In spite of continuous research efforts directed at early detection and treatment of pancreatic cancer, the outlook for patients affected by the disease remains dismal. With most cases still being diagnosed at advanced stages, no improvement in survival prognosis is achieved with current diagnostic imaging approaches. In the absence of a dominant precancerous condition, several risk factors have been identified including family history, chronic pancreatitis, smoking, diabetes mellitus, as well as certain genetic disorders such as hereditary pancreatitis, cystic fibrosis, familial atypical multiple mole melanoma, and Peutz-Jeghers and Lynch syndromes. Most pancreatic carcinomas, however, remain sporadic. Current progress in experimental molecular techniques has enabled detailed understanding of the molecular processes of pancreatic cancer development. According to the latest information, malignant pancreatic transformation involves multiple oncogenes and tumor-suppressor genes that are involved in a variety of signaling pathways. The most characteristic aberrations (somatic point mutations and allelic losses) affect oncogenes and tumor-suppressor genes within RAS, AKT and Wnt signaling, and have a key role in transcription and proliferation, as well as systems that regulate the cell cycle (SMAD/DPC, CDKN2A/p16) and apoptosis (TP53). Understanding of the underlying molecular mechanisms should promote development of new methodology for early diagnosis and facilitate improvement in current approaches for pancreatic cancer treatment.

Charles University 1st Medical Faculty Internal Clinic 128 00 Prague 2 Czech Republic

Zobrazit více v PubMed

Lowenfels AB, Maisonneuve P. Epidemiology and risk factors for pancreatic cancer. Best Pract Res Clin Gastroenterol. 2006;20:197–209. PubMed

Chu D, Kohlmann W, Adler DG. Identification and screening of individuals at increased risk for pancreatic cancer with emphasis on known environmental and genetic factors and hereditary syndromes. JOP. 2010;11:203–212. PubMed

Dusek L, Muzík J, Gelnarová E, Fínek J, Vyzula R, Abrahámová J. Cancer incidence and mortality in the Czech Republic. Klin Onkol. 2010;23:311–324. PubMed

Genkinger JM, Spiegelman D, Anderson KE, Bergkvist L, Bernstein L, van den Brandt PA, English DR, Freudenheim JL, Fuchs CS, Giles GG, et al. Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies. Cancer Epidemiol Biomarkers Prev. 2009;18:765–776. PubMed PMC

Decker GA, Batheja MJ, Collins JM, Silva AC, Mekeel KL, Moss AA, Nguyen CC, Lake DF, Miller LJ. Risk factors for pancreatic adenocarcinoma and prospects for screening. Gastroenterol Hepatol (N Y) 2010;6:246–254. PubMed PMC

Harnack LJ, Anderson KE, Zheng W, Folsom AR, Sellers TA, Kushi LH. Smoking, alcohol, coffee, and tea intake and incidence of cancer of the exocrine pancreas: the Iowa Women's Health Study. Cancer Epidemiol Biomarkers Prev. 1997;6:1081–1086. PubMed

Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–1638. PubMed

Nkondjock A, Krewski D, Johnson KC, Ghadirian P. Dietary patterns and risk of pancreatic cancer. Int J Cancer. 2005;114:817–823. PubMed

BEIR V: implications for the nuclear workforce. Science. 1990;247:620–622. PubMed

Nöthlings U, Wilkens LR, Murphy SP, Hankin JH, Henderson BE, Kolonel LN. Meat and fat intake as risk factors for pancreatic cancer: the multiethnic cohort study. J Natl Cancer Inst. 2005;97:1458–1465. PubMed

Ojajärvi A, Partanen T, Ahlbom A, Boffetta P, Hakulinen T, Jourenkova N, Kauppinen T, Kogevinas M, Vainio H, Weiderpass E, et al. Risk of pancreatic cancer in workers exposed to chlorinated hydrocarbon solvents and related compounds: a meta-analysis. Am J Epidemiol. 2001;153:841–850. PubMed

Tilyou SM. BEIR V report. Experts urge cautious interpretation of higher risk estimates. J Nucl Med. 1990;31:13A–19A. PubMed

Li D, Morris JS, Liu J, Hassan MM, Day RS, Bondy ML, Abbruzzese JL. Body mass index and risk, age of onset, and survival in patients with pancreatic cancer. JAMA. 2009;301:2553–2562. PubMed PMC

Silverman DT, Hoover RN, Brown LM, Swanson GM, Schiffman M, Greenberg RS, Hayes RB, Lillemoe KD, Schoenberg JB, Schwartz AG, et al. Why do Black Americans have a higher risk of pancreatic cancer than White Americans? Epidemiology. 2003;14:45–54. PubMed

Kreiger N, Lacroix J, Sloan M. Hormonal factors and pancreatic cancer in women. Ann Epidemiol. 2001;11:563–567. PubMed

Skinner HG, Michaud DS, Colditz GA, Giovannucci EL, Stampfer MJ, Willett WC, Fuchs CS. Parity, reproductive factors, and the risk of pancreatic cancer in women. Cancer Epidemiol Biomarkers Prev. 2003;12:433–438. PubMed

Wahi MM, Shah N, Schrock CE, Rosemurgy AS 2nd, Goldin SB. Reproductive factors and risk of pancreatic cancer in women: a review of the literature. Ann Epidemiol. 2009;19:103–111. PubMed

Eppel A, Cotterchio M, Gallinger S. Allergies are associated with reduced pancreas cancer risk: A population-based case-control study in Ontario, Canada. Int J Cancer. 2007;121:2241–2245. PubMed

Olson SH, Chou JF, Ludwig E, O'Reilly E, Allen PJ, Jarnagin WR, Bayuga S, Simon J, Gonen M, Reisacher WR, et al. Allergies, obesity, other risk factors and survival from pancreatic cancer. Int J Cancer. 2010;127:2412–2419. PubMed

Cavestro GM, Comparato G, Nouvenne A, Sianesi M, Di Mario F. The race from chronic pancreatitis to pancreatic cancer. JOP. 2003;4:165–168. PubMed

Farrow B, Evers BM. Inflammation and the development of pancreatic cancer. Surg Oncol. 2002;10:153–169. PubMed

Lowenfels AB, Maisonneuve P, Lankisch PG. Chronic pancreatitis and other risk factors for pancreatic cancer. Gastroenterol Clin North Am. 1999;28:673–685, x. PubMed

Talamini G, Falconi M, Bassi C, Sartori N, Salvia R, Caldiron E, Frulloni L, Di Francesco V, Vaona B, Bovo P, et al. Incidence of cancer in the course of chronic pancreatitis. Am J Gastroenterol. 1999;94:1253–1260. PubMed

Malka D, Hammel P, Maire F, Rufat P, Madeira I, Pessione F, Lévy P, Ruszniewski P. Risk of pancreatic adenocarcinoma in chronic pancreatitis. Gut. 2002;51:849–852. PubMed PMC

Dítĕ P, Pazourková M, Růzicka M, Precechtĕlová M, Novotný I, Dastych M. [Chronic pancreatitis as a risk factor for pancreatic carcinoma] Vnitr Lek. 2002;48:638–641. PubMed

Lynch HT, Lanspa SJ, Fitzgibbons RJ Jr, Smyrk T, Fitzsimmons ML, McClellan J. Familial pancreatic cancer (Part 1): Genetic pathology review. Nebr Med J. 1989;74:109–112. PubMed

Ferrone CR, Levine DA, Tang LH, Allen PJ, Jarnagin W, Brennan MF, Offit K, Robson ME. BRCA germline mutations in Jewish patients with pancreatic adenocarcinoma. J Clin Oncol. 2009;27:433–438. PubMed PMC

Neglia JP, FitzSimmons SC, Maisonneuve P, Schöni MH, Schöni-Affolter F, Corey M, Lowenfels AB. The risk of cancer among patients with cystic fibrosis. Cystic Fibrosis and Cancer Study Group. N Engl J Med. 1995;332:494–499. PubMed

Lynch HT, Fusaro RM, Lynch JF, Brand R. Pancreatic cancer and the FAMMM syndrome. Fam Cancer. 2008;7:103–112. PubMed

Latchford A, Greenhalf W, Vitone LJ, Neoptolemos JP, Lancaster GA, Phillips RK. Peutz-Jeghers syndrome and screening for pancreatic cancer. Br J Surg. 2006;93:1446–1455. PubMed

Yamamoto H, Itoh F, Nakamura H, Fukushima H, Sasaki S, Perucho M, Imai K. Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res. 2001;61:3139–3144. PubMed

Keiles S, Kammesheidt A. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006;33:221–227. PubMed

Pannala R, Basu A, Petersen GM, Chari ST. New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol. 2009;10:88–95. PubMed PMC

Pelaez-Luna M, Takahashi N, Fletcher JG, Chari ST. Resectability of presymptomatic pancreatic cancer and its relationship to onset of diabetes: a retrospective review of CT scans and fasting glucose values prior to diagnosis. Am J Gastroenterol. 2007;102:2157–2163. PubMed

Chari ST. Detecting early pancreatic cancer: problems and prospects. Semin Oncol. 2007;34:284–294. PubMed PMC

Pour P, Althoff J, Krüger FW, Mohr U. Improvement of pancreatic cancer model by modified treatment with N-nitroso-bis (2-oxopropyl) amine. Cancer Lett. 1977;2:233–237. PubMed

Sayers HJ, Orloff MJ. Development of an animal model of pancreatic cancer. Surg Forum. 1976;27:456–458. PubMed

Morosco GJ, Goeringer GC. Lifestyle factors and cancer of the pancreas: a hypothetical mechanism. Med Hypotheses. 1980;6:971–985. PubMed

Lin RS, Kessler II. A multifactorial model for pancreatic cancer in man. Epidemiologic evidence. JAMA. 1981;245:147–152. PubMed

Berlin NI, Williams M. Pancreatic cancer: an epidemiologic approach and model. JAMA. 1981;245:171. PubMed

Hruban RH, Goggins M, Parsons J, Kern SE. Progression model for pancreatic cancer. Clin Cancer Res. 2000;6:2969–2972. PubMed

Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra DS, Klöppel G, Longnecker DS, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 2001;25:579–586. PubMed

Serra E, Puig S, Otero D, Gaona A, Kruyer H, Ars E, Estivill X, Lázaro C. Confirmation of a double-hit model for the NF1 gene in benign neurofibromas. Am J Hum Genet. 1997;61:512–519. PubMed PMC

Herman JG, Jen J, Merlo A, Baylin SB. Hypermethylation-associated inactivation indicates a tumor suppressor role for p15INK4B. Cancer Res. 1996;56:722–727. PubMed

Jackson MA, Lea I, Rashid A, Peddada SD, Dunnick JK. Genetic alterations in cancer knowledge system: analysis of gene mutations in mouse and human liver and lung tumors. Toxicol Sci. 2006;90:400–418. PubMed

Bamford S, Dawson E, Forbes S, Clements J, Pettett R, Dogan A, Flanagan A, Teague J, Futreal PA, Stratton MR, et al. The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer. 2004;91:355–358. PubMed PMC

Chmielowiec J, Borowiak M, Morkel M, Stradal T, Munz B, Werner S, Wehland J, Birchmeier C, Birchmeier W. c-Met is essential for wound healing in the skin. J Cell Biol. 2007;177:151–162. PubMed PMC

Ebert M, Yokoyama M, Friess H, Büchler MW, Korc M. Coexpression of the c-met proto-oncogene and hepatocyte growth factor in human pancreatic cancer. Cancer Res. 1994;54:5775–5778. PubMed

Di Renzo MF, Poulsom 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. PubMed

Kiehne K, Herzig KH, Fölsch UR. c-met expression in pancreatic cancer and effects of hepatocyte growth factor on pancreatic cancer cell growth. Pancreas. 1997;15:35–40. PubMed

Yu J, Ohuchida K, Mizumoto K, Ishikawa N, Ogura Y, Yamada D, Egami T, Fujita H, Ohashi S, Nagai E, et al. Overexpression of c-met in the early stage of pancreatic carcinogenesis; altered expression is not sufficient for progression from chronic pancreatitis to pancreatic cancer. World J Gastroenterol. 2006;12:3878–3882. PubMed PMC

Otte JM, Kiehne K, Schmitz F, Fölsch UR, Herzig KH. C-met protooncogene expression and its regulation by cytokines in the regenerating pancreas and in pancreatic cancer cells. Scand J Gastroenterol. 2000;35:90–95. PubMed

Molina JR, Adjei AA. The Ras/Raf/MAPK pathway. J Thorac Oncol. 2006;1:7–9. PubMed

Carnero A, Blanco-Aparicio C, Renner O, Link W, Leal JF. The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications. Curr Cancer Drug Targets. 2008;8:187–198. PubMed

Perugini RA, McDade TP, Vittimberga FJ Jr, Callery MP. Pancreatic cancer cell proliferation is phosphatidylinositol 3-kinase dependent. J Surg Res. 2000;90:39–44. PubMed

Lu X, Qian J, Yu Y, Yang H, Li J. Expression of the tumor suppressor ARHI inhibits the growth of pancreatic cancer cells by inducing G1 cell cycle arrest. Oncol Rep. 2009;22:635–640. PubMed

Roy SK, Srivastava RK, Shankar S. Inhibition of PI3K/AKT and MAPK/ERK pathways causes activation of FOXO transcription factor, leading to cell cycle arrest and apoptosis in pancreatic cancer. J Mol Signal. 2010;5:10. PubMed PMC

Yao Z, Okabayashi Y, Yutsudo Y, Kitamura T, Ogawa W, Kasuga M. Role of Akt in growth and survival of PANC-1 pancreatic cancer cells. Pancreas. 2002;24:42–46. PubMed

Mortenson MM, Galante JG, Gilad O, Schlieman MG, Virudachalam S, Kung HJ, Bold RJ. BCL-2 functions as an activator of the AKT signaling pathway in pancreatic cancer. J Cell Biochem. 2007;102:1171–1179. PubMed

Ripka S, Neesse A, Riedel J, Bug E, Aigner A, Poulsom R, Fulda S, Neoptolemos J, Greenhalf W, Barth P, et al. CUX1: target of Akt signalling and mediator of resistance to apoptosis in pancreatic cancer. Gut. 2010;59:1101–1110. PubMed

Ma J, Sawai H, Ochi N, Matsuo Y, Xu D, Yasuda A, Takahashi H, Wakasugi T, Takeyama H. PTEN regulates angiogenesis through PI3K/Akt/VEGF signaling pathway in human pancreatic cancer cells. Mol Cell Biochem. 2009;331:161–171. PubMed

Maitra A, Hruban RH. A new mouse model of pancreatic cancer: PTEN gets its Akt together. Cancer Cell. 2005;8:171–172. PubMed

Buettner R, Mora LB, Jove R. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin Cancer Res. 2002;8:945–954. PubMed

Hanley AB, Burch R. Re: The role of STAT-3 in the induction of apoptosis in pancreatic cancer cells by benzyl isothiocyanate. J Natl Cancer Inst. 2009;101:893; author reply 893–894. PubMed

Schutte M, Rozenblum E, Moskaluk CA, Guan X, Hoque AT, Hahn SA, da Costa LT, de Jong PJ, Kern SE. An integrated high-resolution physical map of the DPC/BRCA2 region at chromosome 13q12. Cancer Res. 1995;55:4570–4574. PubMed

Levy L, Hill CS. Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol. 2005;25:8108–8125. PubMed PMC

Dessimoz J, Grapin-Botton A. Pancreas development and cancer: Wnt/beta-catenin at issue. Cell Cycle. 2006;5:7–10. PubMed

Rulifson IC, Karnik SK, Heiser PW, ten Berge D, Chen H, Gu X, Taketo MM, Nusse R, Hebrok M, Kim SK. Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci USA. 2007;104:6247–6252. PubMed PMC

Al-Aynati MM, Radulovich N, Riddell RH, Tsao MS. Epithelial-cadherin and beta-catenin expression changes in pancreatic intraepithelial neoplasia. Clin Cancer Res. 2004;10:1235–1240. PubMed

Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ, et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997;57:1731–1734. PubMed

Sasaki S, Yamamoto H, Kaneto H, Ozeki I, Adachi Y, Takagi H, Matsumoto T, Itoh H, Nagakawa T, Miyakawa H, et al. Differential roles of alterations of p53, p16, and SMAD4 expression in the progression of intraductal papillary-mucinous tumors of the pancreas. Oncol Rep. 2003;10:21–25. PubMed

Poley JW, Kluijt I, Gouma DJ, Harinck F, Wagner A, Aalfs C, van Eijck CH, Cats A, Kuipers EJ, Nio Y, et al. The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer. Am J Gastroenterol. 2009;104:2175–2181. PubMed

Harsha HC, Kandasamy K, Ranganathan P, Rani S, Ramabadran S, Gollapudi S, Balakrishnan L, Dwivedi SB, Telikicherla D, Selvan LD, et al. A compendium of potential biomarkers of pancreatic cancer. PLoS Med. 2009;6:e1000046. PubMed PMC

Vestergaard EM, Hein HO, Meyer H, Grunnet N, Jørgensen J, Wolf H, Orntoft TF. Reference values and biological variation for tumor marker CA 19-9 in serum for different Lewis and secretor genotypes and evaluation of secretor and Lewis genotyping in a Caucasian population. Clin Chem. 1999;45:54–61. PubMed

Bussom S, Saif MW. Methods and rationale for the early detection of pancreatic cancer. Highlights from the "2010 ASCO Gastrointestinal Cancers Symposium". Orlando, FL, USA. January 22-24, 2010. JOP. 2010;11:128–130. PubMed

Brand RE, Lerch MM, Rubinstein WS, Neoptolemos JP, Whitcomb DC, Hruban RH, Brentnall TA, Lynch HT, Canto MI. Advances in counselling and surveillance of patients at risk for pancreatic cancer. Gut. 2007;56:1460–1469. PubMed PMC

Sakorafas GH, Sarr MG. Pancreatic cancer after surgery for chronic pancreatitis. Dis Liver Dis. 2003;35:482–485. PubMed

Wong T, Howes N, Threadgold J, Smart HL, Lombard MG, Gilmore I, Sutton R, Greenhalf W, Ellis I, Neoptolemos JP. Molecular diagnosis of early pancreatic ductal adenocarcinoma in high-risk patients. Pancreatology. 2001;1:486–509. PubMed

Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Cameron JL, Yeo CJ, Hruban RH, Goggins M. p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol. 2003;27:1495–1501. PubMed

Ockenga J, Vogel A, Teich N, Keim V, Manns MP, Strassburg CP. UDP glucuronosyltransferase (UGT1A7) gene polymorphisms increase the risk of chronic pancreatitis and pancreatic cancer. Gastroenterology. 2003;124:1802–1808. PubMed

Salek C, Benesova L, Zavoral M, Nosek V, Kasperova L, Ryska M, Strnad R, Traboulsi E, Minarik M. Evaluation of clinical relevance of examining K-ras, p16 and p53 mutations along with allelic losses at 9p and 18q in EUS-guided fine needle aspiration samples of patients with chronic pancreatitis and pancreatic cancer. World J Gastroenterol. 2007;13:3714–3720. PubMed PMC

Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137:482–488. PubMed PMC

Diabetes Mellitus in Pancreatic Cancer: A Distinct Approach to Older Subjects with New-Onset Diabetes Mellitus

MicroRNAs in Pancreatic Cancer: Involvement in Carcinogenesis and Potential Use for Diagnosis and Prognosis