Advertisement

Cholangiocarcinoma: Disease Pathogenesis and New Treatment Paradigms

  • Gregory J. GoresEmail author
  • Boris Blechacz
Chapter
  • 763 Downloads

Abstract

Cholangiocarcinoma (CCA) is a malignancy arising in the biliary tree. Its incidence rates have increased, and it has surpassed gallbladder carcinoma as the most common biliary tract malignancy. Most patients are diagnosed with advanced stage disease and are not amenable to potentially curative surgical therapies. The prognosis is dismal with a median survival of <24 months. Novel possible epidemiologic risk factors (i.e., diabetes, cirrhosis, metabolic syndrome) have been identified. Based upon clinical behavior and distinct molecular patterns, intrahepatic, perihilar, and distal CCAs are characterized as distinct malignancies that need to be treated as such in their management and clinical trials. While cholestasis and inflammation are key factors for all three CCA subtypes, their genetic profile differs. Because knowledge of the genetic landscape of CCA has resulted in multiple new therapeutic strategies and clinical trials, it will become increasingly possible to develop precision medicine-based therapies for CCA patients.

Keywords

Hepatocyte Growth Factor KRAS Mutation Gallbladder Carcinoma Stem Cell Feature Hepatic Progenitor Cell 
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.

References

  1. 1.
    Allen RA, Lisa JR. Combined liver cell and bile duct carcinoma. Am J Pathol. 1949;25:647–55.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Andersen JB, Spee B, Blechacz BR, Avital I, Komuta M, Barbour A, Conner EA, Gillen MC, Roskams T, Roberts LR, et al. Genomic and genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors. Gastroenterology. 2012;142:1021–31. e1015CrossRefPubMedGoogle Scholar
  3. 3.
    Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD. Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol. 2004;99:523–6.CrossRefPubMedGoogle Scholar
  4. 4.
    Cardinale V, Bragazzi MC, Carpino G, Torrice A, Fraveto A, Gentile R, Pasqualino V, Melandro F, Aliberti C, Bastianelli C, et al. Cholangiocarcinoma: increasing burden of classifications. Hepatobiliary Surg Nutr. 2013;2:272–80.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Cardinale V, Wang Y, Carpino G, Mendel G, Alpini G, Gaudio E, Reid LM, Alvaro D. The biliary tree--a reservoir of multipotent stem cells. Nat Rev Gastroenterol Hepatol. 2012;9:231–40.CrossRefPubMedGoogle Scholar
  6. 6.
    Carpino G, Cardinale V, Renzi A, Hov JR, Berloco PB, Rossi M, Karlsen TH, Alvaro D, Gaudio E. Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis. J Hepatol. 2015;63:1220–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Chalasani N, Baluyut A, Ismail A, Zaman A, Sood G, Ghalib R, McCashland TM, Reddy KR, Zervos X, Anbari MA, Hoen H. Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology. 2000;31:7–11.CrossRefPubMedGoogle Scholar
  8. 8.
    Chan-On W, Nairismagi ML, Ong CK, Lim WK, Dima S, Pairojkul C, Lim KH, McPherson JR, Cutcutache I, Heng HL, et al. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat Genet. 2013;45:1474–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Endo I, Gonen M, Yopp AC, Dalal KM, Zhou Q, Klimstra D, D’Angelica M, DeMatteo RP, Fong Y, Schwartz L, et al. Intrahepatic cholangiocarcinoma: rising frequency, improved survival, and determinants of outcome after resection. Ann Surg. 2008;248:84–96.CrossRefPubMedGoogle Scholar
  10. 10.
    Everhart JE, Ruhl CE. Burden of digestive diseases in the United States Part III: Liver, biliary tract, and pancreas. Gastroenterology. 2009;136:1134–44.CrossRefPubMedGoogle Scholar
  11. 11.
    Fan B, Malato Y, Calvisi DF, Naqvi S, Razumilava N, Ribback S, Gores GJ, Dombrowski F, Evert M, Chen X, Willenbring H. Cholangiocarcinomas can originate from hepatocytes in mice. J Clin Invest. 2012;122:2911–5.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Guest RV, Boulter L, Kendall TJ, Minnis-Lyons SE, Walker R, Wigmore SJ, Sansom OJ, Forbes SJ. Cell lineage tracing reveals a biliary origin of intrahepatic cholangiocarcinoma. Cancer Res. 2014;74:1005–10.CrossRefPubMedGoogle Scholar
  13. 13.
    Holczbauer A, Factor VM, Andersen JB, Marquardt JU, Kleiner DE, Raggi C, Kitade M, Seo D, Akita H, Durkin ME, Thorgeirsson SS. Modeling pathogenesis of primary liver cancer in lineage-specific mouse cell types. Gastroenterology. 2013;145:221–31.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Ishimura N, Bronk SF, Gores GJ. Inducible nitric oxide synthase up-regulates Notch-1 in mouse cholangiocytes: implications for carcinogenesis. Gastroenterology. 2005;128:1354–68.CrossRefPubMedGoogle Scholar
  15. 15.
    Jiao Y, Pawlik TM, Anders RA, Selaru FM, Streppel MM, Lucas DJ, Niknafs N, Guthrie VB, Maitra A, Argani P, et al. Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas. Nat Genet. 2013;45:1470–3.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Kitade M, Factor VM, Andersen JB, Tomokuni A, Kaji K, Akita H, Holczbauer A, Seo D, Marquardt JU, Conner EA, et al. Specific fate decisions in adult hepatic progenitor cells driven by MET and EGFR signaling. Genes Dev. 2013;27:1706–17.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Kobayashi S, Asano T, Yamasaki M, Kenmochi T, Nakagohri T, Ochiai T. Risk of bile duct carcinogenesis after excision of extrahepatic bile ducts in pancreaticobiliary maljunction. Surgery. 1999;126:939–44.CrossRefPubMedGoogle Scholar
  18. 18.
    Komuta M, Spee B, Vander Borght S, De Vos R, Verslype C, Aerts R, Yano H, Suzuki T, Matsuda M, Fujii H, et al. Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin. Hepatology. 2008;47:1544–56.CrossRefPubMedGoogle Scholar
  19. 19.
    Kosters A, Karpen SJ. The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis. 2010;30:186–94.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, Jang JS, Jeung HC, Kang JH, Lee HW, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncology. 2012;13:181–8.CrossRefPubMedGoogle Scholar
  21. 21.
    Mertens JC, Fingas CD, Christensen JD, Smoot RL, Bronk SF, Werneburg NW, Gustafson MP, Dietz AB, Roberts LR, Sirica AE, Gores GJ. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma. Cancer Res. 2013;73:897–907.CrossRefPubMedGoogle Scholar
  22. 22.
    Nakamura H, Arai Y, Totoki Y, Shirota T, Elzawahry A, Kato M, Hama N, Hosoda F, Urushidate T, Ohashi S, et al. Genomic spectra of biliary tract cancer. Nat Genet. 2015;47:1003–10.CrossRefPubMedGoogle Scholar
  23. 23.
    Rizvi S, Borad MJ, Patel T, Gores GJ. Cholangiocarcinoma: molecular pathways and therapeutic opportunities. Semin Liver Dis. 2014;34:456–64.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Saha SK, Parachoniak CA, Ghanta KS, Fitamant J, Ross KN, Najem MS, Gurumurthy S, Akbay EA, Sia D, Cornella H, et al. Mutant IDH inhibits HNF-4alpha to block hepatocyte differentiation and promote biliary cancer. Nature. 2014;513:110–4.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Shaib YH, El-Serag HB, Davila JA, Morgan R, McGlynn KA. Risk factors of intrahepatic cholangiocarcinoma in the United States: a case-control study. Gastroenterology. 2005;128:620–6.CrossRefPubMedGoogle Scholar
  26. 26.
    Tyson GL, El-Serag HB. Risk factors for cholangiocarcinoma. Hepatology. 2011;54:173–84.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81.CrossRefPubMedGoogle Scholar
  28. 28.
    Voss JS, Holtegaard LM, Kerr SE, Fritcher EG, Roberts LR, Gores GJ, Zhang J, Highsmith WE, Halling KC, Kipp BR. Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions. Hum Pathol. 2013;44:1216–22.CrossRefPubMedGoogle Scholar
  29. 29.
    Welzel TM, Graubard BI, Zeuzem S, El-Serag HB, Davila JA, McGlynn KA. Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database. Hepatology. 2011;54:463–71.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Wilson WH, O'Connor OA, Czuczman MS, LaCasce AS, Gerecitano JF, Leonard JP, Tulpule A, Dunleavy K, Xiong H, Chiu YL, et al. Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity. Lancet Oncol. 2010;11:1149–59.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Woo HG, Lee JH, Yoon JH, Kim CY, Lee HS, Jang JJ, Yi NJ, Suh KS, Lee KU, Park ES, et al. Identification of a cholangiocarcinoma-like gene expression trait in hepatocellular carcinoma. Cancer Res. 2010;70:3034–41.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Yamada D, Rizvi S, Razumilava N, Bronk SF, Davila JI, Champion MD, Borad MJ, Bezerra JA, Chen X, Gores GJ. IL-33 facilitates oncogene-induced cholangiocarcinoma in mice by an interleukin-6-sensitive mechanism. Hepatology. 2015;61:1627–42.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yoon JH, Higuchi H, Werneburg NW, Kaufmann SH, Gores GJ. Bile acids induce cyclooxygenase-2 expression via the epidermal growth factor receptor in a human cholangiocarcinoma cell line. Gastroenterology. 2002;122:985–93.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Mayo ClinicRochesterUSA
  2. 2.MD Anderson Cancer CenterHoustonUSA

Personalised recommendations