References
1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int
J Cancer. 2010;127(12):2893–2917.
2. Ferlay J. Cancer incidence in five continents. Processing of data. IARC Sci Publ. 1992;120:39–44.
3. Brune KA, Lau B, Palmisano E, et al. Importance of age of onset in pancreatic cancer kindreds. J Natl
Cancer Inst. 2010;102(2):119–126.
4. Cronin-Fenton DP, Erichsen R, Mortensen FV, et al. Pancreatic cancer survival in central and northern
Denmark from 1998 through 2009: a population-based cohort study. Clin Epidemiol. 2011;3(suppl 1):19–
25.
5. Harinck F, Poley JW, Kluijt I, et al. Is early diagnosis of pancreatic cancer fiction? Surveillance of
individuals at high risk for pancreatic cancer. Dig Dis. 2010;28(4-5):670–678.
6. Matthaei H, Schulick RD, Hruban RH, et al. Cystic precursors to invasive pancreatic cancer. Nat Rev
Gastroenterol Hepatol. 2011;8(3):141–150.
7. Adsay NV. Cystic neoplasia of the pancreas: pathology and biology. J Gastrointest Surg.
2008;12(3):401–404.
8. Hruban RH, Maitra A, Goggins M. Update on pancreatic intraepithelial neoplasia. Int J Clin Exp Pathol.
2008;1(4):306–316.
9. Buxbaum JL, Eloubeidi MA. Molecular and clinical markers of pancreas cancer. JOP. 2010;11(6):536–
544.
10. Gonda TA, Saif MW. Early detection and screening of pancreatic cancer. Highlights from the “2011
ASCO Gastrointestinal Cancers Symposium”. San Francisco, CA, USA. January 20-22, 2011. JOP.
2011;12(2):83–85.
11. Boffetta P, Tubiana M, Hill C, et al. The causes of cancer in France. Ann Oncol. 2009;20(3):550–555.
12. Petersen GM, Boffetta P. Carcinogenesis of pancreatic cancer: challenges, collaborations, progress.
Mol Carcinog. 2012;51:1–2.
13. Grant WB. Ecological studies of the UVB-vitamin D-cancer hypothesis. Anticancer Res.
2012;32(1):223–236.
14. Kato I, Tajima K, Kuroishi T, et al. Latitude and pancreatic cancer. Jpn J Clin Oncol. 1985;15(2):403–
413.
15. Kinoshita S, Wagatsuma Y, Okada M. Geographical distribution for malignant neoplasm of the
pancreas in relation to selected climatic factors in Japan. Int J Health Geogr. 2007;6:34.
16. Freedman DM, Looker AC, Chang SC, et al. Prospective study of serum vitamin D and cancer
mortality in the United States. J Natl Cancer Inst. 2007;99(21):1594–1602.
17. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al. Circulating 25-hydroxyvitamin D and risk of
pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol.
2010;172(1):81–93.
18. Sanchez GV, Weinstein SJ, Stolzenberg-Solomon RZ. Is dietary fat, vitamin D, or folate associated
with pancreatic cancer? Mol Carcinog. 2012;51(1):119–127.
19. Helzlsouer KJ. Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J
Epidemiol. 2010;172(1):4–9.
20. Baggerly LL, Garland CF. Vitamin d and pancreatic cancer risk—no U-shaped curve. Anticancer Res.
2012;32(3):981–984.
21. Weinstein SJ, Stolzenberg-Solomon RZ, Kopp W, et al. Impact of circulating vitamin D binding protein
levels on the association between 25-hydroxyvitamin D and pancreatic cancer risk: a nested case-control
study. Cancer Res. 2012;72(5):1190–1198.
22. Hassan MM, Li D, El-Deeb AS, et al. Association between hepatitis B virus and pancreatic cancer. J
Clin Oncol. 2008;26(28):4557–4562.
23. de Martel C, Llosa AE, Friedman GD, et al. Helicobacter pylori infection and development of
pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2008;17(5):1188–1194.
24. Risch HA. Pancreatic cancer: Helicobacter pylori colonization, N-nitrosamine exposures, and ABO
blood group. Mol Carcinog. 2012;51(1):109–118.
25. Farrell JJ, Zhang L, Zhou H, et al. Variations of oral microbiota are associated with pancreatic diseases
including pancreatic cancer. Gut. 2012;61(4):582–588.
26. Serraino D, Dal Maso L, De Paoli A, et al. On changes in cancer mortality among HIV-infected
patients: is there an excess risk of death from pancreatic cancer? Clin Infect Dis. 2009;49(3):481–482.
27. Talamini R, Polesel J, Gallus S, et al. Tobacco smoking, alcohol consumption and pancreatic cancer
risk: a case-control study in Italy. Eur J Cancer. 2010;46(2):370–376.
28. Vrieling A, Bueno-de-Mesquita HB, Boshuizen HC, et al. Cigarette smoking, environmental tobacco
smoke exposure and pancreatic cancer risk in the European Prospective Investigation into Cancer and
Nutrition. Int J Cancer. 2010;126(10):2394–2403.
29. Heinen MM, Verhage BA, Goldbohm RA, et al. Active and passive smoking and the risk of pancreatic
cancer in the Netherlands Cohort Study. Cancer Epidemiol Biomarkers Prev. 2010;19(6):1612–1622.
30. Iodice S, Gandini S, Maisonneuve P, et al. Tobacco and the risk of pancreatic cancer: a review and
meta-analysis. Langenbecks Arch Surg. 2008;393(4):535–545.
31. Lynch SM, Vrieling A, Lubin JH, et al. Cigarette smoking and pancreatic cancer: a pooled analysis from
the Pancreatic Cancer Cohort Consortium. Am J Epidemiol. 2009;170(4):403–413.
32. Stolzenberg-Solomon RZ, Cross AJ, Silverman DT, et al. Meat and meat-mutagen intake and
pancreatic cancer risk in the NIH-AARP cohort. Cancer Epidemiol Biomarkers Prev. 2007;16(12):2664–
2675.
33. Anderson KE, Mongin SJ, Sinha R, et al. Pancreatic cancer risk: associations with meat-derived
carcinogen intake in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort.
Mol Carcinog. 2012;51(1):128–137.
34. Thiebaut AC, Jiao L, Silverman DT, et al. Dietary fatty acids and pancreatic cancer in the NIH-AARP
diet and health study. J Natl Cancer Inst. 2009;101(14):1001–1011.
35. Tsugane S, Inoue M. Insulin resistance and cancer: epidemiological evidence. Cancer Sci.
2010;101(5):1073–1079.
36. Vrieling A, Verhage BA, van Duijnhoven FJ, et al. Fruit and vegetable consumption and pancreatic
cancer risk in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer.
2009;124(8):1926–1934.
37. MacMahon B, Yen S, Trichopoulos D, et al. Coffee and cancer of the pancreas. N Engl J Med.
1981;304(11):630–633.
38. Nkondjock A. Coffee consumption and the risk of cancer: an overview. Cancer Lett. 2009;277(2):121–
125.
39. Krejs GJ. Pancreatic cancer: epidemiology and risk factors. Dig Dis. 2010;28(2):355–358.
40. Dong J, Zou J, Yu XF. Coffee drinking and pancreatic cancer risk: a meta-analysis of cohort studies.
World J Gastroenterol. 2011;17(9):1204–1210.
41. Turati F, Galeone C, La Vecchia C, et al. Coffee and cancers of the upper digestive and respiratory
tracts: meta-analyses of observational studies. Ann Oncol. 2011;22(3):536–544.
42. Gapstur SM, Jacobs EJ, Deka A, et al. Association of alcohol intake with pancreatic cancer mortality in
never smokers. Arch Intern Med. 2011;171(5):444–451.
43. Lucenteforte E, La Vecchia C, Silverman D, et al. Alcohol consumption and pancreatic cancer: a
pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol.
2012;23(2):374–382.
44. Duell EJ. Epidemiology and potential mechanisms of tobacco smoking and heavy alcohol
consumption in pancreatic cancer. Mol Carcinog. 2012;51(1):40–52.
45. Gupta S, Wang F, Holly EA, et al. Risk of pancreatic cancer by alcohol dose, duration, and pattern of
consumption, including binge drinking: a population-based study. Cancer Causes Control.
2010;21(7):1047–1059.
46. Jiao L, Berrington de Gonzalez A, Hartge P, et al. Body mass index, effect modifiers, and risk of
pancreatic cancer: a pooled study of seven prospective cohorts. Cancer Causes Control. 2010;21:1305–
1314.
47. Bracci PM. Obesity and pancreatic cancer: overview of epidemiologic evidence and biologic
mechanisms. Mol Carcinog. 2012;51(1):53–63.
48. Lin Y, Kikuchi S, Tamakoshi A, et al. Obesity, physical activity and the risk of pancreatic cancer in a
large Japanese cohort. Int J Cancer. 2007;120(12):2665–2671.
49. Li D, Morris JS, Liu J, et al. Body mass index and risk, age of onset, and survival in patients with
pancreatic cancer. JAMA. 2009;301(24):2553–2562.
50. Urayama KY, Holcatova I, Janout V, et al. Body mass index and body size in early adulthood and risk
of pancreatic cancer in a central European multicenter case-control study. Int J Cancer.
2011;129(12):2875–2884.
51. Andreotti G, Silverman DT. Occupational risk factors and pancreatic cancer: a review of recent
findings. Mol Carcinog. 2012;51(1):98–108.
52. Olson SH. Selected medical conditions and risk of pancreatic cancer. Mol Carcinog. 2012;51(1):75–
97.
53. Braat H, Bruno M, Kuipers EJ, et al. Pancreatic cancer: promise for personalised medicine? Cancer
Lett. 2012;318(1):1–8.
54. Raimondi S, Lowenfels AB, Morselli-Labate AM, et al. Pancreatic cancer in chronic pancreatitis;
aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol. 2010;24(3):349–358.
55. Bracci PM, Wang F, Hassan MM, et al. Pancreatitis and pancreatic cancer in two large pooled casecontrol studies. Cancer Causes Control. 2009;20(9):1723–1731.
56. Balakrishnan V, Unnikrishnan AG, Thomas V, et al. Chronic pancreatitis. A prospective nationwide
study of 1,086 subjects from India. JOP. 2008;9(5):593–600.
57. Wang W, Liao Z, Li G, et al. Incidence of pancreatic cancer in chinese patients with chronic
pancreatitis. Pancreatology. 2011;11(1):16–23.
58. Ben Q, Cai Q, Li Z, et al. The relationship between new-onset diabetes mellitus and pancreatic cancer
risk: a case-control study. Eur J Cancer. 2011;47(2):248–254.
59. Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, et al. Type-II diabetes and pancreatic
cancer: a meta-analysis of 36 studies. Br J Cancer. 2005;92(11):2076–2083.
60. Chari ST, Leibson CL, Rabe KG, et al. Pancreatic cancer-associated diabetes mellitus: prevalence and
temporal association with diagnosis of cancer. Gastroenterology. 2008;134(1):95–101.
61. Chari ST, Leibson CL, Rabe KG, et al. Probability of pancreatic cancer following diabetes: a
population-based study. Gastroenterology. 2005;129(2):504–511.
62. Gapstur SM, Gann PH, Lowe W, et al. Abnormal glucose metabolism and pancreatic cancer mortality.
JAMA. 2000;283(19):2552–2558.
63. Li D. Diabetes and pancreatic cancer. Mol Carcinog. 2012;51(1):64–74.
64. Stadler ZK, Salo-Mullen E, Patil SM, et al. Prevalence of BRCA1 and BRCA2 mutations in Ashkenazi
Jewish families with breast and pancreatic cancer. Cancer. 2012;118(2):493–499.
65. Klein AP. Genetic susceptibility to pancreatic cancer. Mol Carcinog. 2012;51(1):14–24.
66. Slater EP, Langer P, Niemczyk E, et al. PALB2 mutations in European familial pancreatic cancer
families. Clin Genet. 2010;78(5):490–494.
67. Jones S, Zhang X, Parsons DW, et al. Core signaling pathways in human pancreatic cancers revealed
by global genomic analyses. Science. 2008;321(5897):1801–1806.
68. Grover S, Syngal S. Hereditary pancreatic cancer. Gastroenterology. 2010;139(4):1076–1080, 1080.
69. Kastrinos F, Mukherjee B, Tayob N, et al. Risk of pancreatic cancer in families with Lynch syndrome.
JAMA. 2009;302(16):1790–1795.
70. Yamaguchi K. How to define patients at high risk for pancreatic cancer. Pancreatology. 2011;11(suppl
2):3–6.
71. Maisonneuve P, Marshall BC, Lowenfels AB. Risk of pancreatic cancer in patients with cystic fibrosis.
Gut. 2007;56(9):1327–1328.
72. Jacobs EJ, Chanock SJ, Fuchs CS, et al. Family history of cancer and risk of pancreatic cancer: a pooled
analysis from the Pancreatic Cancer Cohort Consortium (PanScan). Int J Cancer. 2010;127(6):1421–1428.
73. Shi C, Hruban RH, Klein AP. Familial pancreatic cancer. Arch Pathol Lab Med. 2009;133(3):365–374.
74. Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic
cancer kindreds. Cancer Res. 2004;64(7):2634–2638.
75. Hruban RH, Canto MI, Goggins M, et al. Update on familial pancreatic cancer. Adv Surg.
2010;44:293–311.
76. Amundadottir L, Kraft P, Stolzenberg-Solomon RZ, et al. Genome-wide association study identifies
variants in the ABO locus associated with susceptibility to pancreatic cancer. Nat Genet. 2009;41(9):986–
990.
77. Petersen GM, Amundadottir L, Fuchs CS, et al. A genome-wide association study identifies pancreatic
cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010;42(3):224–
228.
78. Iodice S, Maisonneuve P, Botteri E, et al. ABO blood group and cancer. Eur J Cancer.
2010;46(18):3345–3350.
79. Duell EJ, Holly EA, Bracci PM, et al. A population-based, case-control study of polymorphisms in
carcinogen-metabolizing genes, smoking, and pancreatic adenocarcinoma risk. J Natl Cancer Inst.
2002;94(4):297–306.
80. Li D, Jiao L, Li Y, et al. Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes,
smoking, and risk of pancreatic cancer. Carcinogenesis. 2006;27(1):103–111.
81. Kanda J, Matsuo K, Suzuki T, et al. Impact of alcohol consumption with polymorphisms in alcoholmetabolizing enzymes on pancreatic cancer risk in Japanese. Cancer Sci. 2009;100(2):296–302.
82. Lin Y, Yagyu K, Egawa N, et al. An overview of genetic polymorphisms and pancreatic cancer risk in
molecular epidemiologic studies. J Epidemiol. 2011;21(1):2–12.
83. Duell EJ, Holly EA, Bracci PM, et al. A population-based study of the Arg399Gln polymorphism in Xray repair cross-complementing group 1 (XRCC1) and risk of pancreatic adenocarcinoma. Cancer Res.
2002;62(16):4630–4636.
84. Li D, Li Y, Jiao L, et al. Effects of base excision repair gene polymorphisms on pancreatic cancer
survival. Int J Cancer. 2007;120(8):1748–1754.
85. Zhang J, Zhang X, Dhakal IB, et al. Sequence variants in antioxidant defense and DNA repair genes,
dietary antioxidants, and pancreatic cancer risk. Int J Mol Epidemiol Genet. 2011;2(3):236–244.
86. Suzuki H, Li Y, Dong X, et al. Effect of insulin-like growth factor gene polymorphisms alone or in
interaction with diabetes on the risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev.
2008;17(12):3467–3473.
87. Fendrich V. Chemoprevention of pancreatic cancer—one step closer. Langenbecks Arch Surg. 2012.
88. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362(17):1605–1617.
89. Laurent-Puig P, Taieb J. Lessons from Tarceva in pancreatic cancer: where are we now, and how
should future trials be designed in pancreatic cancer? Curr Opin Oncol. 2008;20(4):454–458.
90. Cleary-Wheeler AL, McWilliams R, Fernandez-Zapico ME. Aberrant signaling pathways in pancreatic
cancer: a two compartment view. Mol Carcinog. 2012;51(1):25–39.
91. Remmers N, Bailey JM, Mohr AM, et al. Molecular pathology of early pancreatic cancer. Cancer
Biomark. 2011;9(1):421–440.
92. Lauth M. RAS and Hedgehog—partners in crime. Front Biosci. 2011;17:2259–2270.
93. Mulcahy HE, Lyautey J, Lederrey C, et al. A prospective study of K-ras mutations in the plasma of
pancreatic cancer patients. Clin Cancer Res. 1998;4(2):271–275.
94. Collins MA, Bednar F, Zhang Y, et al. Oncogenic Kras is required for both the initiation and
maintenance of pancreatic cancer in mice. J Clin Invest. 2012;122(2):639–653.
95. Ohtani N, Zebedee Z, Huot TJ, et al. Opposing effects of Ets and Id proteins on p16INK4a expression
during cellular senescence. Nature. 2001;409(6823):1067–1070.
96. Li J, Poi MJ, Tsai MD. Regulatory mechanisms of tumor suppressor P16(INK4A) and their relevance to
cancer. Biochemistry. 2011;50(25):5566–5582.
97. Schutte M, Hruban RH, Geradts J, et al. Abrogation of the Rb/p16 tumor-suppressive pathway in
virtually all pancreatic carcinomas. Cancer Res. 1997;57(15):3126–3130.
98. Soussi T. TP53 mutations in human cancer: database reassessment and prospects for the next
decade. Adv Cancer Res. 2011;110:107–139.
99. Salek C, Benesova L, Zavoral M, et al. 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(27):3714–
3720.
100. Redston MS, Caldas C, Seymour AB, et al. p53 mutations in pancreatic carcinoma and evidence of
common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994;54(11):3025–
3033.
101. Talar-Wojnarowska R, Gasiorowska A, Smolarz B, et al. Comparative evaluation of p53 mutation in
pancreatic adenocarcinoma and chronic pancreatitis. Hepatogastroenterology. 2006;53(70):608–612.
102. Itoi T, Takei K, Sofuni A, et al. Immunohistochemical analysis of p53 and MIB-1 in tissue specimens
obtained from endoscopic ultrasonography-guided fine needle aspiration biopsy for the diagnosis of
solid pancreatic masses. Oncol Rep. 2005;13(2):229–234.
103. Rhim AD, Stanger BZ. Molecular biology of pancreatic ductal adenocarcinoma progression: aberrant
activation of developmental pathways. Prog Mol Biol Transl Sci. 2010;97:41–78.
104. Hidalgo M, Maitra A. The hedgehog pathway and pancreatic cancer. N Engl J Med.
2009;361(21):2094–2096.
105. Cleary-Wheeler AL, McWilliams R, Fernandez-Zapico ME. Aberrant signaling pathways in pancreatic
cancer: a two compartment view. Mol Carcinog. 2012;51(1):25–39.
106. Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic
cancer tumorigenesis. Nature. 2003;425(6960):851–856.
107. Olive KP, Jacobetz MA, Davidson CJ, et al. Inhibition of Hedgehog signaling enhances delivery of
chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457–1461.
108. Kelleher FC. Hedgehog signaling and therapeutics in pancreatic cancer. Carcinogenesis.
2011;32(4):445–451.
109. Kim EJ, Simeone DM. Advances in pancreatic cancer. Curr Opin Gastroenterol. 2011;27(5):460–466.
110. Mo W, Xu X, Xu L, et al. Resveratrol inhibits proliferation and induces apoptosis through the
hedgehog signaling pathway in pancreatic cancer cell. Pancreatology. 2012;11(6):601–609.
111. Stecca B, Ruiz IA. Context-dependent regulation of the GLI code in cancer by HEDGEHOG and nonHEDGEHOG signals. J Mol Cell Biol. 2010;2(2):84–95.
112. He S, Wang F, Yang L, et al. Expression of DNMT1 and DNMT3a are regulated by GLI1 in human
pancreatic cancer. PLoS One. 2011;6(11):e27684.
113. Ferretti E, De Smaele E, Miele E, et al. Concerted microRNA control of Hedgehog signalling in
cerebellar neuronal progenitor and tumour cells. EMBO J. 2008;27(19):2616–2627.
114. Bosetti C, Bertuccio P, Negri E, et al. Pancreatic cancer: overview of descriptive epidemiology. Mol
Carcinog. 2012;51(1):3–13.
115. Le Scodan R, Mornex F, Girard N, et al. Preoperative chemoradiation in potentially resectable
pancreatic adenocarcinoma: feasibility, treatment effect evaluation and prognostic factors, analysis of
the SFRO-FFCD 9704 trial and literature review. Ann Oncol. 2009;20(8):1387–1396.
116. Bogoevski D, Strate T, Yekebas EF, et al. Pancreatic cancer: a generalized disease-prognostic impact
of cancer cell dissemination. Langenbecks Arch Surg. 2008;393(6):911–917.
117. Partensky C. Pancreatic surgery in France. Surg Today. 2010;40(10):895–901.
118. Nakao A, Kanzaki A, Fujii T, et al. Correlation between radiographic classification and pathological
grade of portal vein wall invasion in pancreatic head cancer. Ann Surg. 2012;255(1):103–108.
119. Yokoyama Y, Nimura Y, Nagino M. Advances in the treatment of pancreatic cancer: limitations of
surgery and evaluation of new therapeutic strategies. Surg Today. 2009;39(6):466–475.
120. Yekebas EF, Bogoevski D, Cataldegirmen G, et al. En bloc vascular resection for locally advanced
pancreatic malignancies infiltrating major blood vessels: perioperative outcome and long-term survival
in 136 patients. Ann Surg. 2008;247(2):300–309.
121. Bockhorn M, Burdelski C, Bogoevski D, et al. Arterial en bloc resection for pancreatic carcinoma. Br
J Surg. 2011;98(1):86–92.
122. Bilimoria KY, Bentrem DJ, Ko CY, et al. Validation of the 6th edition AJCC Pancreatic Cancer Staging
System: report from the National Cancer Database. Cancer. 2007;110(4):738–744.
123. Hartwig W, Hackert T, Hinz U, et al. Pancreatic cancer surgery in the new millennium: better
prediction of outcome. Ann Surg. 2011;254(2):311–319.
124. Mossner J. What's new in therapy of pancreatic cancer? Dig Dis. 2010;28(4-5):679–683.
125. Van Laethem JL, Verslype C, Iovanna JL, et al. New strategies and designs in pancreatic cancer
research: consensus guidelines report from a European expert panel. Ann Oncol. 2012;23(3):570–576.
126. Almhanna K, Philip PA. Defining new paradigms for the treatment of pancreatic cancer. Curr Treat
Options Oncol. 2011;12(2):111–125.
127. Neesse A, Michl P, Frese KK, et al. Stromal biology and therapy in pancreatic cancer. Gut.
2011;60(6):861–868.
128. Wouters MD, van G, Hoeijmakers JH, et al. MicroRNAs, the DNA damage response and cancer.
Mutat Res. 2011;717(1-2):54–66.
129. Matthaios D, Zarogoulidis P, Balgouranidou I, et al. Molecular pathogenesis of pancreatic cancer
and clinical perspectives. Oncology. 2011;81(3-4):259–272.
130. Fryer RA, Barlett B, Galustian C, et al. Mechanisms underlying gemcitabine resistance in pancreatic
cancer and sensitisation by the iMiD™; lenalidomide. Anticancer Res. 2011;31(11):3747–3756.
131. Herceg Z, Vaissiere T. Epigenetic mechanisms and cancer: an interface between the environment
and the genome. Epigenetics. 2011;6(7):804–819.
132. Sincic N, Herceg Z. DNA methylation and cancer: ghosts and angels above the genes. Curr Opin
Oncol. 2011;23(1):69–76.
133. Heijmans BT, Tobi EW, Lumey LH, et al. The epigenome: archive of the prenatal environment.
Epigenetics. 2009;4(8):526–531.
134. Lopez J, Percharde M, Coley HM, et al. The context and potential of epigenetics in oncology. Br J
Cancer. 2009;100(4):571–577.
135. Zhong X, Coukos G, Zhang L. miRNAs in human cancer. Methods Mol Biol. 2012;822:295–306.
136. Kozomara A, Griffiths-Jones S. miRBase: integrating microRNA annotation and deep-sequencing
data. Nucleic Acids Res. 2011;39(Database issue):D152–D157.
137. Friedman RC, Farh KK, Burge CB, et al. Most mammalian mRNAs are conserved targets of
microRNAs. Genome Res. 2009;19(1):92–105.
138. Volinia S, Calin GA, Liu CG, et al. A microRNA expression signature of human solid tumors defines
cancer gene targets. Proc Natl Acad Sci U S A. 2006;103(7):2257–2261.
139. Steele CW, Oien KA, McKay CJ, et al. Clinical potential of microRNAs in pancreatic ductal
adenocarcinoma. Pancreas. 2011;40(8):1165–1171.
140. Szafranska AE, Davison TS, John J, et al. MicroRNA expression alterations are linked to
tumorigenesis and non-neoplastic processes in pancreatic ductal adenocarcinoma. Oncogene.
2007;26(30):4442–4452.
141. Panarelli NC, Chen YT, Zhou XK, et al. MicroRNA expression aids the preoperative diagnosis of
pancreatic ductal adenocarcinoma. Pancreas. 2012;41(5):685–690.
142. Pan X, Wang ZX, Wang R. MicroRNA-21: a novel therapeutic target in human cancer. Cancer Biol
Ther. 2011;10(12):1224–1232.
143. Nagao Y, Hisaoka M, Matsuyama A, et al. Association of microRNA-21 expression with its targets,
PDCD4 and TIMP3, in pancreatic ductal adenocarcinoma. Mod Pathol. 2012;25(1):112–121.
144. Moriyama T, Ohuchida K, Mizumoto K, et al. MicroRNA-21 modulates biological functions of
pancreatic cancer cells including their proliferation, invasion, and chemoresistance. Mol Cancer Ther.
2009;8(5):1067–1074.
145. Ryu JK, Hong SM, Karikari CA, et al. Aberrant MicroRNA-155 expression is an early event in the
multistep progression of pancreatic adenocarcinoma. Pancreatology. 2010;10(1):66–73.
146. Hamada S, Shimosegawa T. Biomarkers of pancreatic cancer. Pancreatology. 2011;11(suppl 2):14–
19.
147. Preis M, Gardner TB, Gordon SR, et al. MicroRNA-10b expression correlates with response to
neoadjuvant therapy and survival in pancreatic ductal adenocarcinoma. Clin Cancer Res.
2011;17(17):5812–5821.
148. Wang J, Chen J, Chang P, et al. MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients
as novel blood-based biomarkers of disease. Cancer Prev Res (Phila). 2009;2(9):807–813.
149. Ho AS, Huang X, Cao H, et al. Circulating miR-210 as a novel hypoxia marker in pancreatic cancer.
Transl Oncol. 2010;3(2):109–113.
150. Li A, Omura N, Hong SM, et al. Pancreatic cancers epigenetically silence SIP1 and hypomethylate
and overexpress miR-200a/200b in association with elevated circulating miR-200a and miR-200b levels.
Cancer Res. 2010;70(13):5226–5237.
151. Kong X, Du Y, Wang G, et al. Detection of differentially expressed microRNAs in serum of pancreatic
ductal adenocarcinoma patients: miR-196a could be a potential marker for poor prognosis. Dig Dis Sci.
2011;56(2):602–609.
152. Ali S, Almhanna K, Chen W, et al. Differentially expressed miRNAs in the plasma may provide a
molecular signature for aggressive pancreatic cancer. Am J Transl Res. 2010;3(1):28–47.
153. Liu J, Gao J, Du Y, et al. Combination of plasma microRNAs with serum CA19-9 for early detection of
pancreatic cancer. Int J Cancer. 2012;131(3):683–691.
154. Morimura R, Komatsu S, Ichikawa D, et al. Novel diagnostic value of circulating miR-18a in plasma
of patients with pancreatic cancer. Br J Cancer. 2011;105(11):1733–1740.
155. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature.
2005;435(7043):834–838.
156. Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat
Rev Cancer. 2011;11(6):426–437.
157. Zhang L, Farrell JJ, Zhou H, et al. Salivary transcriptomic biomarkers for detection of resectable
pancreatic cancer. Gastroenterology. 2010;138(3):949–957.
158. Jung T, Castellana D, Klingbeil P, et al. CD44v6 dependence of premetastatic niche preparation by
exosomes. Neoplasia. 2009;11(10):1093–1105.
159. Zen K, Zhang CY. Circulating microRNAs: a novel class of biomarkers to diagnose and monitor
human cancers. Med Res Rev. 2012;32(2):326–348.
160. Hunter MP, Ismail N, Zhang X, et al. Detection of microRNA expression in human peripheral blood
microvesicles. PLoS One. 2008;3(11):e3694.
161. Camussi G, Deregibus MC, Bruno S, et al. Exosome/microvesicle-mediated epigenetic
reprogramming of cells. Am J Cancer Res. 2011;1(1):98–110.
162. Rabinowits G, Gercel-Taylor C, Day JM, et al. Exosomal microRNA: a diagnostic marker for lung
cancer. Clin Lung Cancer. 2009;10(1):42–46.
163. Ribatti D. Cancer stem cells and tumor angiogenesis. Cancer Lett. 2012;321(1):13–17.
164. Mishra A, Verma M. Epigenetics of solid cancer stem cells. Methods Mol Biol. 2012;863:15–31.
165. Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res.
2007;67(3):1030–1037.
166. Li SC, Lee KL, Luo J, et al. Convergence of normal stem cell and cancer stem cell developmental
stage: implication for differential therapies. World J Stem Cells. 2011;3(9):83–88.
167. Rasheed ZA, Yang J, Wang Q, et al. Prognostic significance of tumorigenic cells with mesenchymal
features in pancreatic adenocarcinoma. J Natl Cancer Inst. 2010;102(5):340–351.
168. Li C, Wu JJ, Hynes M, et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target.
Gastroenterology. 2011;141(6):2218–2227.
169. Rhim AD, Mirek ET, Aiello NM, et al. EMT and dissemination precede pancreatic tumor formation.
Cell. 2012;148(1-2):349–361.
170. Cano CE, Motoo Y, Iovanna JL. Epithelial-to-mesenchymal transition in pancreatic adenocarcinoma.
ScientificWorldJournal. 2010;10:1947–1957.
171. Gupta PB, Chaffer CL, Weinberg RA. Cancer stem cells: mirage or reality? Nat Med.
2009;15(9):1010–1012.
172. Provenzano PP, Cuevas C, Chang AE, et al. Enzymatic targeting of the stroma ablates physical
barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21(3):418–429.
173. Uhr JW, Pantel K. Controversies in clinical cancer dormancy. Proc Natl Acad Sci U S A.
2011;108(30):12396–12400.
174. Folkman J, Kalluri R. Cancer without disease. Nature. 2004;427(6977):787.
175. Cabarcas SM, Mathews LA, Farrar WL. The cancer stem cell niche—there goes the neighborhood?
Int J Cancer. 2011;129(10):2315–2327.
176. Berdasco M, Esteller M. Aberrant epigenetic landscape in cancer: how cellular identity goes awry.
Dev Cell. 2010;19(5):698–711.
177. Bloomston M, Frankel WL, Petrocca F, et al. MicroRNA expression patterns to differentiate
pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA. 2007;297(17):1901–
1908.
178. Nana-Sinkam SP, Fabbri M, Croce CM. MicroRNAs in cancer: personalizing diagnosis and therapy.
Ann N Y Acad Sci. 2010;1210:25–33.
179. Ohuchida K, Mizumoto K, Kayashima T, et al. MicroRNA expression as a predictive marker for
gemcitabine response after surgical resection of pancreatic cancer22. Ann Surg Oncol. 2011;18(8):2381–
2387.
180. Huff CA, Matsui W, Smith BD, et al. The paradox of response and survival in cancer therapeutics.
Blood. 2006;107(2):431–434.
181. Morrison R, Schleicher SM, Sun Y, et al. Targeting the mechanisms of resistance to chemotherapy
and radiotherapy with the cancer stem cell hypothesis. J Oncol. 2011;2011:941876.
182. Hermann PC, Bhaskar S, Cioffi M, et al. Cancer stem cells in solid tumors. Semin Cancer Biol.
2010;20(2):77–84.
183. Du Z, Qin R, Wei C, et al. Pancreatic cancer cells resistant to chemoradiotherapy rich in “stem-celllike” tumor cells. Dig Dis Sci. 2011;56(3):741–750.
184. Scheel C, Weinberg RA. Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and
normal stem cells? Int J Cancer. 2011;129(10):2310–2314.
185. Shah AN, Summy JM, Zhang J, et al. Development and characterization of gemcitabine-resistant
pancreatic tumor cells. Ann Surg Oncol. 2007;14(12):3629–3637.
186. Sergeant G, Vankelecom H, Gremeaux L, et al. Role of cancer stem cells in pancreatic ductal
adenocarcinoma. Nat Rev Clin Oncol. 2009;6(10):580–586.
187. Hermann PC, Huber SL, Herrler T, et al. Distinct populations of cancer stem cells determine tumor
growth and metastatic activity in human pancreatic cancer. Cell Stem Cell. 2007;1(3):313–323.
188. Hermann PC, Mueller MT, Heeschen C. Pancreatic cancer stem cells—insights and perspectives.
Expert Opin Biol Ther. 2009;9(10):1271–1278.
189. Lonardo E, Hermann PC, Heeschen C. Pancreatic cancer stem cells—update and future
perspectives. Mol Oncol. 2010;4(5):431–442.
190. Patel RS, Jakymiw A, Yao B, et al. High resolution of microRNA signatures in human whole saliva.
Arch Oral Biol. 2011;56(12):1506–1513.
191. Cortez MA, Bueso-Ramos C, Ferdin J, et al. MicroRNAs in body fluids—the mix of hormones and
biomarkers. Nat Rev Clin Oncol. 2011;8(8):467–477.
192. Kroh EM, Parkin RK, Mitchell PS, et al. Analysis of circulating microRNA biomarkers in plasma and
serum using quantitative reverse transcription-PCR (qRT-PCR). Methods. 2010;50(4):298–301.
193. Kosaka N, Iguchi H, Ochiya T. Circulating microRNA in body fluid: a new potential biomarker for
cancer diagnosis and prognosis. Cancer Sci. 2010;101(10):2087–2092.
194. Habbe N, Koorstra JB, Mendell JT, et al. MicroRNA miR-155 is a biomarker of early pancreatic
neoplasia. Cancer Biol Ther. 2009;8(4):340–346.
195. Yu J, Li A, Hong SM, et al. MicroRNA alterations of pancreatic intraepithelial neoplasias. Clin Cancer
Res. 2012;18(4):981–992.
196. Jamieson NB, Morran DC, Morton JP, et al. MicroRNA molecular profiles associated with diagnosis,
clinicopathologic criteria, and overall survival in patients with resectable pancreatic ductal
adenocarcinoma. Clin Cancer Res. 2012;18(2):534–545.
197. Lodes MJ, Caraballo M, Suciu D, et al. Detection of cancer with serum miRNAs on an
oligonucleotide microarray. PLoS One. 2009;4(7):e6229.
198. Liu R, Chen X, Du Y, et al. Serum microRNA expression profile as a biomarker in the diagnosis and
prognosis of pancreatic cancer. Clin Chem. 2012;58(3):610–618.
199. Matsubayashi H. Familial pancreatic cancer and hereditary syndromes: screening strategy for highrisk individuals. J Gastroenterol. 2011;46(11):1249–1259.
200. Delpu Y, Hanoun N, Lulka H, et al. Genetic and epigenetic alterations in pancreatic carcinogenesis.
Curr Genomics. 2011;12(1):15–24.
201. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of
pancreatic cancer. Nature. 2010;467(7319):1114–1117.
202. Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet. 2011;378(9791):607–620.
203. Bartels CL, Tsongalis GJ. MicroRNAs: novel biomarkers for human cancer. Ann Biol Clin (Paris).
2010;68(3):263–272.
204. Cioffi M, Dorado J, Baeuerle PA, et al. EpCAM/CD3-Bispecific T-cell engaging antibody MT110
eliminates primary human pancreatic cancer stem cells. Clin Cancer Res. 2012;18(2):465–474.
205. Krutovskikh V, Partensky C. New insights in oncology: epigenetics and cancer stem cells. Cancer
Radiother. 2011;15(8):716–722.
206. Mordant P, Loriot Y, Lahon B, et al. Minimal residual disease in solid neoplasia: new frontier or redherring? Cancer Treat Rev. 2012;38(2):101–110.
207. Balic A, Dorado J, Alonso-Gomez M, et al. Stem cells as the root of pancreatic ductal
adenocarcinoma. Exp Cell Res. 2012;318(6):691–704.
208. Liu C, Tang DG. MicroRNA regulation of cancer stem cells. Cancer Res. 2011;71(18):5950–5954.
209. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861–874.
210. Park JY, Helm J, Coppola D, et al. MicroRNAs in pancreatic ductal adenocarcinoma. World J
Gastroenterol. 2011;17(7):817–827.
211. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.
212. Nalls D, Tang SN, Rodova M, et al. Targeting epigenetic regulation of miR-34a for treatment of
pancreatic cancer by inhibition of pancreatic cancer stem cells. PLoS One. 2011;6(8):e24099.
213. Mueller MT, Hermann PC, Witthauer J, et al. Combined targeted treatment to eliminate
tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology. 2009;137(3):1102–1113.
214. Davidson BL, McCray PB Jr. Current prospects for RNA interference-based therapies. Nat Rev Genet.
2011;12(5):329–340.
215. Krutzfeldt J, Rajewsky N, Braich R, et al. Silencing of microRNAs in vivo with ‘antagomirs’. Nature.
2005;438(7068):685–689.
216. Ganguli S, Mitra S, Datta A. Antagomirbase—a putative antagomir database. Bioinformation.
2011;7(1):41–43.
217. Morrisey EE. The magic and mystery of miR-21. J Clin Invest. 2010;120(11):3817–3819.
218. Rupaimoole R, Han HD, Lopez-Berestein G, et al. MicroRNA therapeutics: principles, expectations,
and challenges. Chin J Cancer. 2011;30(6):368–370.
219. Babashah S, Soleimani M. The oncogenic and tumour suppressive roles of microRNAs in cancer and
apoptosis. Eur J Cancer. 2011;47(8):1127–1137.
220. Setoyama T, Ling H, Natsugoe S, et al. Non-coding RNAs for medical practice in oncology. Keio J
Med. 2011;60(4):106–113.
221. Haldar S, Basu A. Modulation of microRNAs by chemical carcinogens and anticancer drugs in human
cancer: potential inkling to therapeutic advantage. Mol Cell Pharmacol. 2011;3(3):135–141.
222. Kasinski AL, Slack FJ. MicroRNAs en route to the clinic: progress in validating and targeting
microRNAs for cancer therapy. Nat Rev Cancer. 2011;11(12):849–864.
223. Bao B, Ali S, Kong D, et al. Anti-tumor activity of a novel compound-CDF is mediated by regulating
miR-21, miR-200, and PTEN in pancreatic cancer. PLoS One. 2011;6(3):e17850.
224. Shahzad MM, Mangala LS, Han HD, et al. Targeted delivery of small interfering RNA using
reconstituted high-density lipoprotein nanoparticles. Neoplasia. 2011;13(4):309–319.
225. Pramanik D, Campbell NR, Karikari C, et al. Restitution of tumor suppressor microRNAs using a
systemic nanovector inhibits pancreatic cancer growth in mice. Mol Cancer Ther. 2011;10(8):1470–1480.
226. Scatena R, Bottoni P, Pontoglio A, et al. Cancer stem cells: the development of new cancer
therapeutics. Expert Opin Biol Ther. 2011;11(7):875–892.
227. Pan FC, Wright C. Pancreas organogenesis: from bud to plexus to gland. Dev Dyn. 2011;240(3):530–
565.
228. Delude C. Tumorigenesis: testing ground for cancer stem cells. Nature. 2011;480(7377):S43–S45.
229. Dorado J, Lonardo E, Miranda-Lorenzo I, et al. Pancreatic cancer stem cells: new insights and
perspectives. J Gastroenterol. 2011;46(8):966–973.