담관암에 있어서 분자생물학적 측면과 종양표지자들의 역할

Molecular pathogenesis and the role of tumor markers in cholangiocarcinoma

  • 이진 (한림대학교 의과대학 내과학교실) ;
  • 고동희 (한림대학교 의과대학 내과학교실)
  • Lee, Jin (Department of Internal Medicine, Hallym University College of Medicine) ;
  • Koh, Dong-Hee (Department of Internal Medicine, Hallym University College of Medicine)
  • 발행 : 2010.12.01

초록

Cholangiocarcinoma is a devastating cancer originating from the epithelial cell lining of the bile duct, whose prognosis is poor due to suboptimal response to therapy despite the fact that the incidence is increasing. Hence surgery still remains the only curative treatment option for cholangiocarcinoma. Recent investigations into the underlying biochemical and molecular mechanisms in biliary carcinogenesis and tumor growth, may illuminate new therapeutic modalities and suggest some new serum and bile markers that could be useful for the diagnosis of cholangiocarcinoma. In this review, we discuss the molecular mechanisms of pathogenesis in cholangiocarcinoma and the role of new tumor makers for the diagnosis of cholangiocarcinoma.

키워드

참고문헌

  1. Bonney GK, Craven RA, Prasad R, Melcher AF, Selby PJ, Banks RE. Circulating markers of biliary malignancy: opportunities in proteomics? Lancet Oncol 9:149-158, 2008 https://doi.org/10.1016/S1470-2045(08)70027-5
  2. Davila JA, El-Serag HB. Cholangiocarcinoma: the ''other'' liver cancer on the rise. Am J Gastroenterol 97:3199-3200, 2002
  3. Patel T. Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States. Hepatology 33:1353-1357, 2001 https://doi.org/10.1053/jhep.2001.25087
  4. Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BS J, Youssef BA M, Klimstra D, Blumgart LH. Staging, resectability,and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg 234:507-517; discussion 517-519, 2001 https://doi.org/10.1097/00000658-200110000-00010
  5. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1996. CA Cancer J Clin 46:5-27, 1996 https://doi.org/10.3322/canjclin.46.1.5
  6. Gores GJ. Cholangiocarcinoma: current concepts and insights. Hepatology 37:961-969, 2003 https://doi.org/10.1053/jhep.2003.50200
  7. De Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med 341:1368-1378, 1999 https://doi.org/10.1056/NEJM199910283411807
  8. Hejna M, Pruckmayer M, Raderer M. The role of chemotherapy and radiation in the management of biliary cancer: a review of the literature. Eur J Cancer 34:977-986, 1998 https://doi.org/10.1016/S0959-8049(97)10166-6
  9. Rashid A. Cellular and molecular biology of biliary tract cancers. Surg Oncol Clin N Am 11:995-1009, 2002 https://doi.org/10.1016/S1055-3207(02)00042-X
  10. Van Heek NT, Rauws EA, Caspers E, Drillenburg P, Gouma DJ, Offerhaus GJ. Long-term follow-up of patients with clinically benign extrahepatic biliary stenosis and K-ras mutation in endobiliary brush cytology. Gastrointest Endosc 55:883-888, 2002 https://doi.org/10.1067/mge.2002.124561
  11. Berthiaume EP, Wands J. The molecular pathogenesis of cholangiocarcinoma. Semin Liver Dis 24:127-137, 2004
  12. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 100:57-70, 2000 https://doi.org/10.1016/S0092-8674(00)81683-9
  13. Fava G, Marzioni M, Benedetti A, Glaser S, DeMorrow S, Francis H, Alpini G. Molecular pathology of biliary tract cancers. Cancer Lett 250:155-167, 2007 https://doi.org/10.1016/j.canlet.2006.09.011
  14. Matsumoto K, Fujii H, Michalopoulos G, Fung JJ, Demetris AJ. Human biliary epithelial cells secrete and respond to cytokines and hepatocyte growth factors in vitro: interleukin-6, hepatocyte growth factor and epidermal growth factor promote DNA synthesis in vitro. Hepatology 20:376-382, 1994
  15. Yokomuro S, Tsuji H, Lunz JG 3rd, Sakamoto T, Ezure T, Murase N, Demetris AJ. Growth control of human biliary epithelial cells by interleukin 6, hepatocyte growth factor, transforming growth factor beta1, and activin A: comparison of a cholangiocarcinoma cell line with primary cultures of non-neoplastic bilieary epithelial cells. Hepatology 32:26-35, 2000 https://doi.org/10.1053/jhep.2000.8535
  16. Park J, Tadlock L, Gores GJ, Patel T. Inhibition of interleukin 6-mediated mitogen-activated protein kinase activation attenuates growth of a cholangiocarcinoma cell line. Hepatology 30:1128-1133, 1999 https://doi.org/10.1002/hep.510300522
  17. Okuda K, Nakanuma Y, Miyazaki M. Cholangiocarcinoma: recent progress: part 2. molecular pathology and treatment. J Gastroenterol Hepatol 17:1056-1063, 2002 https://doi.org/10.1046/j.1440-1746.2002.02780.x
  18. Lipsett PA, Pitt HA, Colombani PM, Boitnott JK, Cameron JL. Choledochal cyst disease: a changing pattern of presentation. Ann Surg 220:644-652, 1994 https://doi.org/10.1097/00000658-199411000-00007
  19. Kiguchi K, Carbajal S, Chan K, Beltrán L, Ruffino L, Shen J, Matsumoto T, Yoshimi N, DiGiovanni J. Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma. Cancer Res 61:6971-6976, 2001
  20. 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 122:985-993, 2002 https://doi.org/10.1053/gast.2002.32410
  21. Williams CS, Mann M, DuBios RN. The role of cyclooxygenases in inflammation, cancer and development. Oncogene 18:7908-7916, 1999 https://doi.org/10.1038/sj.onc.1203286
  22. Sirica AE, Lai GH, Endo K, Yoon BI. Cyclooxygenase-2 and ERBB-2 in cholangiocarcinoma: potential therapeutic targets. Semin Liver Dis 22:303-313, 2002
  23. Tannapfel A, Benicke M, Katalinic A, Uhlmann D, Köckerling F, Hauss J, Wittekind C. Frequency of p16-INK4A alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut 47:721-727, 2000 https://doi.org/10.1136/gut.47.5.721
  24. Blechacz B, Gores GJ. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology 48:308-321, 2008.
  25. Green DR, Reed JC. Mitochondria and apoptosis. Science 281:1309-1312, 1998 https://doi.org/10.1126/science.281.5381.1309
  26. Que FG, Phan VA, Phan VH, Celli A, Batts K, LaRusso NF, Gores GJ. Cholangiocarcinomas express Fas ligand and disable the Fas receptor. Hepatology 30:1398-1404, 1999 https://doi.org/10.1002/hep.510300618
  27. Torok NJ, Higuchi H, Bronk S, Gores GJ. Nitric oxide inhibits apoptosis downstream of cytochrome C release by nitrosylating caspase 9. Cancer Res 62:1648-1653, 2002
  28. Nzeako UC, Guicciardi ME, Yoon JH, Bronk SF, Gores GJ. COX-2 inhibits Fas-mediated apoptosis in cholangiocarcinoma cells. Hepatology 35:552-559, 2002 https://doi.org/10.1053/jhep.2002.31774
  29. Benckert C, Jonas S, Cramer T, Von Marschall Z, Schafer G, Peters M, Wagner K, Radke C, Wiedenmann B, Neuhaus P, Höcker M, Rosewicz S. Transfoming growth factor beta 1 stimulates vascular endothelial growth factor gene transcrtiption in human cholangiocellular carcinoma cells. Cancer Res 63:1083-1092, 2003
  30. Terada T, Okada Y, Nakanuma Y. Expression of immunoreactive matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in human normal livers and primary liver tumors. Hepatology 23:1341-1344, 1996 https://doi.org/10.1002/hep.510230608
  31. Lavaissiere L, Jia S, Nishiyama M, de la Monte S, Stern AM, Wands JR, Friedman PA. Overexpression of human aspartyl (asparaginyl) beta-hydroxylase in hepatocellular carcinoma and cholangiocarcinoma. J Clin Invest 98:1313-1323, 1996 https://doi.org/10.1172/JCI118918
  32. Kim HJ, Kim MH, Myung SJ, Lim BC, Park ET, Yoo KS, Seo DW, Lee SK, Min YI. A new strategy for the application of CA 19-9 in the differentiation of pancreaticobiliary cancer: analysis using a receiver operating characteristic curve. Am J Gastroenterol 94:1941-1946, 1999 https://doi.org/10.1111/j.1572-0241.1999.01234.x
  33. Ong SL, Sachdeva A, Garcea G, Gravante G, Metcalfe MS, Lloyd DM, Berry DP, Dennison AR. Elevation of carbohydrate antigen 19.9 in benign hepatobiliary conditions and its correlation with serum bilirubin concentration. Dig Dis Sci 53:3213-3217, 2008 https://doi.org/10.1007/s10620-008-0289-8
  34. Alvaro D. Serum and bile biomarkers for cholangiocarcinoma. Curr Opin Gastroenterol 25:279-284, 2009 https://doi.org/10.1097/MOG.0b013e328325a894
  35. Goydos JS, Brumfield AM, Frezza E, Booth A, Lotze MT, Carty SE. Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma: validation of utility as a clinical marker. Ann Surg 227:398-404, 1998 https://doi.org/10.1097/00000658-199803000-00012
  36. Cheon YK, Cho YD, Moon JH, Jang JY, Kim YS, Kim YS, Lee MS, Lee JS, Shim CS. 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 102:2164-2170, 2007 https://doi.org/10.1111/j.1572-0241.2007.01403.x
  37. Nehls O, Gregor M, Klump B. Serum and bile markers for cholangiocarcinoma. Semin Liver Dis 24:139-154, 2004
  38. Lempinen M, Isoniemi H, Mäkisalo H, Nordin A, Halme L, Arola J, Höckerstedt K, Stenman UH. Enhanced detection of cholangiocarcinoma with serum trypsinogen-2 in patients with severe bile duct strictures. J Hepatol 47:677-683, 2007 https://doi.org/10.1016/j.jhep.2007.05.017
  39. Briggs CD, Neal CP, Mann CD, Stward WP, Manson MM, Berry DP. Prognostic molecular markers in cholangiocarcinoma: a systematic review. Eur J Cancer 45:33-47, 2009 https://doi.org/10.1016/j.ejca.2008.08.024
  40. Bamrungphon W, Prempracha N, Bunchu N, Rangdaeng S, Sandhu T, Srisukho S, Boonla C, Wongkham S. A new mucin antibody/enzyme-linked lectin-sandwich assay of serum MUC5AC mucin for the diagnosis of cholangiocarcinoma. Cancer Lett 247:301-308, 2007 https://doi.org/10.1016/j.canlet.2006.05.007
  41. Matull WR, Andreola F, Loh A, Adiguzel Z, Deheragoda M, Qureshi U, Batra SK, Swallow DM, Pereira SP. MUC4 and MUC5AC are highly specific tumour-associated mucins in biliary tract cancer. Br J Cancer 98:1675-1681, 2008 https://doi.org/10.1038/sj.bjc.6604364
  42. Uenishi T, Yamazaki O, Tanaka H, Takemura S, Yamamoto T, Tanaka S, Nishiguchi S, Kubo S. Serum cytokeratin 19 fragment (CYFRA21-1) as a prognostic factor in intrahepatic cholangiocarcinoma. Ann Surg Oncol 15:583-589, 2008 https://doi.org/10.1245/s10434-007-9650-y
  43. Alvaro D, Macarri G, Mancino MG, Marzioni M, Bragazzi M, Onori P, Corradini SG, Invernizzi P, Franchitto A, Attili AF, Gaudio E, Benedetti A. Serum andbiliary insulin-like growth factor I and vascular endothelial growth factor in determining the cause of obstructive cholestasis. Ann Intern Med 147:451-459, 2007 https://doi.org/10.7326/0003-4819-147-7-200710020-00003
  44. Chen CY, Tsai WL, Wu HC, Syu MJ, Wu CC, Shiesh SC. Diagnostic role of biliary pancreatic elastase for cholangiocarcinoma in patients with cholestasis. Clin Chim Acta 390:82-89, 2008 https://doi.org/10.1016/j.cca.2008.01.011
  45. Ayaru L, Stoeber K, Webster GJ, Hatfield AR, Wollenschlaeger A, Okoturo O, Rashid M, Williams G, Pereira SP. Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in bile aspirates. Br J Cancer 98:1548-1554, 2008 https://doi.org/10.1038/sj.bjc.6604342
  46. Sturm PD, Rauws EA, Hruban RH, Caspers E, Ramsoekh TB, Huibregtse K, Noorduyn LA, Offerhaus GJ. Clinical value of K-ras codon 12 analysis and endobiliary brush cytology for the diagnosis of malignant extrahepatic bile duct stenosis. Clin Cancer Res 5:629-635, 1999
  47. Kubicka S, Kühnel F, Flemming P, Hain B, Kezmic N, Rudolph KL, Manns M, Meier PN. K-ras mutations in the bile of patients with primary sclerosing cholangitis. Gut 48:403-408, 2001 https://doi.org/10.1136/gut.48.3.403
  48. Laurent-Puig P, Lubin R, Semhoun-Ducloux S, Pelletier G, Fourre C, Ducreux M, Briantais MJ, Buffet C, Soussi T. Antibodies against p53 protein in serum of patients with benign or malignant pancreatic and biliary diseases. Gut 36:455-458, 1995 https://doi.org/10.1136/gut.36.3.455
  49. Wang Y, Yamaguchi Y, Watanabe H, Ohtsubo K, Wakabayashi T, Sawabu N. Usefulness of p53 gene mutations in the supernatant of bile for diagnosis of biliary tract carcinoma: comparison with K-ras mutation. J Gastroenterol 37:831-839, 2002 https://doi.org/10.1007/s005350200137
  50. Belinsky SA, Nikula KJ, Palmisano WA, Michels R, Saccomanno G, Gabrielson E, Baylin SB, Herman JG. Aberrant methylation of p16 (INK4a) is an early event in lung cancer and a potential biomarker for early diagnosis. Proc Natl Acad Sci USA 95:11891-11896, 1998 https://doi.org/10.1073/pnas.95.20.11891
  51. Klump B, Hsieh CJ, Dette S, Holzmann K, Kiebetalich R, Jung M, Sinn U, Ortner M, Porschen R, Gregor M. Promoter methylation of INK4a/ARF as detected in bile-significance for differential diagnosis in biliary disease. Clin Cancer Res 9:1773-1778, 2003
  52. Ryan ME, Baldauf MC. Comparison of flow cytometry for DNA content and brush cytology for detection of malignancy in pancreaticobiliary strictures. Gastrointest Endosc 40:133-139, 1994 https://doi.org/10.1016/S0016-5107(94)70154-7
  53. Rumalla A, Baron TH, Leontovich O, Burgart LJ, Yacavone RF, Therneau TM, de Groen PC, Sebo TJ. Improved diagnostic yield of endoscopic biliary brush cytology by digital image analysis. Mayo Clin Proc 76:29-33, 2001 https://doi.org/10.4065/76.1.29