Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Langenbeck's Archives of Surgery
Published in: Langenbeck's Archives of Surgery 4/2008

01-07-2008 | Original Article

Morphogenesis of pancreatic cancer: role of pancreatic intraepithelial neoplasia (PanINs)

Authors: Jan-Bart M. Koorstra, Georg Feldmann, Nils Habbe, Anirban Maitra

Published in: Langenbeck's Archives of Surgery | Issue 4/2008

Login to get access

Abstract

Introduction

Pancreatic ductal adenocarcinoma (i.e., pancreatic cancer) is an almost universally lethal disease. The identification of precursor lesions of pancreatic cancer provides an opportunity for early detection and potential therapeutic intervention before the development of invasive cancer.

Discussion

It is now established that pancreatic cancers do not arise de novo but rather exhibit a sequential histological and genetic progression of precursor lesions culminating in frank, invasive neoplasia. Pancreatic intraepithelial neoplasia (PanIN) is the most common non-invasive precursor lesion of pancreatic cancer. The development of a consensus nomenclature scheme for PanINs has facilitated research into pancreatic cancer precursors and enabled standardization of results across institutions.

Conclusion

PanINs harbor many of the molecular alterations observed in invasive pancreatic cancer, confirming their status as true non-invasive precursor lesions. Recently developed genetically engineered mouse models of pancreatic cancer also demonstrate the stepwise PanIN progression model, underscoring the commonalities in pancreatic neoplasia between mouse and man.
Literature
1.
Parker JF, Florell SR, Alexander A, DiSario JA, Shami PJ, Leachman SA (2003) Pancreatic carcinoma surveillance in patients with familial melanoma. Arch Dermatol 139:1019–1025PubMedCrossRef
2.
Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ (2006) Cancer statistics, 2006. CA Cancer J Clin 56:106–130PubMed
3.
American Cancer Society (2007) Cancer facts & figures 2007. American Cancer Society, Atlanta, pp 1–52
4.
Sohn TA, Yeo CJ, Cameron JL, Koniaris L, Kaushal S, Abrams RA, Sauter PK, Coleman J, Hruban RH, Lillemoe KD (2000) Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 4:567–579PubMedCrossRef
5.
Winter JM, Cameron JL, Campbell KA, Arnold MA, Chang DC, Coleman J, Hodgin MB, Sauter PK, Hruban RH, Riall TS, Schulick RD, Choti MA, Lillemoe KD, Yeo CJ (2006) 1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg 10:1199–1210PubMedCrossRef
6.
7.
Isozaki H, Okajima K, Morita S, Takeda Y, Ishibashi T, Tanimura M, Hara H, Niki M, Akimoto H, Kobayashi M (1990) Review of pancreatic cancer. Bull Osaka Med Coll 36:1–11PubMed
8.
Matsuno S, Egawa S, Arai K (2001) Trends in treatment for pancreatic cancer. J Hepatobiliary Pancreat Surg 8:544–548PubMedCrossRef
9.
Negm RS, Verma M, Srivastava S (2002) The promise of biomarkers in cancer screening and detection. Trends Mol Med 8:288–293PubMedCrossRef
10.
Smith RA, Cokkinides V, Eyre HJ (2006) American Cancer Society guidelines for the early detection of cancer, 2006. CA Cancer J Clin 56:11–25PubMed
11.
Hulst SPL (1905) Information on the genesis of the adenocarcinoma and carcinoma of the pancreas. Virchows Archiv fur Pathologische Anatomie und Physiologie und fur Klinische Medizin 180:288–316CrossRef
12.
Cubilla AL, Fitzgerald PJ (1976) Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 36:2690–2698PubMed
13.
Andea A, Sarkar F, Adsay VN (2003) Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma. Mod Pathol 16:996–1006PubMedCrossRef
14.
Schwartz AM, Henson DE (2007) Familial and sporadic pancreatic carcinoma, epidemiologic concordance. Am J Surg Pathol 31:645–646PubMedCrossRef
15.
Brat DJ, Lillemoe KD, Yeo CJ, Warfield PB, Hruban RH (1998) Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas. Am J Surg Pathol 22:163–169PubMedCrossRef
16.
Brockie E, Anand A, Albores-Saavedra J (1998) Progression of atypical ductal hyperplasia/carcinoma in situ of the pancreas to invasive adenocarcinoma. Ann Diagn Pathol 2:286–292PubMedCrossRef
17.
Hruban RH, Goggins M, Parsons J, Kern SE (2000) Progression model for pancreatic cancer. Clin Cancer Res 6:2969–2972PubMed
18.
Hruban RH, Adsay NV, Bores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra DS, Kloppel G, Longnecker DS, Luttges J, Offerhaus GJ (2001) Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol 25:579–586PubMedCrossRef
19.
Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, Biankin AV, Biankin SA, Compton C, Fukushima N, Furukawa T, Goggins M, Kato Y, Kloppel G, Longnecker DS, Luttges J, Maitra A, Offerhaus GJ, Shimizu M, Yonezawa S (2004) An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J Surg Pathol 28:977–987PubMedCrossRef
20.
Hruban RH, Fukushima N (2007) Pancreatic adenocarcinoma: update on the surgical pathology of carcinomas of ductal origin and PanINs. Mod Pathol 20(Suppl 1):S61–S70PubMedCrossRef
21.
Winter JM, Cameron JL, Lillemoe KD, Campbell KA, Chang D, Riall TS, Coleman J, Sauter PK, Canto M, Hruban RH, Schulick RD, Choti MA, Yeo CJ (2006) Periampullary and pancreatic incidentaloma: a single institution’s experience with an increasingly common diagnosis. Ann Surg 243:673–680PubMedCrossRef
22.
Schmitz-Winnenthal FH, Z, graggen K, Volk C, Schmied BM, Buchler MW (2003) Intraductal papillary mucinous tumors of the pancreas. Curr Gastroenterol Rep 5:133–140PubMedCrossRef
23.
Longnecker DS, Adsay NV, Fernandez-del Castillo C, Hruban RH, Kasugai T, Klimstra DS, Kloppel G, Luttges J, Memoli VA, Tosteson TD, Yanagisawa A, Wilentz R, Zamboni G (2005) Histopathological diagnosis of pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms: interobserver agreement. Pancreas 31:344–349PubMedCrossRef
24.
Fukushima N, Mukai K (1997) ‘Ovarian-type’ stroma of pancreatic mucinous cystic tumor expresses smooth muscle phenotype. Pathol Int 47:806–808PubMedCrossRef
25.
Hruban RH, Klimstra DS, Pitman MB (2007) Atlas of tumor pathology. Tumors of the pancreas. AFIP, Armed Forces Institute of Pathology, Washington, DC
26.
Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M (1988) Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53:549–554PubMedCrossRef
27.
Hruban RH, van Mansfeld AD, Offerhaus GJ, van Weering DH, Allison DC, Goodman SN, Kensler TW, Bose KK, Cameron JL, Bos JL (1993) 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 143:545–554PubMed
28.
Deramaudt T, Rustgi AK (2005) Mutant KRAS in the initiation of pancreatic cancer. Biochim Biophys Acta 1756:97–101PubMed
29.
30.
Hingorani SR, Tuveson DA (2003) Ras redux: rethinking how and where Ras acts. Curr Opin Genet Dev 13:6–13PubMedCrossRef
31.
Lohr M, Kloppel G, Maisonneuve P, Lowenfels AB, Luttges J (2005) Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis. Neoplasia 7:17–23PubMedCrossRef
32.
Luttges J, Diederichs A, Menke MA, Vogel I, Kremer B, Kloppel G (2000) Ductal lesions in patients with chronic pancreatitis show K-ras mutations in a frequency similar to that in the normal pancreas and lack nuclear immunoreactivity for p53. Cancer 88:2495–2504PubMedCrossRef
33.
Laghi L, Orbetegli O, Bianchi P, Zerbi A, Di C V, Boland CR, Malesci A (2002) Common occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers. Oncogene 21:4301–4306PubMedCrossRef
34.
Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J, Redston MS, DePinho RA (2003) Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 17:3112–3126PubMedCrossRef
35.
Hingorani SR, Petricoin EF, Maitra A, Rajapakse V, King C, Jacobetz MA, Ross S, Conrads TP, Veenstra TD, Hitt BA, Kawaguchi Y, Johann D, Liotta LA, Crawford HC, Putt ME, Jacks T, Wright CV, Hruban RH, Lowy AM, Tuveson DA (2003) Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4:437–450PubMedCrossRef
36.
Fleming JB, Shen GL, Holloway SE, Davis M, Brekken RA (2005) Molecular consequences of silencing mutant K-ras in pancreatic cancer cells: justification for K-ras-directed therapy. Mol Cancer Res 3:413–423PubMedCrossRef
37.
Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE (1994) Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8:27–32PubMedCrossRef
38.
Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W, Baylin SB, Kern SE, Herman JG (1997) Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 57:3126–3130PubMed
39.
Sherr CJ (2000) Cell cycle control and cancer. Harvey Lect 96:73–92PubMed
40.
Sellers WR, Rodgers JW, Kaelin WG Jr (1995) A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites. Proc Natl Acad Sci U S A 92:11544–11548PubMedCrossRef
41.
Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M, Yeo CJ, Kern SE, Hruban RH (1998) Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 58:4740–4744PubMed
42.
Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Cameron JL, Yeo CJ, Hruban RH, Goggins M (2003) p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol 27:1495–1501PubMedCrossRef
43.
Kern SE (1994) p53: tumor suppression through control of the cell cycle. Gastroenterology 106:1708–1711PubMed
44.
Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE (1994) p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 54:3025–3033PubMed
45.
Maitra A, Adsay NV, Argani P, Iacobuzio-Donahue C, De Marzo A, Cameron JL, Yeo CJ, Hruban RH (2003) Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol 16:902–912PubMedCrossRef
46.
Moore PS, Sipos B, Orlandini S, Sorio C, Real FX, Lemoine NR, Gress T, Bassi C, Kloppel G, Kalthoff H, Ungefroren H, Lohr M, Scarpa A (2001) Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch 439:798–802PubMed
47.
Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH, Kern SE (1996) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350–353PubMedCrossRef
48.
Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH (2000) Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 60:2002–2006PubMed
49.
Wilentz RE, Su GH, Dai JL, Sparks AB, Argani P, Sohn TA, Yeo CJ, Kern SE, Hruban RH (2000) Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas: a new marker of DPC4 inactivation. Am J Pathol 156:37–43PubMed
50.
Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, Weinstein CL, Bova GS, Isaacs WB, Cairns P, Nawroz H, Sidransky D, Casero RA Jr, Meltzer PS, Hahn SA, Kern SE (1996) DPC4 gene in various tumor types. Cancer Res 56:2527–2530PubMed
51.
Massague J, Blain SW, Lo RS (2000) TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 103:295–309PubMedCrossRef
52.
53.
Maitra A, Kern SE, Hruban RH (2006) Molecular pathogenesis of pancreatic cancer. Best Pract Res Clin Gastroenterol 20:211–226PubMedCrossRef
54.
Han HJ, Yanagisawa A, Kato Y, Park JG, Nakamura Y (1993) Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res 53:5087–5089PubMed
55.
Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH (1998) Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol 152:1501–1507PubMed
56.
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M, Johnson K, Tascilar M, Offerhaus GJ, Hruban RH, Kern SE (2000) Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity. Am J Pathol 156:1641–1651PubMed
57.
Yamamoto H, Itoh F, Nakamura H, Fukushima H, Sasaki S, Perucho M, Imai K (2001) Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res 61:3139–3144PubMed
58.
van der Heijden MS, Yeo CJ, Hruban RH, Kern SE (2003) Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res 63:2585–2588PubMed
59.
van der Heijden MS, Brody JR, Gallmeier E, Cunningham SC, Dezentje DA, Shen D, Hruban RH, Kern SE (2004) Functional defects in the Fanconi anemia pathway in pancreatic cancer cells. Am J Pathol 165:651–657PubMed
60.
Klein AP, Hruban RH, Brune KA, Petersen GM, Goggins M (2001) Familial pancreatic cancer. Cancer J 7:266–273PubMed
61.
Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH, Kern SE (1996) Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56:5360–5364PubMed
62.
Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, Gerdes B, Kress R, Ziegler A, Raeburn JA, Campra D, Grutzmann R, Rehder H, Rothmund M, Schmiegel W, Neoptolemos JP, Bartsch DK (2003) BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 95:214–221PubMedCrossRef
63.
Goggins M, Hruban RH, Kern SE (2000) BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications. Am J Pathol 156:1767–1771PubMed
64.
Van Heek NT, Meeker AK, Kern SE, Yeo CJ, Lillemoe KD, Cameron JL, Offerhaus GJ, Hicks JL, Wilentz RE, Goggins MG, De Marzo AM, Hruban RH, Maitra A (2002) Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am J Pathol 161:1541–1547PubMed
65.
Gisselsson D, Jonson T, Petersen A, Strombeck B, Dal CP, Hoglund M, Mitelman F, Mertens F, Mandahl N (2001) Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc Natl Acad Sci U S A 98:12683–12688PubMedCrossRef
66.
O’Hagan RC, Chang S, Maser RS, Mohan R, Artandi SE, Chin L, DePinho RA (2002) Telomere dysfunction provokes regional amplification and deletion in cancer genomes. Cancer Cell 2:149–155PubMedCrossRef
67.
Clark SJ (2007) Action at a distance: epigenetic silencing of large chromosomal regions in carcinogenesis. Hum Mol Genet 16(Spec No 1):R88–R95PubMedCrossRef
68.
Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168–174PubMedCrossRef
69.
Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21:5427–5440PubMedCrossRef
70.
71.
Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH, Goggins M (2000) Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res 60:1835–1839PubMed
72.
Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, Yeo CJ, Hruban RH, Goggins M (2002) Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol 160:1573–1581PubMed
73.
Sato N, Goggins M (2006) The role of epigenetic alterations in pancreatic cancer. J Hepatobiliary Pancreat Surg 13:286–295PubMedCrossRef
74.
Goggins M (2007) Identifying molecular markers for the early detection of pancreatic neoplasia. Semin Oncol 34:303–310PubMedCrossRef
75.
Luttges J, Zamboni G, Longnecker D, Kloppel G (2001) The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol 25:942–948PubMedCrossRef
76.
Terada T, Ohta T, Sasaki M, Nakanuma Y, Kim YS (1996) Expression of MUC apomucins in normal pancreas and pancreatic tumours. J Pathol 180:160–165PubMedCrossRef
77.
Nagata K, Horinouchi M, Saitou M, Higashi M, Nomoto M, Goto M, Yonezawa S (2007) Mucin expression profile in pancreatic cancer and the precursor lesions. J Hepatobiliary Pancreat Surg 14:243–254PubMedCrossRef
78.
Adsay NV, Merati K, Andea A, Sarkar F, Hruban RH, Wilentz RE, Goggins M, Iocobuzio-Donahue C, Longnecker DS, Klimstra DS (2002) The dichotomy in the preinvasive neoplasia to invasive carcinoma sequence in the pancreas: differential expression of MUC1 and MUC2 supports the existence of two separate pathways of carcinogenesis. Mod Pathol 15:1087–1095PubMedCrossRef
79.
Kim GE, Bae HI, Park HU, Kuan SF, Crawley SC, Ho JJ, Kim YS (2002) Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas. Gastroenterology 123:1052–1060PubMedCrossRef
80.
Foss CA, Fox JJ, Feldmann G, Maitra A, Iacobuzio-Donohue C, Kern SE, Hruban RH, Pomper MG (2007) Radiolabeled anti-claudin 4 and anti-prostate stem cell antigen: initial imaging in experimental models of pancreatic cancer. Mol Imaging 6:131–139PubMed
81.
Singh AP, Chaturvedi P, Batra SK (2007) Emerging roles of MUC4 in cancer: a novel target for diagnosis and therapy. Cancer Res 67:433–436PubMedCrossRef
82.
Ohuchida K, Mizumoto K, Yamada D, Fujii K, Ishikawa N, Konomi H, Nagai E, Yamaguchi K, Tsuneyoshi M, Tanaka M (2006) Quantitative analysis of MUC1 and MUC5AC mRNA in pancreatic juice for preoperative diagnosis of pancreatic cancer. Int J Cancer 118:405–411PubMedCrossRef
83.
Gansauge S, Gansauge F, Ramadani M, Stobbe H, Rau B, Harada N, Beger HG (1997) Overexpression of cyclin D1 in human pancreatic carcinoma is associated with poor prognosis. Cancer Res 57:1634–1637PubMed
84.
Biankin AV, Kench JG, Morey AL, Lee CS, Biankin SA, Head DR, Hugh TB, Henshall SM, Sutherland RL (2001) Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. Cancer Res 61:8830–8837PubMed
85.
Kornmann M, Ishiwata T, Itakura J, Tangvoranuntakul P, Beger HG, Korc M (1998) Increased cyclin D1 in human pancreatic cancer is associated with decreased postoperative survival. Oncology 55:363–369PubMedCrossRef
86.
Sarkar FH, Adsule S, Li Y, Padhye S (2007) Back to the future: COX-2 inhibitors for chemoprevention and cancer therapy. Mini Rev Med Chem 7:599–608PubMedCrossRef
87.
Wu KK (2005) Control of cyclooxygenase-2 transcriptional activation by pro-inflammatory mediators. Prostaglandins Leukot Essent Fatty Acids 72:89–93PubMedCrossRef
88.
Maitra A, Ashfaq R, Gunn CR, Rahman A, Yeo CJ, Sohn TA, Cameron JL, Hruban RH, Wilentz RE (2002) Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am J Clin Pathol 118:194–201PubMedCrossRef
89.
Sclabas GM, Uwagawa T, Schmidt C, Hess KR, Evans DB, Abbruzzese JL, Chiao PJ (2005) Nuclear factor kappa B activation is a potential target for preventing pancreatic carcinoma by aspirin. Cancer 103:2485–2490PubMedCrossRef
90.
Miyamoto Y, Maitra A, Ghosh B, Zechner U, Argani P, Iacobuzio-Donahue CA, Sriuranpong V, Iso T, Meszoely IM, Wolfe MS, Hruban RH, Ball DW, Schmid RM, Leach SD (2003) Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 3:565–576PubMedCrossRef
91.
Berman DM, Karhadkar SS, Maitra A, Montes De OR, Gerstenblith MR, Briggs K, Parker AR, Shimada Y, Eshleman JR, Watkins DN, Beachy PA (2003) Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425:846–851PubMedCrossRef
92.
Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY, Qi YP, Gysin S, Fernandez-del CC, Yajnik V, Antoniu B, McMahon M, Warshaw AL, Hebrok M (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425:851–856PubMedCrossRef
93.
Zeng G, Germinaro M, Micsenyi A, Monga NK, Bell A, Sood A, Malhotra V, Sood N, Midda V, Monga DK, Kokkinakis DM, Monga SP (2006) Aberrant Wnt/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 8:279–289PubMedCrossRef
94.
Kimura K, Satoh K, Kanno A, Hamada S, Hirota M, Endoh M, Masamune A, Shimosegawa T (2007) Activation of Notch signaling in tumorigenesis of experimental pancreatic cancer induced by dimethylbenzanthracene in mice. Cancer Sci 98:155–162PubMedCrossRef
95.
Prasad NB, Biankin AV, Fukushima N, Maitra A, Dhara S, Elkahloun AG, Hruban RH, Goggins M, Leach SD (2005) Gene expression profiles in pancreatic intraepithelial neoplasia reflect the effects of Hedgehog signaling on pancreatic ductal epithelial cells. Cancer Res 65:1619–1626PubMedCrossRef
96.
Taipale J, Beachy PA (2001) The Hedgehog and Wnt signaling pathways in cancer. Nature 411:349–354PubMedCrossRef
97.
Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K, Brennan M, Cameron JL, Wu TT, Hruban RH (2002) Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol 160:1361–1369PubMed
98.
Abraham SC, Wu TT, Hruban RH, Lee JH, Yeo CJ, Conlon K, Brennan M, Cameron JL, Klimstra DS (2002) Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway. Am J Pathol 160:953–962PubMed
99.
Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright CV (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122:983–995PubMed
100.
Bardeesy N, Aguirre AJ, Chu GC, Cheng KH, Lopez LV, Hezel AF, Feng B, Brennan C, Weissleder R, Mahmood U, Hanahan D, Redston MS, Chin L, DePinho RA (2006) Both p16(Ink4a) and the p19(Arf)-p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc Natl Acad Sci U S A 103:5947–5952PubMedCrossRef
101.
Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S, Tuveson DA (2005) Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7:469–483PubMedCrossRef
102.
Archer H, Jura N, Keller J, Jacobson M, Bar-Sagi D (2006) A mouse model of hereditary pancreatitis generated by transgenic expression of R122H trypsinogen. Gastroenterology 131:1844–1855PubMedCrossRef
103.
Guerra C, Schuhmacher AJ, Canamero M, Grippo PJ, Verdaguer L, Perez-Gallego L, Dubus P, Sandgren EP, Barbacid M (2007) Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11:291–302PubMedCrossRef
104.
Lowenfels AB, Maisonneuve P, Dimagno EP, Elitsur Y, Gates LK Jr, Perrault J, Whitcomb DC (1997) Hereditary pancreatitis and the risk of pancreatic cancer. International hereditary pancreatitis study group. J Natl Cancer Inst 89:442–446PubMedCrossRef
Metadata
Title
Morphogenesis of pancreatic cancer: role of pancreatic intraepithelial neoplasia (PanINs)
Authors
Jan-Bart M. Koorstra
Georg Feldmann
Nils Habbe
Anirban Maitra
Publication date
01-07-2008
Publisher
Springer-Verlag
Published in
Langenbeck's Archives of Surgery / Issue 4/2008
Print ISSN: 1435-2443
Electronic ISSN: 1435-2451
DOI
https://doi.org/10.1007/s00423-008-0282-x

Other articles of this Issue 4/2008

Langenbeck's Archives of Surgery 4/2008 Go to the issue

How to do it

Hepatobiliary resection with inferior vena cava resection and reconstruction using an autologous patch graft for intrahepatic cholangiocarcinoma

Original Article

Role of a hepatectomy for the treatment of large hepatocellular carcinomas measuring 10 cm or larger in diameter

Original Article

Ischemic colitis—analysis of risk factors for postoperative mortality

How to do it

Simple segmental resection of the second portion of the duodenum for the treatment of gastrointestinal stromal tumors

Original Article

Redo-endorectal pull through following various pull through procedures in Hirschsprung's disease

Case Management and Clinical Consequences

Solitary fibrous tumour of the liver with IGF-II-related hypoglycaemia. A case report