Cancer Treatment Reviews
Volume 26, Issue 1 , Pages 29-52 , February 2000

Molecular biology of pancreatic cancer; oncogenes, tumour suppressor genes, growth factors, and their receptors from a clinical perspective

References 

    REFERENCES
  1. Warshaw AL, Fernandez-Del Castillo C. Pancreatic carcinoma. N Engl J Med. 1992;326:455–465
  2. Murr MM, Sarr MG, Oishi AJ, van Heerden JA. Pancreatic cancer. CA Cancer J Clin. 1994;44:304–318
  3. Wagener DJ, Punt CJ, Wilk H. Current status and future directions in the perioperative treatment of pancreatic cancer. Ann Oncol. 1994;5 (S3):87–90
  4. Vezeridis MP, Wanebo HJ. Pancreatic cancer. RI Med J. 1994;77:115–118
  5. Ahlgren JD. Epidemiology and risk factors in pancreatic cancer. Sem Oncol. 1996;23:241–250
  6. Wanebo HJ, Vezeridis MP. Pancreatic carcinoma in perspective. A continuing challenge. Cancer. 1996;78:580–591
  7. Ahlgren JD, Hill MC, Roberts IM. Pancreatic cancer: patterns, diagnosis and approaches to treatment. In:  Ahlgren JD, McDonald  editor. Gastrointestinal Oncology. Philadelphia: JB Lippincott; 1992;p. 197–207
  8. Boyle P, Hsieh CC, Maisonneuve P, La Vecchia C, Marfarlane GJ, Walker AM, et al. Epidemiology of pancreas cancer (1988). Int J Pancreatol. 1989;5:327–346
  9. Poston GJ, Gillespie J, Guillou PJ. Biology of pancreatic cancer. Gut. 1991;32:800–812
  10. Mack TM, Yu MC, Hanisch R, Henderson BE. Pancreas cancer and smoking, beverage consumption and past medical history. J Natl Cancer Instit. 1986;76:49–60
  11. Falk JF. Life style risk factors for pancreatic cancer in Louisiana: a case-control study. Am J Epidemiol. 1988;128:324–326
  12. Cuzick J, Babiker AG. Pancreatic cancer, alcohol, diabetes mellitus and gall-bladder disease. Int J Cancer. 1989;43:415–421
  13. Farrow DC, Davis S. Risk of pancreatic cancer in relation to medical history and the use of tobacco, alcohol and coffee. Int J Cancer. 1990;45:816–820
  14. Ghadirian P, Simard A, Baillargeon J. Tobacco, alcohol and coffee and cancer of the pancreas. Cancer. 1991;6:2664–2670
  15. Hirayama T. Epidemiology of pancreatic cancer in Japan. Jpn J Clin Oncol. 1989;19:208–215
  16. Howe GR, Jain M, Bursch JD, Miller AB. Cigarrette smoking and cancer of the pancreas: evidence from a population-based case control-study in Toronto, Canada. Int J Cancer. 1991;47:323–328
  17. Norell SE, Ahlbom A, Erwald R. Diet and pancreatic cancer: a case control study. Am J Epidemiol. 1986;124:894–902
  18. Mills PK, Beeson WL, Abbey DE, Fraser GE, Phillips RL. Dietary habits and past medical history as related to fatal pancreas cancer risk Adventists. Cancer. 1988;61:2578–2585
  19. Farrow DC, Davis S. Diet and the risk of pancreatic cancer in men. Am J Epidemiol. 1990;132:423–431
  20. Redmond CK, Strobino BR, Cypess RH. Cancer experience among coke by-product workers. Ann NY Acad Scie. 1976;271:102–115
  21. Milham S. Neoplasia in the wood and pulp industry. Ann NY Acad Scie. 1976;271:294–300
  22. Mancuso TF, el-Altar AA. Cohort study of workers exposed to betanaphtylamine and benzidine. J Occup Med. 196;9:277–285
  23. Guralnik L. Mortality by occupational level and cause of death. Vital statistics special reports 53(5). 1963;
  24. Lin RS, Hessler H. A multifactorial model for pancreatic cancer in man. JAMA. 1981;245:147–152
  25. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Anderson JR. Pancreatitis and the risk of pancreatic cancer. N Engl J Med. 1993;328:1433–1437
  26. Gold E, Cameron JL. Chronic pancreatitis and pancreatic cancer. N Engl J Med. 1993;328:1485–1486
  27. Lin A, Feller ER. Pancreatic carcinoma as a cause of unexplained pancreatitis: report of ten cases. Ann Intern Med. 1990;113:166–167
  28. Ekborn A, McLanghlin JK, Marlson BM, Britt-Marrie K, Nyren O, Gridley U. Pancreatitis and pancreatic cancer: a population based study. J Natl Cancer Instit. 1994;86:625–627
  29. Kozuka S, Sassa K, Taki T, Masamoto K, Nagasawa S, Saga S. Relation of pancreatic duct hyperlpasia to carcinoma. Cancer. 1979;43:1418–1428
  30. Permert I, Ihse I, Jorfeldt L, von Scenck H, Arnquist HJ, Larsson J. Improved glucose metabolism after subtotal pancreatectomy for pancreatic cancer. Br J Surg. 1993;80:1047–1055
  31. Lynch HT. Genetics and pancreatic cancer. Arch Surg. 1994;129:266–268
  32. Flanders TY, Foulkes WP. Pancreatic adenocarcinoma: epidemiology and genetics. J Med Genet. 1996;33:889–898
  33. Lionetto R, Pugliese V, Bruzzi P, Rosso R. No standard treatment is available for advanced pancreatic cancer. Eur J Cancer. 1995;31A:882–887
  34. Crist DW, Cameron JL. The current status of the Whipple operation for periampullary carcinoma. Adv Surg. 1992;25:21–49
  35. Fernandez-delCastillo C, Rattner DW, Warshaw AL. Standards for pancreatic resection in the 1990s. Arch Surg. 1995;130:295–300
  36. Lumadue JA, Griffin CA, Osman M, Hruban RH. Familial pancreatic cancer and the genetics of pancreatic cancer. Surg Clin North Am. 1995;75:845–855
  37. Hahn SA, Kern SE. Molecular genetics of exocrine pancreatic neoplasms. Surg Clin North Am. 1995;75:857–869
  38. Moley JF, Kim SH. The molecular genetics of tumors commonly treated by the surgical oncologist. In:  Moley JF,  Kim SH editor. Molecular genetics in surgical oncology. Austin: RG Landes Company; 1994;p. 73–95
  39. Seymour AB, Hruban RH, Redston M. Allelotype of pancreatic adenocarcinoma. Cancer Res. 1994;54:2761–2765
  40. Gelehrtrer TD, Collis FS. Cancer genetics. In:  Gelehrtrer TD,  Collins ES editor. Genetics. Baltimore: Williams and Wilkins; 1990;p. 229–252
  41. Miller WH, Dmitrovsky E. Oncogenes and clinical oncology. Curr Opin Oncol. 1991;3:65–69
  42. Pillai R. Oncogenes and oncoproteins as tumor markers. Eur J Surg Oncol. 1992;18:417–424
  43. Sakorafas, G. H. Glynatsis, M. T. The clinical significance of oncogenes. Monography, Infomedia (Ed), Athens, 1993
  44. Fishleder AJ. Oncogenes and cancer. Clinical applications. Cleveland Clin J Med. 1990;57:721–726
  45. Bishop JM. The molecular genetics of cancer. Science. 1987;235:305–311
  46. Weinberg RA. Oncogenes, antioncogenes and the molecular basis of multistep carcinogenesis. Cancer Res. 1989;49:3713–3719
  47. Sakorafas GH, Glynatsis MT. Oncogenes. Diagnostic and therapeutic applications in oncology. latriki. 1995;68:563–578
  48. Krontiris TG. Molecular medicine: oncogenes. N Engl J Med. 1995;333:303–306
  49. Lowy DR, Willumsen BM. Function and regulation of ras. Annu Rev Biochem. 1993;62:851–891
  50. Bos JL. The ras gene family and human carcinogenesis. Mutat Res. 1988;195:255–271
  51. Bos JL. Ras oncogenes in human cancer: a review. Cancer Res. 1989;49:4682–4689
  52. McCormick F. Ras GTPase activating protein: signal transmitter and signal terminator. Cell. 1989;56:5–11
  53. Barbacid M. Ras genes. Annu Rev Biochem. 1987;56:779–827
  54. Lemoine NR. Ras oncogenes in human cancers. In:  Sluyser M editors. The molecular biology of cancer genes. Chichester, England: Ellis Horwood; 1990;p. 82–118
  55. Lemoine NR. The c-ras oncogenes and GAP. In:  Carney D,  Sikora K editor. Genes and cancer. Chichester, England: Wiley; 1990;p. 19–29
  56. Almoguera C, Shibata D, Forrester K. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988;53:549–554
  57. Smit VTHBM, Boot AJM, Freuren GJ. K-ras codon 12 mutations occur very frequently in pancreatic adenocarcinomas. Nucleic Acid Res. 1988;16:773–7782
  58. Grunewald K, Lyons J, Frohlich A. High frequency of Ki-ras codon 12 mutations in pancreatic adenocarcinomas. Int J Cancer. 1988;43:1033–1041
  59. Mariyama M, Kishi K, Nakamura K. Frequency and types of point mutation at the 12th codon of the c-Ki-ras gene found in pancreatic cancers from Japanese patients. Jpn J Cancer Res. 1989;80:622–626
  60. Nagata Y, Abe M, Motoshima K. Frequent glycine-to-aspartic acid mutations at codon 12 of c-Ki-ras gene in human pancreatic cancer in Japanese. Jpn J Cancer Res. 1990;81:135–149
  61. Tada M, Omata M, Ohto M. Clinical application of ras gene mutation for diagnosis of pancreatic adenocarcinoma. Gastroenterology. 1991;100:233–238
  62. Hruban RH, van Mansfeld AOM, Offerhaus GJ. K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol. 1993;143:545–554
  63. Kalthoff H, Schiegel W, Roeder G. p53 and K-ras alterations in pancreatic epithelial cell lesions. Oncogene. 1993;8:289–293
  64. Pellegata NS, Sessa F, Renault B. K-ras and p53 gene mutations in pancreatic cancer: Ductal and non-ductal tumors progress through different genetic lesions. Cancer Res. 1994;54:1556–1560
  65. Lemoine NR, Jain S, Hughes C, Staddon SL. K-ras oncogene activation in pre-invasive pancretic cancer. Gastroenterology. 1992;102:230–236
  66. Motojima K, Urano T, Nagata Y, Shiku H, Tsurifune T, Kanematsu T. Detection of point mutations in the K-ras oncogene provides evidence for the multicentricity of pancreatic adenocarcinoma. Ann Surg. 1993;217:138–143
  67. Motojima K, Tsunoda T, Kanematsu T, Nagata Y, Urano T, Shiku H. Distinguishing pancreatic carcinoma from other periampullary carcinomas by analysis of mutations in the Kirstein-ras oncogenes. Ann Surg. 1991;214:657–662
  68. Motojima K, Urano T, Nagata Y, Shiku H, Tsunoda T, Kanematsu T. Mutations in the Kirstein-ras oncogene are common but lack correlation with prognosis and tumor stage in human pancreatic adenocarcinoma. Am J Gastroenterol. 1991;86:1784–1788
  69. Malats N, Porta M, Fernandez E. Detection of c-Ki-ras mutation by PCR/PFLP analysis and diagnosis of pancreatic adenocarcinomas. J Natl Cancer Instit. 1994;86:1353–1354
  70. Sugio K, Gazdar AF, Albores-Saavedra J, Kokkinakis DM. High yields of K-ras mutations in intraductal papillary mucinous tumours and invasive adenocarcinomas induced by N-nitroso(2-hydroxy-propyl) (2-oxypropyl) amine in the pancreas of female Syrian hamsters. Carcinogenesis. 1996;17:303–309
  71. Van Laethem JL, Vertongen P, Deviere J, Van Rampelbergh J, Rickaert F, Cremer M, et al. Detection of c-Ki-ras gene codon 12 mutations from pancreatic duct brushings in the diagnosis of pancreatic tumors. Gut. 1995;36:781–787
  72. Shibata D, Capella G, Perucho M. Mutational activation of the c-K-ras gene in human pancreatic cancer. Baillieres Clin Gastroenterol. 1990;4:151–159
  73. Gonzales-Cadavid NF, Zhou D, Battifora H, Bar-Eli M, Cline MJ. Direct sequencing analysis of exon 1 of the c-K-ras gene shows a low frequency of mutations in human pancreatic adenocarcinomas. Oncogene. 1989;4:1137–1140
  74. Shibata D, Almoguera C, Forrester K. Detection of c-K-ras mutations in fine needle aspirates from human pancreatic adenocarcinomas. Cancer Res. 1990;50:1279–1283
  75. Caldas C, Kern SE. K-ras mutation and pancreatic adenocarcinoma. Int J Pancreatol. 1995;18:1–5
  76. Rivera JA, Rall CJN, Graeme-Cook F, Fernandez-delCastillo C, Shu P, Lakey N, et al. Analysis of K-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia. Surgery. 1997;121:42–49
  77. Lynch HT, Smyrk T, Kern SE. Familial pancreatic cancer. A review. Semin Oncol. 1996;23:251–275
  78. Vehara H, Nakaizumi A, Baba M. Diagnosis of pancreatic cancer by K-ras point mutation and cytology of pancreatic juice. Am J Gastroenterol. 1996;91:1616–1621
  79. Yanagisawa A, Ohtake K, Ohashi K. Frequent c-K-ras oncogene in mucous cell hyperplasia of pancreas suffering from chronic inflammation. Cancer Res. 1993;53:953–956
  80. Cerny WL, Mangold KA, Scarpelli DG. K-ras mutations is an early event in pancreatic duct carcinogenesis in the Syrian golden hamster. Cancer Res. 1992;52:4507–4513
  81. Quaife CJ, Pinckert CA, Ornitz DM. Pancreatic neoplasia induced by ras expression in acinar cells by transgenic mice. Cell. 1987;48:1023–1034
  82. Cubilla AL, Fitzgerald PJ. Morphological lesions associated with human primary non-endocrine pancreas cancer. Cancer Res. 1976;36:2690–2698
  83. DiGiuseppe JA, Hruban RH, Offenhaus GJA. Detection of K-ras mutations in mucinous pancreatic duct hyperplasia from a patient with a family history of pancreatic carcinoma. Am J Pathol. 1994;144:889–895
  84. Scaeffer BK, Glasner S, Kuhlmann E. Mutated c-K-ras in small pancreatic adenocarcinomas. Pancreas. 1994;9:161–165
  85. Berthelemy P, Bouisson M, Escouron J, Vaysse N, Rumeak JL, Pradayrol L. Identification of K-ras mutations in pancreatic juice in the early diagnosis of pancreatic cancer. Ann Intern Med. 1995;123:188–191
  86. Tada M, Omata M, Ohto M. Ras gene mutations in intraductal papillary neoplasms of the pancreas. Analysis of five cases. Cancer. 1991;67:634–637
  87. Wakabayashi T, Sawabu N, Watanabe H, Morimoto H, Sugioka G, Takita Y. Detection of K-ras point mutation at codon 12 in pure pancreatic juice collected 3 years and 6 months before the clinical diagnosis of pancreatic cancer. Am J Gastroenterol. 1996;91:1848–1851
  88. Satoh K, Sawai T, Shimosegawa T. The point mutation of K-ras at codon 12 in carcinoma of the pancreatic head region and in intra-ductal mucin-hypersecreting neoplasms of the pancreas. Int J Pancreatol. 1993;14:135–143
  89. Hall PA, Hughes CM, Staddon SL, Richman PI, Gullick WJ, Lemoine NR. The c-erbB-2 protooncogene in human pancreatic cancer. J Pathol. 1990;161:195–200
  90. Schecter AL, Stern DF, Vaidayanathan L. The neu oncogene: an erb-B related gene encoding a 18500 M tumor antigen. Nature. 1984;312:513–516
  91. Gullick WJ, Bege MS, Bennet RL, Rothbard JB, Waterfield MD. Expression of the c-erbB-2 protein in normal and transformed cells. Int J Cance. 1987;40:246–254
  92. Yokota J, Yamamoto T, Toyoshima M. Amplification of c-erbB-2 oncogene in human adenocarcinomas in vivo. Lancet. 1986;i:765–767
  93. Gullick WJ, Venter DJ. The c-erbB-2 gene and its expression in human tumors. In:  Waxman J,  Sikora C editor. The molecular basis of cancer. Oxford: Blackwell Scintific Publications,; 1989;p. 38–53
  94. Slamon DJ, Godolphin W, Jones LA. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–712
  95. Weiner DB, Nordberg J, Nowell PC. Expression of the neu gene encoded protein (p185erbB-2) in human non-small cell carcinomas of the lung. Cancer Res. 1990;50:421–425
  96. Wright C, Angus B, Nicholson S. Expression of c-erbB-2 oncoprotein. A prognostic indicator in human breast cancer. Cancer Res. 1989;49:2087–2090
  97. Berger MS, Locher GW, Saurer S. Correlation of c-erbB-2 gene amplification and protein expression in human breast carcinoma with nodal status and nuclear grading. Cancer Res. 1988;48:1238–1243
  98. Guerin M, Barrois M, Terrier MJ. Overexpression of either c-myc or c-erbB-2. neu proto-oncogenes in human breast carcinomas: correlation with poor prognosis. Oncogene Res. 1988;3:21–31
  99. Slamon DJ, Clark GM, Wong SG. Human breast cancer: correlation of relapse and survival with amplification of the c-erbB-2/neu oncogene. Science. 1987;235:177–182
  100. Sakorafas GH. Oncogenes in the cancer of the pancreas. Ph. D. Thesis. Athens. 1993;90
  101. Sakorafas GH, Lazaris A, Tsiotou AG, Koullias G, Glinatsis MT, Golematis BC. Oncogenes in cancer of the pancreas. Eur J Surg Oncol. 1995;21:251–253
  102. Sakorafas GH, Tsiotou AG. Genetic basis of cancer of the pancreas: Diagnostic and therapeutic applications (Clinical Review). Eur J Surg. 1994;160:529–534
  103. Lemoine NR, Hall PA. Growth factors and oncogenes in pancreatic cancer. Bailliere’s Clini Gastroenterol. 1990;4:815–832
  104. Williams TM, Weiner DB, Greene MT, Maguire HC. Expression of c-erbB-2 in human pancreatic adenocarcinomas. Pathobiology. 1991;59:46–52
  105. Terada T, Ohta T, Nakanuena Y. Expression of oncogene products, antioncogene products and oncofetal antigens in intraductal papillary-mucinous neoplasms of the pancreas. Histopathology. 1996;29:355–361
  106. Maguire HC, Greene MI. The neu (c-erbB-2) oncogene. Semin Oncol. 1989;16:148–155
  107. Lacroix H, Iglehart JD, skinner MA, Krauss MH. Overexpression of erbB-2 or EGF-receptor proteins present in early stage mammary carcinoma is detected simultaneously in matched primary tumors and regional metastases. Oncogene. 1989;4:145–151
  108. Day JD, DiGiuseppe JA, Yeo C, Hruban RH. Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum Pathol. 1996;27:119–124
  109. Stern DF, Kamps MP. EGF-stimulated tyrosine phosphorylation of p185neu: a potential model of receptor interactions. EMBO J. 1989;7:995–1001
  110. Kokai Y, Dobashi K, Weiner DB, Myers JM. Phosphorylation process induced by epidermal growth factor alters the oncogenic and cellular neu (NGL) gene products. Proc Natl Acad Scie. 1988;85:5389–5393
  111. Kokai Y, Myers JN, Wada T. Synergistic interaction of p185c-neuand the EGF receptor leads to transformation of rodent fibroblasts. Cell. 1989;58:287–292
  112. Kloppel G, Maillet B, Schwere K, Kalthoff H, Schmiegel WH. Immunocytochemical detection of epidermal growth fastor receptor (EGFr) and transferrin receptor (TR) on normal, inflammed and neoplastic pancreatic tissue. Pancreas. 1989;4:
  113. Yamanaka Y, Onda M, Uchida E. Immunohistochemical study on epidermal growth factor and its receptor in human pancreatic carcinoma. Pancreas. 1989;4:
  114. Okada N, Ohshio G, Yamaki KI, Imamura T, Imamura M. Elevated serum c-erbB-2 protein levels in patients with pancreatic cancer: correlation to metastasis and shorter survival. Oncology. 1995;52:392–396
  115. Slamon DJ. Expression of cellular oncogenes in human malignancies. Science. 1984;224:256–263
  116. Yuan L, Tong-Lua Liu. Expression of c-myc and N-ras in human hepatocellular carcinoma and pancreatic adenocarcinoma. Chin Med J. 1988;101:523–528
  117. Yamada H, Sakamoto H, Taire M. Amplification of both c-Ki-ras with a point mutation and c-myc in a primary pancreatic cancer and ints metastatic tumors in lymph nodes. Jpn J Cancer Res (Gann). 1986;77:370–375
  118. Friess H, Yamanaka Y, Kobrin MS, Do DA, Buchler MW, Korc M. Enhanced erbB-3 expression in human pancreatic cancer correlates with tumor progression. Clin Cancer Res. 1995;1:1413–1420
  119. Sakorafas, G. H. Tsiotou, A. G. Multistep pancreatic carcinogenesis and its clinical implications. Eur J Surg Oncol
  120. Weinberg RA. Tumor suppressor genes. Science. 1991;254:1138–1142
  121. Skuse GR, Ludlow JW. Tumor suppressor genes in disease and therapy. Lancet. 1995;345:902–906
  122. Knudson JAG. Hereditary cancer, oncogenes and anti-oncogenes. Cancer Res. 1985;45:1437–1441
  123. Culotta E, Koshland DE. p53 sweeps through cancer research. Science. 1993;262:1958–1962
  124. Greenblatt MS, Bennett WP, Hollstein M, Harris LL. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res. 1994;54:4855–4878
  125. Scarpa A, Capelli P, Mukai U, Zamboni G, Oda T, Iacono C, et al. Pancreatic adenocarcinomas frequently show p53 gene mutations. Am J Pathol. 1993;142:1534–1543
  126. Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253:49–53
  127. Levine AJ, Momand J, Finley CA. The p53 tumor suppressor gene. Nature. 1991;351:453–456
  128. Lane DP. p53, guardian of the genome. Nature. 1992;358:15–16
  129. Farmer G, Bargonetti J, Zhu H, Friedman P, Prywes R, Prives C. Wild type p53 activates transcription in vitro. Nature. 1992;358:83–86
  130. Vogelstein B, Kinzler KW. p53. Function and dysfunction. Cell. 1992;70:523–526
  131. Lee JM, Abrahamson JLA, Bernstein A. DNA damage, oncogenesis and the p53 tumor suppressor gene. Mutat Res. 1994;307:573–581
  132. Kouzaridis T. Functions of pRb and p53: what’s the connection?. Trends Cell Biol. 1995;5:448–450
  133. Fields S, Jang SK. Presence of a potent transcription activating sequence in the p53 protein. Science. 1990;249:1046–1049
  134. Lowe SW, Scmitt EM, Smith SW, Osborne BA, Jacks T. p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature. 1993;362:847–849
  135. Suwa H, Ohshio G, Okada N, Wang Z, Fukumoto M, Imamura T, et al. Clinical significance of serum p53 antigen in patients with pancreatic carcinomas. Gut. 1997;40:647–653
  136. Boschman CR, Stryker S, Reddy JK, Rao S. Expression of p53 protein in precursor lesions and adenocarcinoma of human pancreas. Am J Pathol. 1994;145:1291–1295
  137. Luo JC, Neugut AI, Garbrowski G, Forde KA, Treat M, Smith S. Levels of p53 antigen in the plasma of patients with adenomas and carcinomas of the colon. Cancer Lett. 1995;91:235–240
  138. Ruggeri BA, Huang L, Berger D, Chang H. Molecular pathology of primary and metastatic ductal pancreatic lesions. Cancer. 1997;79:700–716
  139. Barton CM, Staddon SL, Hughes CM, Hall PA. Abnormalities of the p53 tumor suppressor gene in human pancreatic cancer. Br J Cancer. 1991;64:1076–1082
  140. Ruggeri B, Zhang SY, Caamano J, DiRado M. Human pancreatic carcinomas and cell lines reveal frequent and multiple alterations in the p53 and RB-1 tumor suppressor genes. Oncogene. 1992;7:1503–1511
  141. Redston MS, Caldas C, Seymour AB, Hruban RH, daCosta L, Yeo CJ. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994;54:3025–3033
  142. Nakamori S, Yashima K, Murakami Y, Ishikawa O, Oligashi H. Association of p53 gene mutations with short survival in pancreatic adenocarcinoma. Jpn J Cancer Res. 1995;86:174–181
  143. Yokoyama M, Yamanaha Y, Friess H, Kobrin MS, Lopez ME, Buchler M. p53 expression in human pancreatic cancer correlates with enhanced biological aggressiveness. Anticancer Res. 1994;14:2477–2484
  144. Casey G, Yamanata Y, Friess H, Buchler M, Korc M. p53 mutations are common in pancreatic cancer and are absent in chronic pancreatitis. Cancer Lett. 1993;69:151–160
  145. Rall CNJ, Yan Y-X, Graeme-Cook F, Beauchamp R. Ki-ras and p53 mutations in pancreatic ductal adenocarcinoma. Pancreas. 1996;12:10–17
  146. Berrozpe G, Schaeffer J, Pienado MA, Real FX, Perucho M. Comparative analysis of mutations in the p53 and K-ras genes in pancreatic cancer. Int J Cancer. 1994;58:185–191
  147. Zhand SY, Ruggeri B, Agarwal P, Sorling AF. Immunohistochemical analysis of p53 expression in human pancreatic carcinomas. Arch Pathol Lab Med. 1994;118:150–154
  148. DiGiuseppe JA, Hruban RH, Goodman SN. Overexpression of p53 protein in adenocarcinoma of the pancreas. Am J Clin Pathol. 1994;101:684–688
  149. Lee EY, Cibull ML, O’Daniel-Pierce E. Expression of p53 protein in pancreatic adenocarcinoma. Int J Pancreatol. 1995;17:237–242
  150. Weyrer K, Feichtinger H, Haun M. p53, Ki-ras and DNA ploidy in human pancreatic ductal adenocarcinomas. Lab Invest. 1996;74:279–289
  151. Suwa H, Yoshimura T, Yamagushi N. K-ras and p53 alterations in genomic DNA and transcripts of human pancreatic adenocarcinoma cell lines. Jpn J Cancer Res. 1994;85:1005–1014
  152. Malkin D, Li FP, Strong LC, Fraumeni JF. Germ-line p53 mutations in familial syndrome of breast cancer, sarcomas and other neoplasms. Science. 1990;250:1233–1238
  153. Reddy JK. Progress in pancreatic cancer: implications of phenotypic and molecular plasticity. Lab Invest. 1995;72:383–386
  154. Hall PA, Lemoine NR. Rapid acinar to ductal transdifferentiation in cultured human exocrine pancreas. J Pathol. 1992;166:97–103
  155. Hinds PW, Finlay CA, Quartin RS. Mutant p53 DNA clones from human colon carcinomas cooperate with ras in transforming primary rat cells: a comparison of the ‘hot spot’ mutant phenotypes. Cell Growth Differ. 1990;1:571–576
  156. Simon B, Weinel R, Hohne M. Frequent alterations of the tumor suppressor genes p53 and DCC in human pancreatic cancer. Gastroenterology. 1994;106:1645–1651
  157. Eliyahu D, Raz A, Gruss P, Givol D. Participation of p53 cellular tumor antigen in transformation of normal embryonic cells. Nature. 1984;312:646–649
  158. Parada LF, Land H, Weinberg RA. Cooperation between gene encoding p53 tumor antigen and ras in cellular transformation. Nature. 1984;312:649–651
  159. Hinds PW, Finlay C, Levine AJ. Mutation is required to activate the p53 gene for cooperation with the ras oncogene and transformation. J Virol. 1989;63:739–746
  160. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–776
  161. Linder S, Parrado C, Falkmer VG, Blasjo M. Prognostic significance of Ki-67 antigen and p53 protein expression in pancreatic duct carcinoma. Br J Cancer. 1997;76:54–59
  162. Lundin J, Nordling S, von Boguslawski K. Prognostic value of immunohistochemical expression of p53 in patients with pancreatic cancer. Oncology. 1996;53:104–111
  163. Hoorens A, Lemoine NR, McLellan E, Morohoshi T. Pancreatic acinar cell carcinoma: an analysis of cell lineage markers, p53 expression and Ki-ras mutation. Am J Pathol. 1993;143:685–698
  164. Yoshimoto K, Iwahana H, Fukuda A, Sano T. Role of p53 mutations in endocrine tumorigenesis: mutation detection by polymerase – chain – reaction single strand conformation polymorphism. Cancer Res. 1992;52:5061–5064
  165. Kamb A, Gruis NA, Weaver-Feldhaus J. A cell cycle regulator potentially involved in genesis of many tomor types. Science. 1994;264:436–440
  166. Marx J. New tumor suppressor may rival p53. Science. 1994;264:344–345
  167. Naumann M, Savitskaia N, Eilert C. Frequent codeletion of p16/MTS1 and p15/MTS2 and genetic alterations in p16/MTS1 in pancreatic tumors. Gastroenterology. 1996;110:1215–1224
  168. Nobori T, Miura K, Wu DJ. Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature. 1994;368:753–756
  169. Okamoto A, Demitrick DJ, Spillare EA. Mutations and altered expression of p16INK4 in human cancer. Proc Natl Acad Sci USA. 1994;91:1145–1149
  170. Cairns P, Polascik TJ, Eby Y. Frequency of homozygous deletion at p16/CDKN2 in primary human tumors. Nat Genet. 1995;11:210–212
  171. Rozenblum E, Schute M, Kern SE. INK4 genes in pancreatic carcinoma. Oncol Reports. 1996;3:743–745
  172. Caldas C, Hahn SA, da Costa LT. Frequent somatic mutations and homozygous deletions of the MTS1 gene in pancreatic adenocarcinoma. Nature Genet. 1994;8:27–33
  173. Liu Q, Yan Y-X, McCiure M, Nakayawa H. MTS1 (CDKN2) tumor suppressor gene deletions are a frequent event in esophagous squamous cancer and pancreatic adenocarcinoma cell lines. Oncogene. 1995;10:619–622
  174. Whelan A, Bartsch D, Goodfellow PJ. Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor suppressor gene. N Engl J Med. 1995;333:975–977
  175. Hussusian CJ, Struewing JP, Goldstein AM. Germline p16 mutations in familial melanoma. Nat Genet. 1994;8:15–21
  176. Kamb A, Shattuck-Eidens D, Eales R. Analysis of the p16 gene (CDKN2) as a candidate for the chromosome 9p melanoma susceptibility locus. Nat Genet. 1994;8:23–26
  177. MacGeoch C, newton Bishop JA, Bataille V. Genetic heterogeneity in familial malignant melanoma. Hum Molec Genet. 1994;3:2195–2200
  178. Ranade K, Hussusian CJ, Sikorski RS. Mutations associated with familial melanoma impair p16ink4function. Nat Genet. 1995;10:114–116
  179. Goldstein AM, Fraser MC, Streuwing JP, Hussusian CJ. Increased risk of pancreatic cancer in melamona prone kindreds with p16INK4mutations. N Engl J Med. 1995;333:970–974
  180. Serrano M, Hannon GJ, Beach D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature. 1993;366:704–712
  181. Cameron JL, Bell RH. Pancreas club meeting, May 19, 1996, San Francisco California. Am J Surg. 1997;173:153–158
  182. Cannon-Albright LA, Goldgar DE, Meyer LJ. Assignment of a locus for familial melanoma, MLM, to chromosome 9p13-p22. Science. 1992;258:1148–1152
  183. Fountain JN, Karayiorgou M, Erustoff MS. Homozygous deletions within human chromosome band 9p21 in melanoma. Proc Natl Acad Sci USA. 1992;89:1057–1061
  184. Petty EM, Gibson LH, Fountain JW. Molecular definition of a chromosome 9p21 germ-line deletion in a woman with multiple melanomas and a plexiform neurofibroma: implications for 9p tumor-suppressor gene(s). Am J Hum Genet. 1993;53:96–104
  185. Hannon GJ, Beach D. p15INK4Bis a potential effector of TGF-â induced cell cycle arrest. Nature. 1994;371:257–261
  186. Hirrai H, Roussel MF, Kato J-Y, Ashmun RA. Novel INK4 proteins, p19 and p18, are specific inhibitors of the cyclin D-dependent kinases cdk4 and cdk6. Mol Cell Biol. 1995;15:2672–2681
  187. Chan FKM, Zhang J, Cheng L. Identidication of human and mouse p19, a novel cdk4 and cdk6 inhibitor with homology to p16INK4. Mol Cell Biol. 1995;15:2682–2688
  188. Huang L, Goodrow TZ, Zhang S-Y, Klein Szanto AJP, Chang H, Ruggeri BA. Deletion and mutation analysis of the p16/MTS-1 tumor suppressor gene in human ductal pancreatic cancer reveals a higher frequency of abnormalities in tumor – derived cell lines than in primary ductal adenocarcinoma. Cancer Res. 1996;56:1137–1141
  189. El-Deiry WS, Tokino T, Velculescku VE. WAF1, a potential mediator of p53 tumor suppression. Cell. 1993;75:817–821
  190. Peters G. Stifled by inhibitions. Nature. 1994;371:204
  191. White E. p53, guardian of Rb. Nature. 1994;371:21–25
  192. Peters M, Herkowitz I. Joining the complex: cyclin-dependent kinase inhibitory proteins and the cell cycle. Cell. 1994;79:181–185
  193. Harper JW, Adami GR, Wei N. The p21 cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell. 1993;75:805–810
  194. Xiong Y, Hannon GJ, Zhang H. p21 is a universal inhibitor of cyclin kinases. Nature. 1993;366:701–705
  195. Kastan MB, Onyekwere O, Sidransky D. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 1991;51:6304–6306
  196. El-Deiry WS, Harper JW, O’Connor PM. WAF1/CIP1 is induced in p53 mediated G1 arrest and apoptosis. Cancer Res. 1994;5:1169–1173
  197. Kern SE. p53.Tumor suppression through control of the cell cycle. Gastroenterology. 1994;106:1708–1711
  198. Narayanan R, Kenneth GL, Schahpveld RQJ, Cho KR, Vogelstein B, Tran PB-V. Antisense RNA to the putative tumor suppressor gene DCC transforms RAT-1 fibroblasts. Oncogene. 1992;7:553–561
  199. Hohne MW, Halatsch ME, Kahl GF, Weinel RJ. Frequent loss of expression of the potential tumor suppressor gene DCC in ductal pancreatic adenocarcinoma. Cancer Res. 1992;52:2616–2619
  200. Hahn SA, Seymour AB, Hoque AT. Allelotype of pancreatic adenocarcinoma using xenograft enrichment. Cancer Res. 1995;55:4670–4675
  201. Simon B, Weinel R, Hohne M. Frequent alterations of the tumor suppressor genes p53 and DCC in human pancreatic carcinoma. Gastroenterology. 1994;106:1645–1651
  202. Edelman GM. Morphoregulatory molecules. Biochemistry. 1988;27:3533–3543
  203. Hedrick L, Cho UR, Fearon ER. The DCC gene product in cellular differentiation and colorectal tumorigenesis. Genes Dev. 1994;8:1174–1183
  204. Reale MA, Hu G, Zafar AI. Expression and alternative splicing of the deleted in colorectal cancer (DCC) gene in normal and malignant tissues. Cancer Res. 1994;54:4493–4501
  205. Hahn SA, Shutte M, Hoque AT. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271:350–353
  206. Yoshida T, Terada M. Oncology. JAMA. 1997;277:1880–1881
  207. Schutte M, Hruban RH, Hedrick L. DPC4 gene in various tumor types. Cancer Res. 1996;56:2527–2530
  208. Hensel CH, Hsieh CL, Gazdar AF, Johnson BE, Sakaguchi AY. Altered structure and expression of the human retinoblastoma susceptibility gene in human breast cancer. Cancer Res. 1990;50:3067–3072
  209. Smith KJ, Johnson KA, Bryan TM. The APC gene product in normal and tumor cells. Proc Natl Acad Sci USA. 1993;90:2846–2849
  210. Horii A, Nakatsuru S, Miyoshi Y. Frequent somatic mutations of the APC gene in human pancreatic cancer. Cancer Res. 1992;52:6696–6698
  211. Giardello FM, Offerhaus GJ, Lee DH. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut. 1993;34:1394–1396
  212. Schutte M, da Costa LT, Hahn SA. Identification by representational difference analysis of a homozygous deletion in pancreatic carcinoma that lies within the BCRA2 region. Proc Natl Acad Sci USA. 1995;92:5950–5954
  213. Tavtigian SV, Simard J, Rommene J. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996;12:333–337
  214. Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL. Germline BRCA2 gene mutation in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 1996;56:5360–5364
  215. Guan UL. The mitogen activated protein kinase signal transduction pathway: from the cell surface to the nucleus. Cell Signalling. 1994;6:581–589
  216. Hill CS, Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995;80:199–211
  217. Ruddon RW. Cell-cycle regulation and apoptosis. Ruddon RW (Ed) Cancer Biology, Oxford University Press, New York. 1995; p. pp 386–401
  218. Friess H, Berberat P, Schilling M, Kunz J, Korc M, Buchler MW. Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. J Mol Med. 1996;74:35–42
  219. Lakshmikesari A, Radhakrishna R, Branumathi A, Ravi D, Stinivas G, Nair MK, et al. Expression of epidermal and transforming growth factors in pancreatic cancer. Oncology Rep. 1996;3:963–966
  220. Lemoine NR, Hughes CM, Barton CM. The epidermal growth factor receptor in human pancreatic cancer. J Pathol. 1992;166:7–12
  221. Lemoine NR, Lobresco M, Leung H. The erbB-3 gene in human pancreatic cancer. J Pathol. 1992;168:269–273
  222. Plowman GD, Gulouscou J, Whitney GS. Ligand-specific activation of HER 4/p180erB4, a fourth member of the epidermal growth factor receptor family. Proc Natl Acad Sci USA. 1993;90:1746–1750
  223. Schlessinger J, Ullrich A. Growth factor signaling by receptor tyrosine kinases. Neuron. 1992;9:383–395
  224. Pusztai L, Lewis CE, Lorenzen J, McGee JO’D. Growth factors: regulation of normal and epidermal growth. J Pathol. 1993;169:191–201
  225. Vaidya P, Kawarada Y, Higashiguchi T, Yochida T, Sakakura T, Yatani R. Overexpression of different members of the type 1 growth factor receptor family and their association with cell proliferation in periampullary carcinoma. J Pathol. 1996;178:140–145
  226. Berger MS, Gullick WJ, Greenfield C, Evans S, Addis BJ. Epidermal growth factor receptors in lung tumors. J Pathol. 1987;152:297–307
  227. Gusterson B, Cowley G, Mcllhinney J, Ozanne B, Fisher C, Reves B. Evidence for increased epidermal growth factor receptors in human sarcomas. Br J Cancer. 1985;36:689–693
  228. Cerny T, Barnes DM, Hasleton P. Expression of epidermal growth factor receptor (EGF-r) in human lung tumors. Br J Cancer. 1986;5:265–269
  229. Tuzi NL, Venter DJ, Kumar S, Staddon SL, Lemoine NR, Gullick WJ. Expression of growth factor receptors in human brain tumors. Br J Cancer. 1991;63:227–233
  230. Wagner M, Cao T, Lopez ME, Hope C, van-Nostrand K, Kobrin MS. Expression of a truncated EGF receptor is associated with inhibition of pancreatic cancer cell growth and enhanced sensitivity to cisplatinum. Int J Cancer. 1996;68:782–787
  231. Kirby RE, Lewandrowski KB, Southern JF, Compton CC, Warshaw AL. Relation of epidermal growth factor receptor and estrogen receptor-independent ps2 protein to the malignant transformation of mucinous cystic neoplasms of the panceas. Arch Surg. 1995;130:69–72
  232. Tachibana I, Imoto M, Adjei PN, Gores GJ, Subramanian M, Spelsberg TC, et al. Overexpression of the TGFbeta-regulated zing finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. J Clin Invest. 1997;99:2365–2374
  233. Vincent F, Hagiwara K, Ke Y, Stoner GD. Mutation analysis of the transforming growth factor beta type II receptor in sporadic human cancers of the pancreas, liver and breast. Biochem Biophys Res Comm. 1996;223:561–564
  234. Sanvito F, Herrera J, Huarte A, Nichols R, Montesano L, Orci JD, et al. TGFâ1 influences the relative development of the exocrine and endocrine pancreas in vitro. Development. 1994;120:3451–3462
  235. Sanvito F, Nichols A, Herrera J, Huarte A, Wohlwend A, Orci JD. TGF-beta 1 overexpression in murine pancreas induces chronic pancreatitis and, together with TNF-alpha, triggers insulin-dependent diabetes. Biochem Biophys Res Comm. 1995;217:1279–1286
  236. Slater SD, Williamson RC, Foster CS. Expression of transforming growth factor beta 1 in chronic pancreatitis. Digestion. 1995;56:237–241
  237. Lee MS, Gu D, Feng L, Curriden S, Arnush M, Krahl T, et al. Accumulation of extracellular matrix and development dysregulation in the pancreas by transgenic production of transforming growth factor-beta 1. Am J Pathol. 1995;147:42–52
  238. van Lacthem JL, Deviere J, Resibois A, Rickaert F, Vertongen P, Ohtani H, et al. Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis. Gastroenterology. 1995;108:1873–1881
  239. Gress T, Muller–Pillash F, Elsasser HP, Bachem M. Enhancement of transforming growth factor beta 1 expression in the rat pancreas during regeneration from caerulein-induced pancreatitis. Eur J Clin Invest. 1994;24:679–685
  240. Friess H, Yamanaka Y, Buchler M, Ebert M, Berger HG, Gold LI, et al. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology. 1993;105:1846–1856
  241. Friess H, Yamanaka Y, Buchler M, Berger HG. Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res. 1993;53:2704–2707
  242. Markowitz S, Wang J, Myeroff L, Parsons R, Sun L, Lutterbaugh J. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995;268:1336–1338
  243. Goyette MC, Cho K, Fasching CL, Levy DB, Kinzler KW. Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer. Mol Cell Biol. 1992;12:1387
  244. Friess H, Yamanaha Y, Buchler M, Korbin MS, Tahara E, Korc M. Cripto, a member of epidermal growth factor family, is overexpressed in human pancreatic cancer and chronic pancreatitis. Int J Cancer. 1994;56:668–674
  245. Moskal TL, Huang SA, Ellis KM, Fritshe HA, Chakrabarty S. Serum level of transforming growth factor alpha in gastrointestinal cancer patients. Cancer Epidemiol Biomark Prev. 1995;4:127–131
  246. Krishnamurtky S, Dayal Y. Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor in gastrointestinal carcinoids. Am J Surg Pathol. 1997;21:327–333
  247. Barton CM, Hall PA, Hughes CM, Gullick WJ, Lemoine NR. Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer. J Pathol. 1991;163:111–114
  248. Giardello FM, McGeady ML, Kim M. Transforming growth factor alpha is enhanced in human mammary epithelial cells transformed by an activated c-Ha-ras proto-oncogene but not by the c-neu proto-oncogene, and overexpression of the transforming growth factor alpha complementary DNA leads to transformation. Cell Growth Different. 1990;1:407–411
  249. Baldwin RL, Friess H, Yokoyama M, Lopez NE. Attenuated ALK5 receptor expression in human pancreatic cancer: correlation with resistance to growth inhibition. Int J Cancer. 1996;6:283–288
  250. Ohta T, Yamamoto M, Numata M, Iseki S. Expression of basic fibroblast growth factor and its receptor in human pancreatic adenocarcinomas. Br J Cancer. 1995;72:824–831
  251. Collier JD, Bennett MK, Bassendine MF, Lendrum R. Immunolocalization of PS2, a putative growth factor, in pancreatic cancer. Br J Cancer. 1995;10:396–400
  252. Tsutsumi M, Yasui W, Naito O, Ohashi K, Kobayashi E, Nogushi O. Expression of cripto in human pancreatic tumors. Jpn J Cancer Res. 1994;85:118–121
  253. Yokoyama M, Funatomi H, Korbrin MS, Ebert M, Friess H, Buchler M. Betacellulin, a member of the epidermal growth factor family, is overexpressed in human pancreatic cancer. Int J Oncol. 1995;7:825–829
  254. Direnzo MF, Pulsom R, Olivero M, Comoglio PM, Lemoine NR. Expression of the MET hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res. 1995;55:1129–1138
  255. Bergmann U, Funamoti H, Yokoyama M, Berger HG, Korc M. Insulin-like growth factor 1 overexpression in human pancreatic cancer-evidence for autocrine and paracrine roles. Cancer Res. 1995;55:2007–2011
  256. Yamanaka Y, Friess H, Buchler M, Berger HG. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res. 1993;53:5289–5296
  257. Leung HY, Gullick WJ, Lemoine NR. Expression and functional activity of fibroblast growth factors and their receptors in human pancreatic cancer. Int J Cancer. 1994;59:665–667
  258. Siddiqi I, Funatomi H, Kobrin MS, Friess H. Increased expression of keratinocyte growth factor in human pancreatic cancer. Biochem Biophys Res Communic. 1995;215:309–315
  259. Ebert M, Yokoyama M, Friess H, Kobrin MS. Induction of platelet-derived growth factor A and B chains and overexpression of their receptors in human pancreatic cancer. Int J Cancer. 1995;62:529–535
  260. Sakorafas, G. H. Tsiotou, A. G. Pancreatic cancer in patients with chronic pancreatitis: a challenge from a surgical perspective. Cancer Treatm Rev
  261. Nakaizumi A, Tatsuta M, Vehara H, Yamamoto R, Tekenaka A. Cytologic examination of pure pancreatic juice in the diagnosis of pancreatic carcinoma. Cancer. 1992;70:2610–2614
  262. Ariyama J, Suyama M, Ogawa K. The detection and prognosis of small pancreatic carcinoma. Int J Pancreatol. 1990;6:37–47
  263. Shemesh E, Czerniak A, Nass S, Klein E. Role of endoscopic retrograde cholangiopancreatography in differentiating pancreatic cancer coexisting with chronic pancreatitis. Cancer. 1990;65:893–896
  264. Palazzo L, Roseau G, Gayet B, Vilgrain V, Belghiti J, Fekete F. Endoscopic ultrasonography in the diagnosis and staging of pancreatic adenocarcinoma: results of a prospective study with comparison to ultrasonography and CT scan. Endoscopy. 1993;25:143–150
  265. Rosch Th, Brais C, Gain TG, Feurbach S, Siewert JR, Schusdziarra V. Staging of pancreatic and ampullary carcinoma by endoscopic ultrasonography. Comparison with conventional sonographic computed tomography and angiography. Gastroenterology. 1992;102:188–199
  266. Mitchell ML, Carney CN. Cytologic criteria for the diagnosis of pancreatic carcinoma. Am J Clin Pathol. 1985;82:171–176
  267. Goodale RL, Gail-Peczalaka K, Dressel T. Cytologic studies for the diagnosis of pancreatic cancer. Cancer. 1981;47:1652–1655
  268. Hattfield ARW, Smithies A, Willins R. Assessment of ERCP and pure pancreatic juice cytology in patients with pancreatic disease. Gut. 1976;17:14–21
  269. Tada M, Omata M, Kawai S, Saisho H, Ohto M, Saiki RK, et al. Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res. 1993;53:2472–2474
  270. Iguchi H, Sugano K, Fukayama N, Ohkura H. Analysis of Ki-ras codon 12 mutations in the duodenal juice of patients with pancreatic cancer. Gastroenterology. 1996;110:221–226
  271. Caldas C, Hahn SA, Hruban RH. Detection of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res. 1994;54:3568–3573
  272. Watanabe H, Sawabu N, Ohta H. Identification of K-ras oncogene mutations in the pure pancreatic juice of patients with ductal pancreatic cancers. Jpn J Cancer Res. 1993;84:961–965
  273. Kondo H, Sugano K, Fukayama N, Kyogoku A, Nose H, Shimada K. Detection of point mutations in the K-ras oncogene at codon 12 in pure pancreatic juice for diagnosis of pancreatic carcinoma. Cancer. 1994;73:1589–1594
  274. Watanabe H, Sawabu N, Songur K, Yamaguchi Y, Yamakawa O, Satomura Y. Detection of K-ras point mutations at codon 12 in pure pancreatic juice for the diagnosis of pancreatic cancer by PCR-RFLP analysis. Pancreas. 1996;12:18–24
  275. Miki H, Matsumoto S, Harada H. Detection of c-K-ras point mutation from pancreatic juice. Int J Pancreatol. 1993;14:145–148
  276. Endo Y, Morii J, Tamura N, Okuda S. Cytodiagnosis of pancreatic malignant tumors by aspiration, under direct vision, using a duodenal fiberscope. Gastroenterology. 1974;67:944–951
  277. Urban T, Ricci S, Grange JD. Detection of c-Ki-ras mutations by PCR-RLFP analysis and diagnosis of pancreatic adenocarcinomas. J Natl Cancer Instit. 1993;85:2008–2012
  278. Evans DB, Frazier ML, Charnsangavej C, Katz RL, Larry L, Abbruzzese JL. Molecular diagnosis of exocrine pancreatic cancer using a percutaneous technique. Ann Surg Oncol. 1996;3:241–246
  279. Rashleigh-Belcher HJC, Russell RCG, Lees WR. Cutaneous seeding of pancreatic cancer by fine – needle aspiration biopsy. Br J Radiol. 1986;59:182–183
  280. Ferrucci JT, Wettenberg J, Margolies MN, Carey RW. Malignant seeding of the tract after thin needle aspiration biopsy. Radiology. 1979;130:345–346
  281. US Preventive Services Task Force. Guide to clinical preventive services. Williams & Wilkins, Baltimore, MD, 1996
  282. Lowenfels AB, Maisonneuve P, DiMagno EP, Elitsur Y, Gates LK, Perraut J, et al. Hereditary pancreatitis and the risk of pancreatic cancer. J Natl Cancer Inst. 1997;89:442–446
  283. Gullo L, Pezzilli R, Morselli-Labate AM. Diabetes and the risk of pancreatic cancer. N Engl J Med. 1994;331:81–84
  284. Tsuchiya R, Noda T, Harada N, Leiyamoto T, Tomioka T, Yamamoto K. Collective review of small carcinomas of the pancreas. Ann Surg. 1986;203:77–81
  285. Kinzler KW, Nilbert MC, Su LK. Identification of FAP locus genes from chromosome 5p21. Science. 1991;253:661–665
  286. Vogelstein B, Kinzler KW. The multistep nature of cancer. Trends Genet. 1993;9:138–143
  287. Narod SA, Feunteun J, Lynch HT. A familial breast/ovarian cancer locus on chromosome 17q12–q21. Lancet. 1991;338:82–83
  288. Sakorafas, G. H. Tsiotou, A. G. Molecular biology of breast cancer. Clinical implications from a surgical perspective. Br J Surg
  289. Harris CC, Mulvihill JJ, Thorgeirsson SS. Individual differences in cancer susceptibility. Ann Intern Med. 1980;92:809–825
  290. Villanueva A, Reyes G, Cuatrecaasas M, Martinez A. Diagnostic utility of K-ras mutations in fine-needle aspirates of pancreatic masses. Gastroenterology. 1996;110:1587–1594
  291. Weichselbaum RR, Kufe D. Gene therapy of cancer. Lancet. 1997;349 (Suppl II):10–12
  292. Caldas C, Ponder BAJ. Cancer genes and molecular oncology in the clinic. Lancet. 1997;349 (Suppl II):16–18
  293. Tzeng E, Shears LL, Lotze MT, Billiar TR. Gene therapy. Curr Probl Surg. 1996;33:961–1052
  294. Fine HA, Kufe DW. Cancer gene therapy. In:  Holland JF,  Bast RC,  Morton DL,  Frei E,  Kufe DW,  Weicheselbaum RR editor. Cancer Medicine (4th Ed). Baltimore, MD: Williams & Wilkins; 1997;
  295. Brennan MF, Kinsella TJ, Gasper ES. Cancer of the pancreas. In:  De Vita VT,  Hellman S,  Rosenberg SA editor. Principles and Practice of Oncology (4th Ed). Philadelphia: JB Lippincott; 1993;
  296. Clark JW, Glicksman AS, Wanebo HJ. Systemic and aadjuvant therapy for patients with pancreatic adenocarcinoma. Cancer. 1996;78:688–693
  297. Moelling H, Strack B, Radziwill G. Signal transduction as target of gene therapy. Rec Results Cancer Res. 1996;142:63–71
  298. Egawa SI, Tsutsumi M, Konishi Y, Kobari M, Matsuno S. The role of angiogenesis in the tumor growth of Syrian hamster pancreatic cancer cell line HPD-NR. Gastroenterology. 1995;108:1526–1533
  299. Raper SE, DeMatteo RP. Adenovirus-mediated in vivo gene transfer and expression in normal rat pancreas. Pancreas. 1996;12:401–410
  300. Magarian-Blander J, Dommenech N, Finn OJ. Specific and effective T-cell recognition of cells transfected with a truncated human mucin cDNA. Ann NY Acad Sci. 1993;690:231–243
  301. Kelloff GJ, Lubet RA, Fay JR, Stecle VE, Boone CW, Crowell JA. Farnesyl protein transferase inhibitors as potential cancer chemopreventives. Cancer Epidemiol Biomarkers Prev. 1997;6:267–282
  302. Scarpa A, Capelli P, Villaneuva A, Zamboni Q. Pancreatic cancer in Europe: Ki-ras gene mutation pattern shows geographical differences. Int J Cancer. 1994;57:16–171
  303. Tabata T, Fujimori T, Maeda S, Yamamoto M, Saitoh H. The role of ras mutation in pancreatic cancer, precancerous lesions and chronic pancreatitis. Int J Pancreatol. 1993;14:237–244
  304. Gibbs JB, Oliff A, Kohl NE. Farnesyltransferase inhibitors: ras research yields a potential cancer therapeutic. Cell. 1994;77:175–178
  305. Lieberman MD, Paty P, Li XK, Naama H, Evoy D, Daly JM. Elevation of intracellular cyclic adenosine monophosphate inhibits the epidermal growth factor signal transduction pathway and cellular growth in pancreatic adenocarcinoma cell lines. Surgery. 1996;120:354–359
  306. Blenis J. Signal transduction via the MAP kinases: proceed at your own RSK. Proc Natl Acad Sci USA. 1993;90:5889–5892
  307. Ally S, Clair T, Katsaros D. Inhibition of growth and modulation of gene expression in human lung carcinoma in athymic mice by site selective 8-Cl-cyclic adenosine monophosphate. Cancer Res. 1989;49:5650–5655
  308. Takanashi A, Yasui W, Yoshida K. Inhibitory effect of 8-chloro-cyclic adenosine 3′, 5′–monophosphate on cell growth of gastric carcinoma cell lines. Jpn J Cancer Res. 1991;82:325–331
  309. Tortora G, Giardello F, Ally S. Site selective 8 chloroadenosine 3′, 5′–cyclic monophosphate inhibits transforming growth factor – a production in K-ras transformed rat fibroblasts. FEBS Lett. 1989;242:363–367
  310. Ally S, Tortora G, Clair T. Selective modulation of protein kinase isozymes by the site selective analog 8–chloroadenosine 3′, 5′–cyclic monophosphate provides a biological means for control of human colon cancer cell growth. Proc Natl Acad Sci USA. 1988;85:6319–6322
  311. Mason W, Malkin M, Lieberman F, Cropp G. Pharmacokinetics of SU101, a novel signal transduction inhibitor, in patients with recurrent glioma. Proc AACR. 1996;37:166
  312. Bayever E, Haines K, Iversen PL, Ruddon RW. Selective cytotoxicity to human leukemic myeloblasts produced by oligodeoxyribonucleotide phosphorothioates complementary to p53 nucleotide sequences. Leuk Lymphoma. 1994;12:223–231
  313. Barton CM, Lemoine NR. Antisense oligonucleotides directed against p53 have antiproliferative effects unrelated to effects in p53 expression. Br J Cancer. 1995;71:429–437
  314. Bi S, Lanza F, Doldman J. The involvement of ‘tumor suppressor’ p53 in normal and chronic myelogenous leukemia hemopoiesis. Cancer Res. 1994;5:582–586
  315. Fan S, El-Deiry WS, Bac I, Freeman J, Jondle D, Bhatia K. p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents. Cancer Res. 1994;54:5824–5830

PII: S0305-7372(99)90144-5

doi: 10.1053/ctrv.1999.0144

Cancer Treatment Reviews
Volume 26, Issue 1 , Pages 29-52 , February 2000

Article Tools