Journal of Hepato-Biliary-Pancreatic Surgery

, Volume 12, Issue 6, pp 463–466 | Cite as

Hepatolithiasis and intrahepatic cholangiocarcinoma: carcinogenesis based on molecular mechanisms

  • Tamotsu Kuroki
  • Yoshitsugu Tajima
  • Takashi Kanematsu
Review article


Hepatolithiasis is more frequently seen in East Asian countries than in Western countries, and it is well known to represent a high-risk state for intrahepatic cholangiocarcinoma. Intrahepatic cholangiocarcinoma is an aggressive tumor that shows a dismal outcome even after resection. Cancer results from multistep carcinogenesis; however, the precise molecular mechanisms involved in the genetic alterations in cancer remain unknown. The accumulation of alterations in cancer-related genes leads to disruptions in cell-cycle regulation and also to continuous cell proliferation. The present review provides an overview of cancer-related genes in intrahepatic cholangiocarcinogenesis arising in hepatolithiasis. Further study of molecular mechanisms in hepatolithiasis-related intrahepatic cholangiocarcinoma, and the delineation of the influence of the genes involved should lead to our understanding of cholangiocarcinogenesis.

Key words

Hepatolithiasis Intrahepatic cholangiocarcinoma Molecular mechanism 


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  1. 1.
    Nakayama, F 1985

    Hepatolithiasis and cholangiohepatitis

    Cohen, SSoloway, RD eds. GallstonesChurchill LivingstoneNew York2376
    Google Scholar
  2. 2.
    Nakayama, F 1994

    Intrahepatic stones

    Blumgart, LH eds. Surgery of the liver and biliary tractChurchill LivingstoneNew York76574
    Google Scholar
  3. 3.
    Ohta, T, Nagakawa, T, Ueda, N, Nakamura, T, Akiyama, T, Ueno, K,  et al. 1991Mucosal dysplasia of the liver and the intraductal variant of peripheral cholangiocarcinoma in hepatolithiasisCancer68221723PubMedGoogle Scholar
  4. 4.
    Chu, KM, Lo, CM, Liu, CL, Fan, ST 1996Malignancy associated with hepatolithiasisHepatogastroenterology4361419Google Scholar
  5. 5.
    Su, CH, Shyr, YM, Lui, WY, P'Eng, FK 1997Hepatolithiasis associated with cholangiocarcinomaBr J Surg8496973PubMedGoogle Scholar
  6. 6.
    Shimonishi, T, Sasaki, M, Nakanuma, Y 2000Precancerous lesions of intrahepatic cholangiocarcinomaJ Hepatobiliary Pancreat Surg754250PubMedCrossRefGoogle Scholar
  7. 7.
    Nakanuma, Y, Harada, K, Ishikawa, A, Zen, Y, Sasaki, M 2003Anatomic and molecular pathology of intrahepatic cholangiocarcinomaJ Hepatobiliary Pancreat Surg1026581PubMedCrossRefGoogle Scholar
  8. 8.
    Liver Cancer Study Group of Japan1990Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatmentAnn Surg21127787Google Scholar
  9. 9.
    Bhuiya, MR, Nimura, Y, Kamiya, J, Kondo, S, Fukata, S, Hayakawa, N,  et al. 1992Clinicopathologic studies on perineural invasion of bile duct carcinomaAnn Surg2153449PubMedGoogle Scholar
  10. 10.
    Shaib, Y, El-Serag, HB 2004The epidemiology of cholangiocarcinomaSemin Liver Dis2411525PubMedCrossRefGoogle Scholar
  11. 11.
    Ahrendt, SA, Rashid, A, Chow, JT, Eisenberger, CF, Pitt, HA, Sidransky, D 2000p53 overexpression and K-rans gene mutations in primary sclerosing cholangitis-associated biliary tract cancerJ Hepatobiliary Pancreat Surg742631PubMedCrossRefGoogle Scholar
  12. 12.
    Yoshida, S, Todoroki, T, Ichikawa, Y, Hanai, S, Suzuki, H, Hori, M,  et al. 1995Mutations of p16Ink4/CDKN2 and p15Ink4B/MTS2 genes in biliary tract cancersCancer Res55275660PubMedGoogle Scholar
  13. 13.
    Terada, T, Nakanuma, Y 1992Cell kinetic analyses and expression of carcinoembryonic antigen, carbohydrate antigen 19-9 and DU-PAN-2 in hyperplastic, pre-neoplastic and neoplastic lesions of intrahepatic bile ducts in livers with hepatolithsVirchows Arch A Pathol Anat Histopathol42032735PubMedCrossRefGoogle Scholar
  14. 14.
    Sherr, CT 1996Cancer cell cyclesScience27616727Google Scholar
  15. 15.
    Liggett, WH,Jr, Sidransky, D 1998Role of the p16 tumor suppressor gene in cancerJ Clin Oncol161197206PubMedGoogle Scholar
  16. 16.
    Ishikawa, A, Sasaki, M, Sato, Y, Ohira, S, Chen, MF, Huang, SF,  et al. 2004Frequent p16ink4a inactivation is an early and frequent event of intraductal papillary neoplasm of the liver arising in hepatolithiasisHum Pathol35150514PubMedCrossRefGoogle Scholar
  17. 17.
    Virmani, AK, Muller, C, Rathi, A, Zoechbauer-Mueller, S, Mathis, M, Gazdar, AF 2001Aberrant methylation during cervical carcinogenesisClin Cancer Res75849PubMedGoogle Scholar
  18. 18.
    Kang, GH, Shim, YH, Jung, HY, Kim, WH, Ro, JY, MG. Cp, Rhyu 2001G island methylation in premalignant stages of gastric carcinomaCancer Res61284751PubMedGoogle Scholar
  19. 19.
    Klump, B, Hsieh, CJ, Nehls, O, Dette, S, Holzmann, K, Kieblich, R,  et al. 2003Methylation status of p14ARF and p16INK4a as detected in pancreatic secretionsBr J Cancer8821722PubMedCrossRefGoogle Scholar
  20. 20.
    Tannapfel, A, Sommerer, F, Benicke, M, Weinans, L, Katalinic, A, Geissler, F,  et al. 2002Genetic and epigenetic alterations of the INK4a-ARF pathway in cholangiocarcinomaJ Pathol19762431PubMedCrossRefGoogle Scholar
  21. 21.
    Kuroki, T, Trapasso, F, Yendamuri, S, Matsuyama, A, Alder, H, Mori, M,  et al. 2003Promoter hypermethylation of RASSF1A in esophageal squamous cell carcinomaClin Cancer Res914415PubMedGoogle Scholar
  22. 22.
    Kuroki, T, Trapasso, F, Yendamuri, S, Matsuyama, A, Alder, H, Williams, NN,  et al. 2003Allelic loss on chromosome 3p21.3 and promoter hypermethylation of Semaphorin 3B in non-small cell lung cancerCancer Res6333525PubMedGoogle Scholar
  23. 23.
    Kuroki, T, Trapasso, F, Yendamuri, S, Matsuyama, A, Alder, H, Mori, M,  et al. 2003Allele loss and promoter hypermethylation of VHL, RAR-β, RASSF1A, and FHIT tumor supporessor genes on chromosome 3p in esophageal squamous cell carcinomaCancer Res6337248PubMedGoogle Scholar
  24. 24.
    Chariyalertsak, S, Sirikulchayanonta, V, Mayer, D, Kopp-Schneider, A, Furstenberger, G, Marks, F,  et al. 2001Aberrant cyclooxygenase isozyme expression in human intrahepatic cholangiocarcinomaCut48806Google Scholar
  25. 25.
    Hayashi, N, Yamamoto, H, Hiraoka, N, Dono, K, Ito, Y, Okami, J,  et al. 2001Differential expression of cyclooxygenase-2 (COX-2) in human bile duct epithelial cells and bile duct neoplasmHepatology3463850PubMedCrossRefGoogle Scholar
  26. 26.
    Sun, Y, Tang, XM, Half, E, Kuo, MT, Sinicrope, FA 2002Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cellsCancer Res6263238PubMedGoogle Scholar
  27. 27.
    Jones, MK, Wang, H, Peskar, BM, Levin, E, Itani, RM, Sarfeh, IJ,  et al. 1999Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healingNat Med5141823PubMedGoogle Scholar
  28. 28.
    Tsujii, M, Kawano, S, Tsuji, S, Sawaoka, H, Hori, M, DuBois, RN 1988Cyclooxygenase regulates angiogenesis induced by colon cancer cellsCell9370516Google Scholar
  29. 29.
    Tsuchida, A, Nagakawa, Y, Kasuya, K, Itoi, T, Endo, M, Ozawa, T,  et al. 2003Immunohistochemical analysis of cyclooxygenase-2 and vascular endothelial growth factor in pancreaticobiliary maljunctionOncol Rep1033943PubMedGoogle Scholar
  30. 30.
    Endo, K, Yoon, BI, Pairojkul, C, Demetris, AJ, Sirica, AE 2002ERBB-2 overexpression and cyclooxygenase-2 up-regulation in human cholangiocarcinoma and risk conditionsHepatology3643950PubMedCrossRefGoogle Scholar
  31. 31.
    Jarnagin, WR, Fong, Y, DeMatteo, RP, Gonen, M, Burke, EC, Bodniewicz, J,  et al. 2001Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinomaAnn Surg23450719PubMedCrossRefGoogle Scholar
  32. 32.
    Kune, GA, Kune, S, Watson, LF 1988Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer StudyCancer Res484399404PubMedGoogle Scholar
  33. 33.
    Giovannucci, E, Egan, KM, Hunter, DJ, Stampfer, MJ, Colditz, GA, Willett, WC,  et al. 1995Aspirin and the risk of colorectal cancer in womenN Engl J Med33360914PubMedCrossRefGoogle Scholar
  34. 34.
    Matsuhashi, N, Nakajima, A, Fukushima, Y, Yazaki, Y, Oka, T 1997Effects of sulindac on sporadic colorectal adenomatous polypsGut403449PubMedGoogle Scholar
  35. 35.
    Tsuneoka, N, Tajima, Y, Kitazato, A, Fukuda, K, Kitajima, T, Kuroki, T,  et al. 2005Chemopreventative effect of a cyclooxygenase-2-specific inhibitor (etodolac) on chemically induced biliary carcinogenesis in hamstersCarcinogenesis264659PubMedGoogle Scholar
  36. 36.
    Shoda, J, Ueda, T, Kawamoto, T, Todoroki, T, Asano, T, Sugimoto, Y,  et al. 2003Prostaglandin E receptors in bile ducts of hepatolithiasis patients and the pathobiological significance for cholangitisClin Gastroenterol Hepatol128596PubMedCrossRefGoogle Scholar
  37. 37.
    Ueki, T, Fujimoto, J, Suzuki, T, Yamamoto, H, Okamoto, E 1997Expression of hepatocyte growth factor and its receptor c-met proto-oncogene in hepatocellular carcinomaHepatology258626PubMedGoogle Scholar
  38. 38.
    Aishima, SI, Taguchi, KI, Sugimachi, K, Shimada, M, Sugimachi, K 2002Tsuneyoshi M. c-erbB-2 and c-Met expression relates to cholangiocarcinogenesis and progression of intrahepatic cholangiocarcinomaHistopathology4026978PubMedCrossRefGoogle Scholar
  39. 39.
    Varnholt, H, Asayama, Y, Aishima, S, Taguchi, K, Sugimachi, K, Tsuneyoshi, M 2002C-met and hepatocyte growth factor expression in combined hepatocellular and cholangiocarcinomaOncol Rep93541PubMedGoogle Scholar
  40. 40.
    Terada, T, Nakanuma, Y, Sirica, AE 1998Immunohistochemical demonstration of MET overexpression in human intrahepatic cholangiocarcinoma and in hepatolithiasisHum Pathol2917580PubMedCrossRefGoogle Scholar
  41. 41.
    Kokuryo, T, Yamamoto, T, Oda, K, Kamiya, J, Nimura, Y, Senga, T,  et al. 2003Profiling of gene expression associated with hepatolithiasis by complementary DNA expression arrayInt J Oncol221759PubMedGoogle Scholar
  42. 42.
    Brabletz, T, Spaderna, S, Kolb, J, Hlubek, F, Faller, G, Bruns, CJ,  et al. 2004Down-regulation of the homeodomain factor Cdx2 in colorectal cancer by collagen type I: an active role for the tumor environment in malignant tumor progressionCancer Res6469737PubMedCrossRefGoogle Scholar
  43. 43.
    Yuasa, Y, Nagasaki, H, Akiyama, Y, Sakai, H, Nakajima, T, Ohkura, Y,  et al. 2005Relationship between CDX2 gene methylation and dietary factors in gastric cancer patientsCarcinogenesis26193200PubMedGoogle Scholar
  44. 44.
    Kawai, H, Tomii, K, Toyooka, S, Yano, M, Murakami, M, Tsukuda, K,  et al. 2005Promoter methylation downregulates CDX2 expression in colorectal carcinomasOncol Rep1354751PubMedGoogle Scholar
  45. 45.
    Ishikawa, A, Sasaki, M, Ohira, S, Ohta, T, Oda, K, Nimura, Y,  et al. 2004Aberrant expression of CDX2 is closely related to the intestinal metaplasia and MUC2 expression in intraductal papillary neoplasm of the liver in hepatolithiasisLab Invest8462938PubMedCrossRefGoogle Scholar
  46. 46.
    Yonezawa, S, Sueyoshi, K, Nomoto, M, Kitamura, H, Nagata, K, Arimura, Y,  et al. 1997MUC2 gene expression is found in noninvasive tumors but not in invasive tumors of the pancreas and liver: its close relationship with prognosis of the patientsHum Pathol283452CrossRefGoogle Scholar
  47. 47.
    Nomura, A, Stemmermann, GN, Chyou, PH, Kato, I, Perez-Perez, GI, Blaser, MJ 1991Helicobacter pylori infection and gastric carcinoma among Japanese Americans in HawaiiN Engl J Med32511326PubMedCrossRefGoogle Scholar
  48. 48.
    Kuipers, EJ, Uyterlinde, AM, Pena, AS, Roosendaal, R, Pals, G, Nelis, GF,  et al. 1995Long-term sequelae of Helicobacter pylori gastritisLancet34515258PubMedCrossRefGoogle Scholar
  49. 49.
    Fox, JG, Dewhirst, FE, Shen, Z, Feng, Y, Taylor, NS, Paster, BJ,  et al. 1998Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitisGastroenterology11475563PubMedCrossRefGoogle Scholar
  50. 50.
    Kuroki, T, Fukuda, K, Yamanouchi, K, Kitajima, T, Matsuzaki, S, Tajima, Y,  et al. 2002Helicobacter pylori accelerates the biliary epithelial cell proliferation activity in hepatolithiasisHepatogastroenterology4964851PubMedGoogle Scholar

Copyright information

© Springer-Verlag Tokyo 2005

Authors and Affiliations

  • Tamotsu Kuroki
    • 1
  • Yoshitsugu Tajima
    • 1
  • Takashi Kanematsu
    • 1
  1. 1.Department of Transplantation and Digestive SurgeryNagasaki University Graduate School of Biomedical SciencesNagasakiJapan

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