Summary
Background. The histogenesis of pancreatic cancer is still debatable. Ductal, ductular, and acinar cells all have been declared the tumor progenitor cells. Our long-term human and experimental studies indicate that pancreatic ductal adenocarcinomas arise within ductal cells and islets. Supporting studies are presented in this article.
Methods. Several human studies and experimental studies on Syrian hamsters conducted within the last 20 years were used in this article. Hamster and human islets were established, and their growth and morphologic changes were examined electron microscopically, immunohistochemically, cytogenetically, and molecular biologically.
Results. Studies using the hamster pancreatic cancer model showed that most pancreatic adenocarcinomas develop within islets, most probably from stem cells, which are also believed to be the progenitor cells for tumors that develop within ducts. Studies in newly established human and hamster islets culture validated the immense potential of islet cells to differentiate and become malignant. The higher susceptibility of islet cells to become malignant could be related to their high drug-metabolizing enzymes and their high proliferation rate. Dietary studies indicate that the promoting effect of a high-fat diet on pancreatic carcinogenesis is unrelated to the energy intake, but rather is related to its effect on islet cell replication.
Conclusion. Experimental and human studies during 20 years of research in our laboratories point to the importance of pancreatic islets in the development of ductal-type adenocarcinomas. We believe that pancreatic cancer that develops within ducts, but more frequently within islets, derives from pancreatic stem cells that are distributed within the ductal trees and within the islets
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References
American Cancer Society. Cancer incidence. CA: A Cancer Journal for Clinicians 1982–1997.
Longnecker DS, Shinozuka H, Dekker A. Focal acinar cell dysplasi in human pancreas. Cancer 1980; 45: 534–540.
Egami H, Takiyama Y, Chaney WG, Cano M, Fujii H, Tomioka T, et al. Comparative studies on expression of tumor-associated antigens in human and induced pancreatic cancer in Syrian hamsters. Int J Pancreatol 1990; 7: 91–100.
Takiyama Y, Egami H, Pour PM. Expression of human tumor-associated antigens in pancreatic cancer induced in Syrian hamsters. Am J Pathol 1990; 136: 707–715.
Fujii HH, Egami H, Chaney W, Pour P, Pelling J. Pancreatic ductal adenocarcinomas induced in Syrian hamsters by N-nitrosobis(2-oxopropy)amine contain a K-ras oncogene with a point-mutated codon 12. Mol Carcinog 1990; 3: 296–301.
Pour PM, Wilson, R. Experimental pancreas tumor, in: Moossa AR, ed. Cancer of the Pancreas. Williams and Wilkins, Baltimore, 1980; pp. 37–158.
Pour PM. Experimental pancreatic cancer. Am J Surg Pathol 1989; 13: 96–103.
Mogaki M, Hirota M, Chaney WG, Pour PM. Comparison of p53 protein expression and cellular localization in human and hamster pancreatic cell lines. Carcinogenesis 1993; 14: 2589–2594.
Pour P, Mohr U, Cardesa A, Althoff J, Krüger FW. Pancreatic neoplasms in an animal model: morphological, biological, and comparative studies. Cancer 1975; 36: 379–389.
Pour PM, Egami H, Takiyama Y. Patterns of growth and metastases of induced pancreatic cancer in relation to the prognosis and its clinical implications. Gastroenterology 1991; 100: 529–536.
Pour, PM. Islet cells as a component of pancreatic ductal neoplasms. I. Experimental study. Ductular cells, including islet cell precursors, and primary progenitor cells of tumors. Am J Pathol 1978; 90: 295–316.
Pour PM, Runge RG, Birt D, Gingell R, Lawson T, Nagel D, et al. Current knowledge of pancreatic carcinogenesis in the hamster and its relevance to the human disease. Cancer 1981; 47: 1573–1589.
Pour, PM. Histogenesis of exocrine pancreatic cancer in the hamster model. Environ Health Perspect 1984; 56: 229–243.
Pour PM, Weide L, Liu G, Kazakoff K, Scheetz M, Toshkov RS, et al. Experimental evidence for the origin of ductal type adenocarcinoma from the islets of Langerhans. Am J Pathol 1997; 150: 2167–2180.
Pour PM. The role of Langerhans islets in pancreatic ductal adenocarcinoma. Frontier Biosci 1997; 2: d271–282.
Fienhold MA, Kazakoff K, Pour PM. The effect of Streptozotocin and high-fat diet on BOP-induced tumors in the pancreas and in the submandibular gland of hamsters bearing transplants of homologous islets. Cancer Let 1997; 117: 155–160.
Pour PM, Sayed SE, Wolf GL. Considerations on the incidence of pancreatic cancer. Cancer Lett 1980; 10: 151–154.
Pour PM, Sayed S, Sayed G, Wolf GL. Hyperplastic preneoplastic and neoplastic lesions found in 83 human pancreas. Am J Clin Pathol 1982; 77: 137–152.
Pour PM, Sayed S, Sayed G, Wolf GL. Exocrine pancreas alterations and related neoplasia in selected autopsy material. Eur J Cancer Clin Oncol 1981; 17: 943.
Pour P, Salmasi SZ. Ductular origin of pancreatic cancer and its multiplicity in man comparable to experimentally induced tumors. A preliminary study. Cancer Lett 1979; 6: 89–97.
Tomioka T, Andrén-Sandberg A, Fujii H, Egami H, Takiyama Y, Pour PM. Comparative histopathological findings in the pancreas of cigarette smokers and nonsmokers. Cancer Lett 1990; 55: 121–128.
Kimura W, Morikane K, Esaki Y, Chan WC, Pour PM. Histological and biological patterns of microscopic ductal adenocarcinomas detected incidentally at autopsy. Cancer 1998; 82: 1839–1849.
Pour PM, Morohoshi T. Ductal adenocarcinoma, in: Atlas of Exocrine Pancreatic Tumors. Morphology, Biology and Diagnosis with an International Guide for Tumor Classification. Springer Verlag, Japan, 1994; pp 117–154.
Bell RH, McCullough PJ, Pour PM. Influence of diabetes on susceptibility to experimental pancreatic cancer. Am J Surg 1988; 155: 159–164.
Bell RH, Sayers HJ, Pour PM, Ray MB, McCullough PJ. Importance of diabetes in inhibition of pancreatic cancer by streptozotocin. J Surg Res 1989; 46: 515–519.
Pour PM, Kazakoff K, Carlson K. Inhibition of Streptozotocin-induced islet cell tumors and BOP-induced exogenous pancreatic tumors in Syrian hamsters. Cancer Res 1990; 50: 1634–1639.
Bell RH, Pour PM. Induction of pancreatic tumors in genetically non-diabetic but not in diabetic Chinese hamsters. Cancer Lett 1987; 34: 221–230.
Pour PM, Kazakoff K. Stimulation of islet cell proliferation enhances pancreatic ductal carcinogenesis in the hamster model. Am J Pathol 1996; 149: 1017–1025.
Pour PM, Weide LG, Ueno K, Corra S, Kazakoff K. Submandibular gland as a site for islet transplantation. Int J Pancreatol 1992; 12: 187–191.
Pour PM, Weide L, Liu G, Kazakoff K, Scheetz M, Toshkov I, et al. Experimental evidence for the origin of ductal type adenocarcinoma from the islets of Langerhans. Am J Pathol 1997; 150: 2167–2180.
Fienhold MA, Kazakoff K, Pour PM. The effect of streptozotocin and a high-fat diet on BOP-induced tumors in the pancreas and in the submandibular gland of hamsters bearing transplants of homologous islets. Cancer Lett 1997; 117: 155–160.
Bouwens L, De Blay E. Islet morphogenesis and stem cell markers in rat pancreas. J Histochem Cytochem 1996; 44: 947–951.
Guz Y, Montminy MR, Stein R, Leonard J, Gamer LW, Wright CVE, et al. Expression of STF1, a putative insulin gene transcription factor, in b-cells of pancreas, duodenal epithelium and pancreatic exocrine and endocrine progenitors during ontogeny. Development (Cambridge, UK) 1995; 121: 11–18.
Jensen J, Serup P, Karlsen C, Funder TF, Madsen OD. mRNA profiling of rat islet tumors reveals Nkx 6.1 as a β-cell specific homeodomain transcription factor. J Biol Chem 1996; 271: 18,749–18,758.
Jonsson J, Carlsson L, Edlund T, Edlund H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 1994; 371: 606–609.
Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, et al. Pdx-1 is required for pancreatic outgrowth and differentiation of rostral duodenum. Development 1996; 122: 983–995.
Ohlsson H, Karlsson K, Edlund T. IDX-1, a homeodomain-containing transactivator of the insulin gene. EMBO J 1993; 12: 4251–4259.
Serup P, Petersen HV, Petersen EE, Edlund H, Leonard J, Petersen JS, et al. Homeodomain protein IDX-1/STF1 is expressed in a subset of islet cells and promotes rat insulin 1 gene expression dependent on an intact E1 helixloop-helix factor binding site. Biochem J 1995; 310: 997–1003.
Schmied B, Liu G, Moyer MP, Hernberg ISB, Sanger W, Batra S, et al. Induction of adenocarcinoma from hameter pancreatic islet cells treated with N-nitrosobis(2-oxopropyl)amine in vitro. Carcinogenesis, 1999; 20: 317–324.
Wacke R, Kirchner A, Prall F, Nizze H, Schmidt W, Fisher W, et al. Up-regulation of cytochrome P450 1A2, 2C9, and 2E1 in chronic pancreatitis. Pancreas 1998; 16: 521–528.
Foster JR, Idle JR, Hardwick JP, Bars R, Scott P, Braganza JM. Induction of drug-metabolizing enzymes in human pancreatic cancer and chronic pancreatitis. J Pathol 1993; 169: 457–463.
Birt DF, Salmasi S, Pour PM. Enhancement of experimental pancreatic cancer in Syrian golden hamsters by dietary fat. J Natl Cancer Inst 1981; 67: 1327–1332.
Kazakoff K, Cardesa T, Liu J, Adrian TE, Bagchi D, Bagchi M, et al. Effects of voluntary physical exercise on high-fat diet-promoted pancreatic carcinogenesis in the hamster model. Nutr Cancer 1996; 26: 265–279.
Birt D, Pour PM, Nagel DL, Barnett T, Blackwood D, Duysen E. Dietary energy restriction does not inhibit pancreatic carcinogenesis by N-nitrosobis(2-oxopropyl)amine in the Syrian hamster. Carcinogenesis 1997; 18: 2107–2111.
Yamao K, Nakazawa S, Fujimoto M, Yamada M, Milchgrub S, Albores-Saavedra J. Intraductal papillary mucinous tumors, non-invasive and invasive. In: Pour P, Konishi Y, Klöppel G, Longnecker DS, eds. Atlas of Exocrine Pancreatic Tumors. Morphology, Biology and Diagnosis with an International Guide for Tumor Classification. Springer Verlag, Japan, 1994; pp 117–154.
Dawiskiba S, Pour PM, Stenram U, Sundler F, Andrén-Sandberg A. Immunohistochemical characterization and endocrine cells in experimental exocrine pancreatic cancer in the Syrian golden hamster. Int J Pancreatol 1992; 11: 87–96.
Pour PM, Permert J, Mogaki M, Fujii H, Kazakoff K. Endocrine aspects of exocrine cancer of the pancreas. Their patterns and suggested biological significance. Am J Clin Pathol 1993; 100: 223–230.
Reid JD, Yuh S-L, Petrelli M, Jaffe MB. Ductuloinsular tumors of the pancreas. Cancer 1982; 49: 908–915.
Schlosnagle DC, Campbell WG. The papillary and solid neoplasm of the pancreas: A report of two cases with electron microscopy, one containing neurosecretory granules. Cancer 1981; 47(11): 2603–2610.
Eusebi V, Capella C, Bondi A, Sessa F, Vezzadinia P, Mancini AM. Endocrine-paracrine cells in pancreatic exocrine carcinomas. Histopathology 1981; 5: 599–613.
Cubilla AL, Fitzgerald PJ. Tumors of the Exocrine Pancreas. Atlas of Tumor Pathology, 2nd Series, Fascicle 19. Armed Forces Institute, Washington DC, 1982.
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Pour, P.M., Schmied, B. The link between exocrine pancreatic cancer and the endocrine pancreas. International Journal of Pancreatology 25, 77–87 (1999). https://doi.org/10.1385/IJGC:25:2:77
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DOI: https://doi.org/10.1385/IJGC:25:2:77