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What Is the Origin of Pancreatic Adenocarcinoma?

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What Is the Origin of Pancreatic Adenocarcinoma? University of Nebraska Medical Center DigitalCommons@UNMC Journal Articles: Biochemistry & Molecular Biology Biochemistry & Molecular Biology Winter 1-22-2013 What is the origin of pancreatic adenocarcinoma? Parviz M. Pour University of Nebraska Medical Center, [email protected] K. K. Panday University of Nebraska Medical Center Surinder K. Batra University of Nebraska Medical Center, [email protected] Follow this and additional works at: https://digitalcommons.unmc.edu/com_bio_articles Part of the Medical Biochemistry Commons, and the Medical Molecular Biology Commons Recommended Citation Pour, Parviz M.; Panday, K. K.; and Batra, Surinder K., "What is the origin of pancreatic adenocarcinoma?" (2013). Journal Articles: Biochemistry & Molecular Biology. 99. https://digitalcommons.unmc.edu/com_bio_articles/99 This Article is brought to you for free and open access by the Biochemistry & Molecular Biology at DigitalCommons@UNMC. It has been accepted for inclusion in Journal Articles: Biochemistry & Molecular Biology by an authorized administrator of DigitalCommons@UNMC. For more information, please contact [email protected]. Molecular Cancer Bio Med Central Review Open Access What is the origin of pancreatic adenocarcinoma? Parviz M Pour* 1,2, Krishan K Pandey 3 and Surinder K Batra 3 Address: 1The Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198 USA, 2Department of Pathology and Microbiology University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198, USA and 3Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198, USA Email: Parviz M Pour* - [email protected]; Krishan K Pandey - [email protected]; Surinder K Batra - [email protected] * Corresponding author Published: 22 January 2003 Received: 21 December 2002 Accepted: 22 January 2003 Molecular Cancer 2003, 2:13 This article is available from: http://www.molecular-cancer.com/content/2/1/13 © 2003 Pour et al; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Abstract The concept of pancreatic cancer origin is controversial. Acinar, ductal or islet cells have been hypothesized as the cell of origin. The pros and cons of each of these hypotheses are discussed. Based on the world literature and recent observations, pancreatic cells seem to have potential for phenotypical transdifferentiation, i.e ductal-islet, ductal-acinar, acinar-ductal, acinar-islet, islet- acinar and islet-ductal cells. Although the possibility is discussed that cancer may arise from either islet, ductal or acinar cells, the circumstances favoring the islet cells as the tumor cell origin include their greater transdifferentiation potency into both pancreatic and extrapancreatic cells, the presence of a variety of carcinogen-metabolizing enzymes, some of which are present exclusively in islet cells and the growth factor-rich environment of islets. Introduction There is accumulating evidence that most pancreatic tu- The complex cellular structure of the pancreas composed mors originate from within islets by islet cell transdiffer- of various exocrine and endocrine cells hampers a clear entiation and that pancreatic islet cells play a significant understanding of the origin of pancreatic ductal-type ade- role in the neoplastic process. There are also observations nocarcinoma. During the embryonic development of the that favor that the ductal cells are the source of cancer pancreas all exocrine and endocrine cells are derived from cells. To better understand the neoplastic process in the the common precursor cells, the stem cells. It is believed pancreas, some anatomic-physiological aspects of the tis- that these stem cells are retained in the adult pancreas and sue should be considered. are the foundation for cell renewal and tumors; however, this claim has remained illusive. Recent studies pointing Review to the enormous plasticity of each type of pancreatic cell Interaction between the exocrine and endocrine cells in changing their phenotype from one type to another It is estimated that the exocrine cells contribute to over (i.e., transdifferentiation) makes the identification of tu- 95% (acinar cells 85%, ductal cells 10%) of the volume of mor cell origin more complex. The islet-ductal, acinar- the pancreas, whereas the endocrine cells are believed to ductal, ductal-islet cell transdifferentiation in purified cell occupy only 1–2% of the pancreatic volume in adults. populations [1–6] and in vivo [7–10] has been observed. Clearly, this estimation is misleading as it does not con- Consequently, all pancreatic cells could be considered as sider the number of individual cell types. When the size of a potential facultative stem cell. the cells is disregarded, the figures would be significantly different. The circular three-dimensional shape of the is- lets composed of relatively small, closely packed cells Page 1 of 10 (page number not for citation purposes) Molecular Cancer 2003, 2 http://www.molecular-cancer.com/content/2/1/13 causes underestimation of their numbers in histological ence of the xenobiotic enzymes in the islets is self sections. Considering the diffuse distribution of the islets, explanatory, as in humans and other mammalian species, accounting for about one islet per 1.1 mm 2 of the tissue part of the arterial blood passes through the islets before [11], and the presence of a large number of a single or nourishing the exocrine pancreas [23–27]. small group of islet cells scattered throughout the pancre- as and within the ductal epithelium it appears that there Evidence for the derivation of tumors from islet cells are as many islet cells as acinar cells. The same applies to Experimental data ductal cells, as the calculation does not consider the often- The following observations support the unequivocal role invisible centroacinar cells that are the components of of !-cells in transdifferentiation and, thus the carcinogen- ducts. According to our observation, within an acinus esis process: 1) Experimentally, the first histological alter- there are as many centroacinar cells as acinar cells. In our ations are the appearance of intrainsular ductular view, centroacinar cells are as multipotential as islet cells structures showing different stages of progression from and can give rise to islet cells, acinar cells and tumor cells normal to malignant pattern. These lesions are initially [12]. confined within the islet boundary and are sharply demar- cated from the surrounding tissue (Fig. 1a,1b,1c). 2) The The tight functional and physical interaction between the pretreatment of hamsters with streptozotocin, which se- endocrine and exocrine cells have been well established lectively destroys !-cells, inhibits the pancreatic tumori- but not sufficiently investigated. The necessary coopera- genesis [28]; 3) Genetically diabetic hamsters with tion between the endocrine and exocrine cells well ex- depleted !-cells are resistant to the pancreatic carcinogen- plains the plasticity of the pancreas to adjust to the ic effect of N-nitrosobis(2-oxopropyl)amine (BOP), internal demands and external stimuli. Hence, each type whereas the pancreas of a non-diabetic strain with intact of pancreatic cells has the ability to provide a function !-cells is not [29]; 4) Stimulation of !-cell neogenesis (ne- that is dictated by the physiological demand in an organ- sidioblastosis) enhances pancreatic carcinogenicity of ized fashion. Islet cells seem to be the frontrunner of the BOP [30]; 5) Transplantation of homologous islets into organization system. the submandibular gland (a non-target tissue of BOP) of hamsters and the subsequent BOP treatment of the recip- Islet cells, the gatekeeper of the pancreas ient hamsters results in the development of ductal-type The diffuse distribution of islet cells throughout the pan- adenocarcinomas in the areas of transplanted islets creas either in the form of aggregate (islet) and single or [31,32]. Histological findings point to the development of small group of islets indicate their important function. malignant glands in the center of islets, the exclusive po- They seem to control the flow of pancreatic exocrine and sition of !-cells in hamsters; 6) Malignant transformation exocrine function as reflected by their unique ability for of freshly isolated hamster pancreatic islets by BOP in vitro transformation to every pancreatic and some extrapancre- [33]. Although the treatment of cultured hamster pancre- atic cell type [1–8]. The controlling effect of islet cells on atic ductal cells also led to the formation of ductal adeno- the exocrine tissue is also highlighted by the presence of carcinomas [34] these tumors, contrary to those derived endocrine cells within the normal, hyperplastic and ma- from islet cells [33], did not show the mutation of the c- lignant ductal epithelium, in both humans and animals K- ras oncogene [35], the most common genetic abnor- [13–17]. Another extremely important function of the is- mality in human pancreatic adenocarcinomas [36,37]. let cells, not similarly shared by other pancreatic cells, is Additionally, only the cultured islets cells treated with the defensive strategy provided by drug-metabolizing en- BOP showed an inactivation of the p16 (INK4a) gene (ho- zymes. Among
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