [Google Scholar]
  167. 167. 
    Bekaii-Saab T, Phelps MA, Li X, Saji M, Goff L et al. 2011. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J. Clin. Oncol. 29:2357–63
    [Google Scholar]
  168. 168. 
    Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM et al. 2018. Dabrafenib and trametinib treatment in patients with locally advanced or metastatic BRAF V600-mutant anaplastic thyroid cancer. J. Clin. Oncol. 36:7–13
    [Google Scholar]
  169. 169. 
    Peng H, Zhang Q, Li J, Zhang N, Hua Y et al. 2016. Apatinib inhibits VEGF signaling and promotes apoptosis in intrahepatic cholangiocarcinoma. Oncotarget 7:17220–29
    [Google Scholar]
  170. 170. 
    El-Khoueiry AB, Rankin CJ, Ben-Josef E, Lenz HJ, Gold PJ et al. 2012. SWOG 0514: a phase II study of sorafenib in patients with unresectable or metastatic gallbladder carcinoma and cholangiocarcinoma. Investig. New Drugs 30:1646–51
    [Google Scholar]
  171. 171. 
    Lu JC, Zeng HY, Sun QM, Meng QN, Huang XY et al. 2019. Distinct PD-L1/PD1 profiles and clinical implications in intrahepatic cholangiocarcinoma patients with different risk factors. Theranostics 9:4678–87
    [Google Scholar]
  172. 172. 
    Czink E, Kloor M, Goeppert B, Frohling S, Uhrig S et al. 2017. Successful immune checkpoint blockade in a patient with advanced stage microsatellite-unstable biliary tract cancer. Cold Spring Harb. Mol. Case Stud. 3:a001974
    [Google Scholar]
  173. 173. 
    Blair AB, Murphy A. 2018. Immunotherapy as a treatment for biliary tract cancers: a review of approaches with an eye to the future. Curr. Probl. Cancer 42:49–58
    [Google Scholar]
  174. 174. 
    Singhi AD, Nikiforova MN, Chennat J, Papachristou GI, Khalid A et al. 2020. Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures. Gut 69:52–61
    [Google Scholar]
/content/journals/10.1146/annurev-pathol-030220-020455
Loading
/content/journals/10.1146/annurev-pathol-030220-020455
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error