Current Insights on Cholangiocarcinoma Research: a Brief Review

  • Mathema, Vivek Bhakta (Chulabhorn International College of Medicine, Thammasat University) ;
  • Na-Bangchang, Kesara (Chulabhorn International College of Medicine, Thammasat University)
  • Published : 2015.03.09


Colangiocarcinoma (CCA) is a progressively fatal disease which generally occurs due to malignant transformation of hepatic biliary cholangiocytes. The incidence of CCA has been increasing worldwide and there is an urgent requirement for effective diagnosis and treatment strategies against this devastating disease. Different factors including liver-fluke infestation, viral hepatitis, exogenous nitrosamine-mediated DNA damage, and chronic inflammation have been linked to CCA genesis. However, the risk factors and underlying complex mechanisms leading to development of CCA are not sufficiently understood to devise an effective targeted treatment therapy. In this review, we summarize currently known epidemiological and pathological aspects of the disease and briefly describe various potential biomarkers and experimental anticancer phytochemicals related to CCA research. In addition, we also sum up recent findings that link chronic inflammation of hepatic biliary cholangiocytes with CCA. The collective information concisely presented in this article would provide useful insights into the current understanding of this cancer.


Cholangiocarcinoma;biomarkers;Opisthorchis viverrini;inflammation


  1. Alvaro D (2009). Serum and bile markers for cholangiocarcinoma. Curr Opin Gastroenterol, 25, 279-84
  2. Anderson CD, Pinson CW, Berlin J, Chari RS (2004). Diagnosis and treatment of cholangiocarcinoma. Oncologist, 9, 43-57
  3. Aneknan P, Kukongviriyapan V, Prawan A, et al (2014). Luteolin arrests cell cycling, induces apoptosis and inhibits the JAK/STAT3 pathway in human cholangiocarcinoma cells. Asian Pac J Cancer Prev, 15, 5071-6
  4. Barr Fritcher EG, Voss JS, Jenkins SM, et al (2013). Primary sclerosing cholangitis with equivocal cytology: fluorescence in situ hybridization and serum CA 19-9 predict risk of malignancy. Cancer Cytopathol, 121, 708-17
  5. Blechacz B, Komuta M, Roskams T, Gores GJ (2011). Clinical diagnosis and staging of cholangiocarcinoma. Nat Rev Gastroenterol Hepatol, 8, 512-22
  6. Boonyanugomol W, Chomvarin C, Hahnvajanawong C, Sripa B, Kaparakis-Liaskos M, Ferrero RL (2013). Helicobacter pylori cag pathogenicity island (cagPAI) involved in bacterial internalization and IL-8 induced responses via NOD1- and MyD88-dependent mechanisms in human biliary epithelial cells. PLoS One, 8, 77358
  7. Boonyanugomol W, Chomvarin C, Sripa B, et al (2012). Helicobacter pylori in Thai patients with cholangiocarcinoma and its association with biliary inflammation and proliferation. HPB (Oxford), 14, 177-84
  8. 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. Hepatol, 51, 881-90
  9. Burak K, Angulo P, Pasha TM, et al (2004). Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol, 99, 523-6
  10. Chan-On W, Kuwahara K, Kobayashi N, et al (2009). Cholangiocarcinomas associated with long-term inflammation express the activation-induced cytidine deaminase and germinal center-associated nuclear protein involved in immunoglobulin V-region diversification. Int J Oncol, 35, 287-95
  11. Fabbri M, Garzon R, Cimmino A, et al (2007). MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA, 104, 15805-10
  12. Han Y, Zhang W, Liu Y (2013). Identification of hepatomaderived growth factor as a potential prognostic and diagnostic marker for extrahepatic cholangiocarcinoma. World J Surg, 37, 2419-27
  13. Jaiswal M, LaRusso NF, Burgart LJ, Gores GJ (2000). Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxidedependent mechanism. Cancer Res, 60, 184-90
  14. Johnson C, Han YY, Nathan H, et al (2012). Interleukin-6 and its receptor, key players in hepatobiliary inflammation and cancer. Transl Gastrointest Cancer, 1, 58-70
  15. Karin M. (2006). Nuclear factor-${\kappa}B$ in cancer development and progression. Nature, 441, 431-6
  16. Kawanishi S, Hiraku Y, Pinlaor S, Ma N (2006). Oxidative and nitrative DNA damage in animals and patients with inflammatory diseases in relation to inflammation-related carcinogenesis. Biol Chem, 387, 365-72
  17. Khan SA, Emadossadaty S, Ladep NG, et al (2012). Rising trends in cholangiocarcinoma: is the ICD classification system misleading us? J Hepatol, 56, 848-54.
  18. Komori J, Marusawa H, Machimoto T, et al (2008). Activationinduced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma. Hepatol, 47, 888-96
  19. Koonrungsesomboon N, Na-Bangchang K, Karbwang J (2014). Therapeutic potential and pharmacological activities of Atractylodes lancea (Thunb.) DC. Asian Pac J Trop Med, 7, 421-8
  20. Laothong U, Pinlaor P, Boonsiri P, et al (2013). Melatonin inhibits cholangiocarcinoma and reduces liver injury in Opisthorchis viverrini-infected and N-nitrosodimethylamine-treated hamsters. J Pineal Res, 55, 257-66
  21. Lee GR, Jang SH, Kim CJ, et al (2014). Capsaicin suppresses the migration of cholangiocarcinoma cells by down-regulating matrix metalloproteinase-9 expression via the AMPK-NF-${\kappa}B$ signaling pathway. Clin Exp Metastasis, 31, 897-907
  22. Ling S, Feng T, Ke Q, Fan N, et al (2014). Metformin inhibits proliferation and enhances chemosensitivity of intrahepatic cholangiocarcinoma cell lines. Oncol Rep, 31, 2611-8
  23. Mahavorasirikul W, Viyanant V, Chaijaroenkul W, Itharat A, Na-Bangchang K (2010). Cytotoxic activity of Thai medicinal plants against human cholangiocarcinoma, laryngeal and hepatocarcinoma cells in vitro. BMC Complement Altern Med, 10, 55
  24. Marrero J (2014). Biomarkers in cholangiocarcinoma. Clin Liver Dis, 3, ??
  25. Matsumoto K, Onoyama T, Kawata S, et al (2014). Hepatitis B and C virus infection is a risk factor for the development of cholangiocarcinoma. Intern Med, 53, 651-4
  26. Matsumoto Y, Marusawa H, Kinoshita K, et al (2007). Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med, 13, 470-6
  27. Nair SS, Bommana A, Bethony JM, et al (2011). The metastasisassociated protein-1 gene encodes a host permissive factor for schistosomiasis, a leading global cause of inflammation and cancer. Hepatol, 54, 285-95
  28. Navaneethan U, Njei B, Venkatesh PG, Vargo JJ, Parsi MA (2013). Fluorescence in situ hybridization for diagnosis of cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest Endosc, 79, 943-50
  29. Oh SW, Yoon YS, Shin SA (2005). Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea national health insurance corporation study. Clin Oncol, 23, 4742-54
  30. Parkin DM (2006). The global health burden of infectionassociated cancers in the year 2002. Int J Cancer, 118, 3030-44
  31. Parkin DM, Ohshima H, Srivatanakul P, Vatanasapt V (1993). Cholangiocarcinoma: epidemiology, mechanisms of carcinogenesis and prevention. Cancer Epidemiol Biomarkers Prev, 2, 537-44.
  32. Patel AH, Harnois DM, Klee GG, LaRusso NF, Gores GJ (2000). The utility of CA 19-9 in the diagnoses of cholangiocarcinoma in patients without primary sclerosing cholangitis. Am J Gastroenterol, 95, 204-7
  33. Plengsuriyakarn T, Viyanant V, Eursitthichai V, et al (2012a). Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models. BMC Complement Altern Med, 12, 12-23
  34. Plengsuriyakarn T, Viyanant V, Eursitthichai V, et al (2012b). Cytotoxicity, toxicity, and anticancer activity of Zingiber officinale Roscoe against cholangiocarcinoma. Asian Pac J Cancer Prev, 13, 4597-606
  35. Prayong P, Mairiang E, Pairojkul C, et al (2014). An interleukin-6 receptor polymorphism is associated with opisthorchiasislinked cholangiocarcinoma risk in Thailand. Asian Pac J Cancer Prev, 15, 5443-7
  36. Qu Z, Cui N, Qin M, Wu X (2012). Epidemiological survey of biomarkers of hepatitis virus in patients with extrahepatic cholangiocarcinomas. Asia Pac J Clin Oncol, 8, 83-7
  37. Razumilava N, Gores GJ (2013). Classification, diagnosis, and management of cholangiocarcinoma. Clin Gastroenterol Hepatol, 11, 13-21
  38. Ruys AT, Groot Koerkamp B, Wiggers JK, et al (2013). Prognostic biomarkers in patients with resected cholangiocarcinoma: a systematic review and meta-analysis. Ann Surg Oncol, 21, 487-500
  39. Shaib Y, El-Serag HB (2004). The epidemiology of cholangiocarcinoma. Semin Liver Dis, 24, 115-25
  40. Shen J, Wang W, Wu J, et al (2012). Comparative proteomic profiling of human bile reveals SSP411 as a novel biomarker of cholangiocarcinoma. PLoS One, 7, 47476
  41. Srikoon P, Kariya R, Kudo E, et al (2013). Diethyldithiocarbamate Suppresses an NF-${\kappa}B$ dependent metastatic pathway in cholangiocarcinoma cells. Asian Pac J Cancer Prev, 14, 4441-6
  42. Sripa B, Mairiang E, Thinkhamrop B, et al (2009). Advanced periductal fibrosis from infection with the carcinogenic human liver fluke Opisthorchis viverrini correlates with elevated levels of interleukin-6. Hepatol, 50, 1273-81
  43. Sripa B, Pairojkul C (2008). Cholangiocarcinoma: lessons from Thailand. Curr Opin Gastroenterol, 24, 349-56
  44. Sriwanitchrak P, Viyanant V, Chaijaroenkul W, et al (2011). Proteomics analysis and evaluation of biomarkers for detection of cholangiocarcinoma. Asian Pac J Cancer Prev, 12, 1503-10
  45. Stroescu C, Herlea V, Dragnea A, Popescu I (2006). The diagnostic value of cytokeratins and carcinoembryonic antigen immunostaining in differentiating hepatocellular carcinomas from intrahepatic cholangiocarcinomas. J Gastrointest Liver Dis, 15, 9-14
  46. Takahashi H, Ojima H, Shimizu H, Furuse J, Furukawa H, Shibata T (2014). Axitinib (AG-013736), an oral specific VEGFR TKI, shows potential therapeutic utility against cholangiocarcinoma. Jpn J Clin Oncol, 44, 570-8
  47. Takeuchi O, Akira S (2010). Pattern recognition receptors and inflammation. Cell, 140, 805-20
  48. Tao LY, Cai L, He XD, Liu W, Qu Q (2010). Comparison of serum tumor markers for inirahepaiic cholangiocarcinoma and hepatocellular carcinoma. Am Surg, 76, 1210-3
  49. Thanan R, Pairojkul C, Pinlaor S, et al (2013). Inflammationrelated DNA damage and expression of CD133 and Oct3/4 in cholangiocarcinoma patients with poor prognosis. Free Rad Biol Med, 65, 1464-72
  50. Tyson GL, El-Serag HB (2011). Risk factors for cholangiocarcinoma. Hepatology, 54, 173-84
  51. Ustundag Y, Bayraktar Y (2008). Cholangiocarcinoma: a compact review of the literature. World J Gastroenterol, 14, 6458-66
  52. Wehbe H, Henson R, Meng F, Mize-Berge J, Patel T (2006). Interleukin-6 contributes to growth in cholangiocarcinoma cells by aberrant promoter methylation and gene expression. Cancer Res, 66, 10517-24
  53. Wu ZF, Yang N, Li DY, Zhang HB, Yang GS (2013). Characteristics of intrahepatic cholangiocarcinoma in patients with hepatitis B virus infection: clinicopathologic study of resected tumours. J Viral Hepat, 20, 306-10
  54. Xiao M, Gao Y, Wang Y (2014). Helicobacter species infection may be associated with cholangiocarcinoma: a metaanalysis. Int J Clin Pract, 68, 262-70
  55. Yao D, Kunam VK, Li X (2014). A review of the clinical diagnosis and therapy of cholangiocarcinoma. J Int Med Res, 42, 3-16
  56. Yeh CN, Chiang KC, Juang HH, et al (2013). Reappraisal of the therapeutic role of celecoxib in cholangiocarcinoma. PLoS One, 8, 69928
  57. Young ND, Nagarajan N, Lin SJ, Korhonen PK et al (2014). The Opisthorchis viverrini genome provides insights into life in the bile duct. Nat Commun, 5, 4378
  58. Zhou HB, Hu JY, Hu HP (2014). Hepatitis B virus infection and intrahepatic cholangiocarcinoma. World J Gastroenterol, 20, 5721-9

Cited by

  1. Taurocholate Induces Cyclooxygenase-2 Expression via the Sphingosine 1-phosphate Receptor 2 in a Human Cholangiocarcinoma Cell Line vol.290, pp.52, 2015,
  2. HOXD10 acts as a tumor-suppressive factor via inhibition of the RHOC/AKT/MAPK pathway in human cholangiocellular carcinoma vol.34, pp.4, 2015,