Pancreatic Intraepithelial Neoplasia and Pancreatic Tumorigenesis: Of Mice and Men by ProQuest

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Context.-Pancreatic cancer has a poor prognosis with a 5-year survival of less than 5%. Early detection is at present the only way to improve this outlook. This review focuses on the recent advances in our understanding of pancreatic carcinogenesis, the scientific evidence for a multistaged tumor progression, and the role genetically engineered mouse models can play in recapitulating the natural course and biology of human disease. Objectives.-To illustrate the stepwise tumor progression of pancreatic cancer and genetic alterations within the different stages of progression and to review the findings made with genetically engineered mouse models concerning pancreatic carcinogenesis. Data Sources.-A review of recent literature on pancreatic tumorigenesis and genetically engineered mouse models. Conclusions.-Pancreatic cancer develops through stepwise tumor progression in which preinvasive stages, called pancreatic intraepithelial neoplasia, precede invasive pancreatic cancer. Genetic alterations in oncogenes and tumor suppressor genes underlying pancreatic cancer are also found in pancreatic intraepithelial neoplasia. These mutations accumulate during progression through the consecutive stages of pancreatic intraepithelial neoplasia lesions. Also in genetically engineered mouse models of pancreatic ductal adenocarcinoma, tumorigenesis occurs through stepwise progression via consecutive mouse pancreatic intraepithelial neoplasia, and these models provide important tools for clinical applications. Nevertheless differences between mice and men still remain.

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									                     Pancreatic Intraepithelial Neoplasia and
                            Pancreatic Tumorigenesis
                                                        Of Mice and Men
           Niki A. Ottenhof, BA; Anya N. A. Milne, MD, PhD; Folkert H. M. Morsink, BSc; Paul Drillenburg, MD, PhD;
                   Fiebo J. W. ten Kate, MD, PhD; Anirban Maitra, MBBS; G. Johan Offerhaus, MD, MPH, PhD

● Context.—Pancreatic cancer has a poor prognosis with a                    Conclusions.—Pancreatic cancer develops through step-
5-year survival of less than 5%. Early detection is at pres-             wise tumor progression in which preinvasive stages, called
ent the only way to improve this outlook. This review fo-                pancreatic intraepithelial neoplasia, precede invasive pan-
cuses on the recent advances in our understanding of pan-                creatic cancer. Genetic alterations in oncogenes and tumor
creatic carcinogenesis, the scientific evidence for a multi-              suppressor genes underlying pancreatic cancer are also
staged tumor progression, and the role genetically engi-                 found in pancreatic intraepithelial neoplasia. These muta-
neered mouse models can play in recapitulating the natural               tions accumulate during progression through the consec-
course and biology of human disease.                                     utive stages of pancreatic intraepithelial neoplasia lesions.
   Objectives.—To illustrate the stepwise tumor progres-
                                                                         Also in genetically engineered mouse models of pancreatic
sion of pancreatic cancer and genetic alterations within
the different stages of progression and to review the find-               ductal adenocarcinoma, tumorigenesis occurs through
ings made with genetically engineered mouse models con-                  stepwise progression via consecutive mouse pancreatic in-
cerning pancreatic carcinogenesis.                                       traepithelial neoplasia, and these models provide impor-
   Data Sources.—A review of recent literature on pancre-                tant tools for clinical applications. Nevertheless differences
atic tumorigenesis and genetically engineered mouse mod-                 between mice and men still remain.
els.                                                                        (Arch Pathol Lab Med. 2009;133:375–381)


P   ancreatic cancer has a poor prognosis. Incidence rates
     equal mortality rates and even though pancreatic can-
cer is not one of the most common cancers, it ranks fourth
                                                                         outlook of patients diagnosed with pancreatic cancer. Re-
                                                                         cent advances in our understanding of pancreatic carci-
                                                                         nogenesis may indeed translate to therapeutic options that
as cause of cancer-related mortality.1 Despite advances in               will benefit pancreatic cancer patients. It is now well es-
surgical and medical treatment, the 5-year survival rate                 tablished that invasive pancreatic cancer develops through
has remained less than 5%.2                                              stepwise tumor progression and it is therefore preceded
   The poor prognosis of pancreatic cancer is mainly be-                 by preinvasive stages amenable to curative treatment. The
cause the disease is almost always detected in a late stage,             precursor lesions of invasive pancreatic cancer are known
when advanced tumor growth exists and curative resec-                    as pancreatic intraepithelial neoplasia (PanIN) and the
tion is no longer possible. Surgery is the only option for               consecutive stages are morphologically well defined.6 Pan-
cure, but even when surgical resection is intended as a                  creatic intraepithelial neoplasias are not the only precur-
measure for complete removal of the malignancy, most                     sors of invasive pancreatic cancer: Intraductal papillary
patients will develop recurrence of the disease and will                 mucinous neoplasms and mucinous cystic neoplasms, for
die due to metastatic growth.3–5                                         example, are also preinvasive stages of carcinoma,7 but
   Early detection, at a stage when there is still an option             PanINs are the most common precursor of conventional
to cure, is at present the only way to improve the dismal                ductal adenocarcinomas of the pancreas, and they are the
                                                                         subject of this review. Pancreatic tumor progression is not
                                                                         only morphologically relatively well defined but many of
   Accepted for publication October 21, 2008.                            the molecular genetic alterations leading to pancreatic can-
   From the Department of Pathology, University Medical Center,
Utrecht, the Netherlands (Ms Ottenhof, Drs Milne, ten Kate, and Of-      cer are also known. Consecutive stages of tumor progres-
ferhaus, and Mr Morsink); the Department of Pathology, Onze Lieve        sion are accompanied by cumulative genetic disarray in
Vrouwe Gasthuis, Amsterdam, the Netherlands (Dr Drillenburg); and        which specific genetic alterations are the major players.8
the Department of Pathology, The Sol Goldman Pancreatic Research         These specific genetic abnormalities are potential markers
Center, The Johns Hopkins Medical Institution, Baltimore, Maryland (Dr   that enable early diagnosis and may become used to target
Maitra).                                                                 intervention. Finally, recent genetically engineered mouse
   The authors have no relevant financial interest in the products or
companies described in this article.
                                                                         models of pancreatic cancer recapitulate the human dis-
   Reprints: G. Johan Offerhaus MD, MPH, PhD, Department of Pa-          ease quite accurately and these transgenic mouse models
thology, University Medical Center, Heidelberglaan 100, 3584 CX          provide potentially interesting tools for translational re-
Utrecht, the Netherlands (e-mail: g.j.a.offerhaus@umcutrecht.nl).        search purposes.9
Arch Pathol Lab Med—Vol 133, March 2009                            PanIN and Pancreatic Tumorigenesis of Mice and Men—Ottenhof et al 375
                                                                            pancreatic carcinoma are also overexpressed in PanIN le-
                                                                            sions. Cyclin D1 overexpression is associated with a poor
                                                                            prognosis in pancreatic cancer.14 Nuclear cyclin D1 over-
                                                        
								
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