Liver Cancer pp 441-449 | Cite as

Extrahepatic Bile Duct Carcinoma: Role of the p53 Protein Family

  • Alexander I. Zaika
  • Seung-Mo Hong
Part of the Methods of Cancer Diagnosis, Therapy and Prognosis book series (HAYAT, volume 5)

Bile duct carcinomas (cholangiocarci-noma) are devastating tumors. Surgical resection is the mainstay of current treatment; however, it is only effective for a limited number of patients diagnosed at early stages of the disease. Unfortunately, the vast majority of patients seek treatment of the advanced disease making them poor candidates for curative surgery. Conventional chemotherapy and radiation therapy have not been shown to be effective in prolonging long-term survival of patients with cholangiocarcinoma. In addition, there are no sensitive and specific tests to diagnose and exclude this disease in high-risk populations. Thus, there is an urgent need for novel biomarkers and therapies based on a better understanding of biliary tumorigenesis that would significantly impact the disease outcome. This chapter reviews current clinical data on the p53 protein family and its role in biliary tumorigenesis.


Bile Duct Choledochal Cyst Extrahepatic Bile Duct Biliary Tract Cancer Bile Duct Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. Ahrendt, S.A., Rashid, A., Chow, J.T., Eisenberger, C.F., Pitt, H.A., and Sidransky, D. 2000. p53 overexpression and K-ras gene mutations in primary sclerosing cholangitis-associated biliary tract cancer. J. HepatoBiliary-Pancreat. Surg. 7: 426–431.PubMedCrossRefGoogle Scholar
  2. Albores-Saavedra, J., Henson, D.E., and Klimstra, D.S. 2000. Tumors of the Gall bladder, Extrahepatic Bile Ducts and Ampulla of Vater. Atlas of Tumor Pathology, Armed Forces Institute of Pathology, Washington, DC.Google Scholar
  3. Argani, P., Shaukat, A., Kaushal, M., Wilentz, R.E., Su, G.H., Sohn, T.A., Yeo, C.J., Cameron, J.L., Kern, S.E., and Hruban, R.H. 2001. Differing rates of loss of DPC4 expression and of p53 overexpression among carcinomas of the proximal and distal bile ducts. Cancer 91: 1332–1341.PubMedCrossRefGoogle Scholar
  4. Choi, B.I., Han, J.K., Hong, S.T., and Lee, K.H. 2004. Clonorchiasis and cholangiocarcinoma: etiologic relationship and imaging diagnosis. Clin. Microbiol. Rev. 17: 540–552.PubMedCrossRefGoogle Scholar
  5. Concin, N., Becker, K., Slade, N., Erster, S., Mueller-Holzner, E., Ulmer, H., Daxenbichler, G., Zeimet, A., Zeillinger, R., Marth, C., and Moll, U.M. 2004. Transdominant DeltaTAp73 isoforms are frequently up-regulated in ovarian cancer. Evidence for their role as epigenetic p53 inhibitors in vivo. Cancer Res. 64: 2449–2460.PubMedCrossRefGoogle Scholar
  6. Diamantis, I., Karamitopoulou, E., Perentes, E., and Zimmermann, A. 1995. p53 protein immunoreactivity in extrahepatic bile duct and gallbladder cancer: correlation with tumor grade and survival, Hepatology 22: 774–779, Baltimore, MD.PubMedCrossRefGoogle Scholar
  7. Farazi, P.A., Zeisberg, M., Glickman, J., Zhang, Y., Kalluri, R., and DePinho, R.A. 2006. Chronic bile duct injury associated with fibrotic matrix microenvironment provokes cholangiocarci-noma in p53-deficient mice. Cancer Res. 66: 6622–6627.PubMedCrossRefGoogle Scholar
  8. Flores, E.R., Sengupta, S., Miller, J.B., Newman, J.J., Bronson, R., Crowley, D., Yang, A., McKeon, F., and Jacks, T. 2005. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell 7: 363–373.PubMedCrossRefGoogle Scholar
  9. Green, F.L., Page, D.L., Fleming, I.D., Fritz, A.G., Balch, C.M., Haller, D.G., and Morrow, M. 2002. AJCC Cancer Staging Manual, Springer, New York.CrossRefGoogle Scholar
  10. Hong, S.M., Cho, H., Moskaluk, C.A., Yu, E., and Zaika, A.I. 2007. p63 and p73 expression in ext-rahepatic bile duct carcinoma and their clinical significance. J. Mol. Histol. 38: 167–175.PubMedCrossRefGoogle Scholar
  11. Hong, S.M., Kim, M.J., Pi, D.Y., Jo, D., Cho, H.J., Yu, E., and Ro, J.Y. 2005. Analysis of extrahe-patic bile duct carcinomas according to the New American Joint Committee on Cancer staging system focused on tumor classification problems in 222 patients. Cancer 104: 802–810.PubMedCrossRefGoogle Scholar
  12. Khan, S.A., Thomas, H.C., Toledano, M.B., Cox, I.J., and Taylor-Robinson, S.D. 2005. p53 Mutations in human cholangiocarcinoma: a review. Liver Int. 25: 704–716.PubMedCrossRefGoogle Scholar
  13. Lee, Y.C., Song, S.Y., Chung, J.B., Kang, J.K., and Park, I.S. 1996. p53 protein expression in extrahepatic bile duct cancer. Yonsei Med. J. 37: 112–117.PubMedGoogle Scholar
  14. Leong, C.O., Vidnovic, N., DeYoung, M.P., Sgroi, D., and Ellisen, L.W. 2007. The p63/p73 network mediates chemosensitivity to cisplatin in a biologically defined subset of primary breast cancers. J. Clin. Invest. 117: 1370–1380.PubMedCrossRefGoogle Scholar
  15. Malhi, H., and Gores, G.J. 2006. Cholangiocarcinoma: modern advances in understanding a deadly old disease. J. Hepatol. 45: 856–867.PubMedCrossRefGoogle Scholar
  16. Momoi, H., Okabe, H., Kamikawa, T., Satoh, S., Ikai, I., Yamamoto, M., Nakagawara, A., Shimahara, Y., Yamaoka, Y., and Fukumoto, M. 2001. Comprehensive allelotyping of human intrahepatic cholangiocarcinoma. Clin. Cancer Res. 7: 2648–2655.PubMedGoogle Scholar
  17. Munro, A.J., Lain, S., and Lane, D.P. 2005. P53 abnormalities and outcomes in colorectal cancer: a systematic review. Br. J. Cancer 92: 434–444.PubMedGoogle Scholar
  18. Murata, T., Nagasaka, T., Kamiya, J., Nimura, Y., Wakai, K., Yoshida, K., and Nakashima, N. 2002. P53 labeling index in cholangioscopic biopsies is useful for determining spread of bile duct carcinomas. Gastrointest. Endos. 56: 688–695.CrossRefGoogle Scholar
  19. Nagakawa, T., Kayahara, M., Ikeda, S., Futakawa, S., Kakita, A., Kawarada, H., Matsuno, M., Takada, T., Takasaki, K., Tanimura, H., Tashiro, S., and Yamaoka, Y. 2002. Biliary tract cancer treatment: results from the Biliary Tract Cancer Statistics Registry in Japan. J. HepatoBiliary-Pancreat. Surg. 9: 569–575.PubMedCrossRefGoogle Scholar
  20. Nathan, H., Pawlik, T.M., Wolfgang, C.L., Choti, M.A., Cameron, J.L., and Schulick, R.D. 2007. Trends in survival after surgery for cholangi-ocarcinoma: a 30-year population-based SEER database analysis. J. Gastrointest. Surg. 11: 1488–1496; discussion: 1496–1487.PubMedCrossRefGoogle Scholar
  21. Nomoto, K., Tsuneyama, K., Cheng, C., Takahashi, H., Hori, R., Murai, Y., and Takano, Y. 2006. Intrahepatic cholangiocarcinoma arising in cir-rhotic liver frequently expressed p63-positive basal/stem-cell phenotype. Pathol. Res. Pract. 202: 71–76.PubMedCrossRefGoogle Scholar
  22. Seyama, Y., and Makuuchi, M. 2007. Current surgical treatment for bile duct cancer. World J. Gastroenterol. 13: 1505–1515.PubMedGoogle Scholar
  23. Suto, T., Sugai, T., Nakamura, S., Uesugi, N., Sasaki, R., Kanno, S., and Saito, K. 1997. Immunohistochemical detection of proliferating cell nuclear antigen and p53 expression in carcinoma of the extrahepatic bile duct. Oncology 54: 407–413.PubMedCrossRefGoogle Scholar
  24. Tan, G., Yilmaz, A., De Young, B.R., Behling, C., Lehman, A., and Frankel, W.L. 2004. Immunohistochemical analysis of biliary tract lesions. Appl. Immunohistochem. Mol. Morphol. 12: 193–197.PubMedGoogle Scholar
  25. Tannapfel, A., Engeland, K., Weinans, L., Katalinic, A., Hauss, J., Mossner, J., and Wittekind, C. 1999. Expression of p73, a novel protein related to the p53 tumour suppressor p53, and apoptosis in cholangiocellular carcinoma of the liver. Br. J. Cancer 80: 1069–1074.PubMedCrossRefGoogle Scholar
  26. Vilgelm, A., El-Rifai, W., and Zaika, A. 2008. Therapeutic prospects for p73 and p63: Rising from the shadow of p53. Drug Resist. Updat. 11: 152–163.PubMedCrossRefGoogle Scholar
  27. Yang, B., House, M.G., Guo, M., Herman, J.G., and Clark, D.P. 2005. Promoter methylation profiles of tumor suppressor genes in intrahepatic and extrahepatic cholangiocarcinoma. Mod. Pathol. 18: 412–420.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media B.V. 2009

Authors and Affiliations

  • Alexander I. Zaika
    • 1
  • Seung-Mo Hong
    • 1
  1. 1.Department of Surgery and Cancer BiologyVanderbilt University Medical CenterNashvilleUSA

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