Histogenesis of pancreatic carcinogenesis in the hamster: ultrastructural evidence (original) (raw)

Abstract

Pancreatic carcinogenesis in the Syrian hamster, induced by beta-oxidized derivatives of N-nitroso-di-n-propylamine, constitutes a valuable model of human cancer of the exocrine pancreas. In both species the majority of tumors are adenocarcinomas: superficially, on the basis of their histological appearance, these appear to be ductal in origin. However, sequential analysis, by electron microscopy, of the development of pancreatic neoplasia in the hamster model indicates that acinar cells may participate in the histogenesis of "ductal" adenomas and carcinomas. Acinar cells appear to undergo changes in differentiation, including pseudoductular transformation, giving rise to a new population of cells that resemble ductular or centroacinar types. This new population may then proliferate to form, first, cystic foci and subsequently cystadenomas and adenocarcinomas. Mucous metaplasia appears to develop at late stages of tumor development. Although the participation of ductular and centroacinar cells in pancreatic carcinogenesis cannot be excluded, very few tumors arise from the ductal epithelium. It is possible that some human pancreatic adenocarcinomas may also have their origin from dysplastic acinar cells, by analogy with the hamster model: focal acinar dysplasia being common in human pancreatic cancer patients.

187

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Althoff J., Pour P., Malick L., Wilson R. B. Pancreatic neoplasms induced in Syrian golden hamsters. I. Scanning electron microscopic observations. Am J Pathol. 1976 Jun;83(3):517–530. [PMC free article] [PubMed] [Google Scholar]
  2. Baylor S. M., Berg J. W. Cross-classification and survival characteristics of 5,000 cases of cancer of the pancreas. J Surg Oncol. 1973;5(4):335–358. doi: 10.1002/jso.2930050410. [DOI] [PubMed] [Google Scholar]
  3. Bockman D. E. Anastomosing tubular arrangement of the exocrine pancreas. Am J Anat. 1976 Sep;147(1):113–118. doi: 10.1002/aja.1001470111. [DOI] [PubMed] [Google Scholar]
  4. Bockman D. E., Black O., Jr, Mills L. R., Mainz D. L., Webster P. D., 3rd Fine structure of pancreatic adenocarcinoma induced in rats by 7,12-dimethylbenz(a)anthracene. J Natl Cancer Inst. 1976 Oct;57(4):931–936. doi: 10.1093/jnci/57.4.931. [DOI] [PubMed] [Google Scholar]
  5. Bockman D. E., Black O., Jr, Mills L. R., Webster P. D. Origin of tubular complexes developing during induction of pancreatic adenocarcinoma by 7,12-dimethylbenz(a)anthracene. Am J Pathol. 1978 Mar;90(3):645–658. [PMC free article] [PubMed] [Google Scholar]
  6. Bockman D. E. Cells of origin of pancreatic cancer: experimental animal tumors related to human pancreas. Cancer. 1981 Mar 15;47(6 Suppl):1528–1534. doi: 10.1002/1097-0142(19810315)47:6+<1528::aid-cncr2820471415>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  7. Boquist L., Edström C. Ultrastructure of pancreatic acinar and islet parenchyma in rats at various intervals after duct ligation. Virchows Arch A Pathol Pathol Anat. 1970;349(1):69–79. doi: 10.1007/BF00548522. [DOI] [PubMed] [Google Scholar]
  8. Burns W. A., Matthews M. J., Hamosh M., Weide G. V., Blum R., Johnson F. B. Lipase-secreting acinar cell carcinoma of the pancreas with polyarthropathy. A light and electron microscopic, histochemical, and biochemical study. Cancer. 1974 Apr;33(4):1002–1009. doi: 10.1002/1097-0142(197404)33:4<1002::aid-cncr2820330415>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  9. Cantrell B. B., Cubilla A. L., Erlandson R. A., Fortner J., Fitzgerald P. J. Acinar cell cystadenocarcinoma of human pancreas. Cancer. 1981 Jan 15;47(2):410–416. doi: 10.1002/1097-0142(19810115)47:2<410::aid-cncr2820470232>3.0.co;2-d. [DOI] [PubMed] [Google Scholar]
  10. Cubilla A. L., Fitzgerald P. J. Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res. 1976 Jul;36(7 Pt 2):2690–2698. [PubMed] [Google Scholar]
  11. Cubilla A. L., Fitzgerald P. J. Morphological patterns of primary nonendocrine human pancreas carcinoma. Cancer Res. 1975 Aug;35(8):2234–2248. [PubMed] [Google Scholar]
  12. Devesa S. S., Silverman D. T. Cancer incidence and mortality trends in the United States: 1935-74. J Natl Cancer Inst. 1978 Mar;60(3):545–571. doi: 10.1093/jnci/60.3.545. [DOI] [PubMed] [Google Scholar]
  13. Dissin J., Mills L. R., Mains D. L., Black O., Jr, Webster P. D., 3rd Experimental induction of pancreatic adenocarcinoma in rats. J Natl Cancer Inst. 1975 Oct;55(4):857–864. doi: 10.1093/jnci/55.4.857. [DOI] [PubMed] [Google Scholar]
  14. Druckrey H., Ivankovic S., Bücheler J., Preussmann R., Thomas C. Erzeugung von Magen- und Pankreas-Krebs beim Meerschweinchen durch Methylnitroso-harnstoff und -urethan. Z Krebsforsch. 1968;71(2):167–182. [PubMed] [Google Scholar]
  15. Flaks A., Moore M. A., Flaks B. Ultrastructural analysis of pancreatic carcinogenesis. II. Establishment and morphology of a transplantable hamster pancreatic adenocarcinoma, FCP. Carcinogenesis. 1980 Jun;1(6):513–522. doi: 10.1093/carcin/1.6.513. [DOI] [PubMed] [Google Scholar]
  16. Flaks B., Moore M. A., Flaks A. Ultrastructural analysis of pancreatic carcinogenesis. III. Multifocal cystic lesions induced by N-nitroso-bis(2-hydroxypropyl)amine in the hamster exocrine pancreas. Carcinogenesis. 1980 Aug;1(8):693–706. doi: 10.1093/carcin/1.8.693. [DOI] [PubMed] [Google Scholar]
  17. Flaks B., Moore M. A., Flaks A. Ultrastructural analysis of pancreatic carcinogenesis. IV. Pseudoductular transformation of acini in the hamster pancreas during N-nitroso-bis(2-hydroxypropyl)amine carcinogenesis. Carcinogenesis. 1981;2(12):1241–1253. doi: 10.1093/carcin/2.12.1241. [DOI] [PubMed] [Google Scholar]
  18. Flaks B., Moore M. A., Flaks A. Ultrastructural analysis of pancreatic carcinogenesis. V. Changes in differentiation of acinar cells during chronic treatment with N-nitrosobis(2-hydroxypropyl)amine. Carcinogenesis. 1982;3(5):485–498. doi: 10.1093/carcin/3.5.485. [DOI] [PubMed] [Google Scholar]
  19. Flaks B., Moore M. A., Flaks A. Ultrastructural analysis of pancreatic carcinogenesis. VI. Early changes in hamster acinar cells induced by N-nitroso-bis(2-hydroxypropyl)amine. Carcinogenesis. 1982;3(9):1063–1070. doi: 10.1093/carcin/3.9.1063. [DOI] [PubMed] [Google Scholar]
  20. Flaks B., Moore M. A., Flaks A. Ultrastructural analysis of pancreatic carcinogenesis: morphological characterization of N-nitroso-bis(2-hydroxypropyl)amine-induced neoplasms in the Syrian hamster. Carcinogenesis. 1980 May;1(5):423–438. doi: 10.1093/carcin/1.5.423. [DOI] [PubMed] [Google Scholar]
  21. HAMMOND E. C. Trends in cancer death rates and cure rates. Ann Intern Med. 1959 Feb;50(2):300–312. doi: 10.7326/0003-4819-50-2-300. [DOI] [PubMed] [Google Scholar]
  22. HERMAN L., FITZGERALD P. J. The degenerative changes in pancreatic acinar cells caused by DL-ethionine. J Cell Biol. 1962 Feb;12:277–296. doi: 10.1083/jcb.12.2.277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Haenszel W., Kurihara M. Studies of Japanese migrants. I. Mortality from cancer and other diseases among Japanese in the United States. J Natl Cancer Inst. 1968 Jan;40(1):43–68. [PubMed] [Google Scholar]
  24. Hayashi Y., Hasegawa T. Experimental pancreatic tumor in rats after intravenous injection of 4-hydroxyaminoquinoline 1-oxide. Gan. 1971 Aug;62(4):329–330. [PubMed] [Google Scholar]
  25. Kakudo K., Sakurai M., Miyaji T., Ikeda Y., Satani M., Manabe H. Pancreatic carcinoma in infancy. An electron microscopic study. Acta Pathol Jpn. 1976 Nov;26(6):719–726. doi: 10.1111/j.1440-1827.1976.tb00527.x. [DOI] [PubMed] [Google Scholar]
  26. Krain L. S. The rising incidence of carcinoma of the pancreas. An epidemiologic appraisal. Am J Gastroenterol. 1970 Nov;54(5):500–507. [PubMed] [Google Scholar]
  27. Krüger F. W., Pour P., Althoff J. Induction of pancreas tumours by di-isopropanolnitrosamine. Naturwissenschaften. 1974 Jul;61(7):328–328. doi: 10.1007/BF00599567. [DOI] [PubMed] [Google Scholar]
  28. LEACH W. B. Carcinoma of the pancreas; a clinical and pathologic analysis of 39 autopsied cases. Am J Pathol. 1950 Mar;26(2):333–347. [PMC free article] [PubMed] [Google Scholar]
  29. Levin D. L., Connelly R. R. Cancer of the pancreas. Available epidemiologic information and its implications. Cancer. 1973 May;31(5):1231–1236. doi: 10.1002/1097-0142(197305)31:5<1231::aid-cncr2820310529>3.0.co;2-c. [DOI] [PubMed] [Google Scholar]
  30. Levin D. L., Connelly R. R., Devesa S. S. Demographic characteristics of cancer of the pancreas: mortality, incidence, and survival. Cancer. 1981 Mar 15;47(6 Suppl):1456–1468. doi: 10.1002/1097-0142(19810315)47:6+<1456::aid-cncr2820471404>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  31. Levitt M. H., Harris C. C., Squire R., Springer S., Wenk M., Mollelo C., Thomas D., Kingsbury E., Newkirk C. Experimental pancreatic carcinogenesis. I. Morphogenesis of pancreatic adenocarcinoma in the Syrian golden hamster induced by N-nitroso-bis(2-hydroxypropyl)amine. Am J Pathol. 1977 Jul;88(1):5–28. [PMC free article] [PubMed] [Google Scholar]
  32. Levitt M., Harris C., Squire R., Wenk M., Mollelo C., Springer S. Experimental pancreatic carcinogenesis. II. Lifetime carcinogenesis studies in the outbred Syrian golden hamster with N-nitroso-bis(2-hydroxypropyl)amine. J Natl Cancer Inst. 1978 Mar;60(3):701–705. doi: 10.1093/jnci/60.3.701. [DOI] [PubMed] [Google Scholar]
  33. Li F. P., Fraumeni J. F., Jr, Mantel N., Miller R. W. Cancer mortality among chemists. J Natl Cancer Inst. 1969 Nov;43(5):1159–1164. [PubMed] [Google Scholar]
  34. Longnecker D. S. Animal model of human disease. Carcinoma of the pancreas in azaserine-treated rats. Am J Pathol. 1981 Oct;105(1):94–96. [PMC free article] [PubMed] [Google Scholar]
  35. Longnecker D. S., Crawford B. G. Hyperplastic nodules and adenomas of exocrine pancreas in azaserine-treated rats. J Natl Cancer Inst. 1974 Aug;53(2):573–577. doi: 10.1093/jnci/53.2.573. [DOI] [PubMed] [Google Scholar]
  36. Longnecker D. S., Curphey T. J. Adenocarcinoma of the pancreas in azaserine-treated rats. Cancer Res. 1975 Aug;35(8):2249–2258. [PubMed] [Google Scholar]
  37. Longnecker D. S., Hashida Y., Shinozuka H. Relationship of age to prevalence of focal acinar cell dysplasia in the human pancreas. J Natl Cancer Inst. 1980 Jul;65(1):63–66. [PubMed] [Google Scholar]
  38. Longnecker D. S., Roebuck B. D., Yager J. D., Jr, Lilja H. S., Siegmund B. Pancreatic carcinoma in azaserine-treated rats: induction, classification and dietary modulation of incidence. Cancer. 1981 Mar 15;47(6 Suppl):1562–1572. doi: 10.1002/1097-0142(19810315)47:6+<1562::aid-cncr2820471419>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  39. Longnecker D. S., Shinozuka H., Dekker A. Focal acinar cell dysplasia in human pancreas. Cancer. 1980 Feb;45(3):534–540. doi: 10.1002/1097-0142(19800201)45:3<534::aid-cncr2820450320>3.0.co;2-g. [DOI] [PubMed] [Google Scholar]
  40. Macdonald J. S., Widerlite L., Schein P. S. Current diagnosis and management of pancreatic carcinoma. J Natl Cancer Inst. 1976 Jun;56(6):1093–1099. doi: 10.1093/jnci/56.6.1093. [DOI] [PubMed] [Google Scholar]
  41. Mack T. M., Paganini-Hill A. Epidemiology of pancreas cancer in Los Angeles. Cancer. 1981 Mar 15;47(6 Suppl):1474–1484. doi: 10.1002/1097-0142(19810315)47:6+<1474::aid-cncr2820471406>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  42. Mainz D., Webster P. D., 3rd Pancreatic carcinoma. A review of etiologic considerations. Am J Dig Dis. 1974 May;19(5):459–464. doi: 10.1007/BF01255609. [DOI] [PubMed] [Google Scholar]
  43. Milham S., Jr Cancer mortality pattern associated with exposure to metals. Ann N Y Acad Sci. 1976;271:243–249. doi: 10.1111/j.1749-6632.1976.tb23118.x. [DOI] [PubMed] [Google Scholar]
  44. Mirvish S. S. N-nitroso compounds: their chemical and in vivo formation and possible importance as environmental carcinogens. J Toxicol Environ Health. 1977 Jul;2(6):1267–1277. doi: 10.1080/15287397709529529. [DOI] [PubMed] [Google Scholar]
  45. Mohr U., Reznik G., Emminger E., Lijinsky W. Induction of pancreatic duct of carcinomas in the Syrian hamster with 2,6-dimethylnitrosomorpholine. J Natl Cancer Inst. 1977 Feb;58(2):429–432. doi: 10.1093/jnci/58.2.429. [DOI] [PubMed] [Google Scholar]
  46. Moore M. A., Takahashi M., Ito N., Bannasch P. Early lesions during pancreatic carcinogenesis induced in Syrian hamster by DHPN or DOPN. I. Histologic, histochemical and radioautographic findings. Carcinogenesis. 1983;4(4):431–437. doi: 10.1093/carcin/4.4.431. [DOI] [PubMed] [Google Scholar]
  47. Moore M. A., Takahashi M., Ito N., Bannasch P. Early lesions during pancreatic carcinogenesis induced in the Syrian hamster by DHPN or DOPN. II. Ultrastructural findings. Carcinogenesis. 1983;4(4):439–448. doi: 10.1093/carcin/4.4.439. [DOI] [PubMed] [Google Scholar]
  48. Pour P. M., Runge R. G., Birt D., Gingell R., Lawson T., Nagel D., Wallcave L., Salmasi S. Z. Current knowledge of pancreatic carcinogenesis in the hamster and its relevance to the human disease. Cancer. 1981 Mar 15;47(6 Suppl):1573–1589. doi: 10.1002/1097-0142(19810315)47:6+<1573::aid-cncr2820471420>3.0.co;2-k. [DOI] [PubMed] [Google Scholar]
  49. Pour P., Althoff J., Gingell R., Kupper R., Krüger F., Mohr U. N-nitroso-bis(2-acetoxypropyl)amine as a further pancreatic carcinogen in Syrian golden hamsters. Cancer Res. 1976 Aug;36(8):2877–2884. [PubMed] [Google Scholar]
  50. Pour P., Althoff J., Krüger F. W., Mohr U. A potent pancreatic carcinogen in Syrian hamsters: N-nitrosobis(2-oxopropyl)amine. J Natl Cancer Inst. 1977 May;58(5):1449–1453. doi: 10.1093/jnci/58.5.1449. [DOI] [PubMed] [Google Scholar]
  51. Pour P., Althoff J., Takahashi M. Early lesions of pancreatic ductal carcinoma in the hamster model. Am J Pathol. 1977 Aug;88(2):291–308. [PMC free article] [PubMed] [Google Scholar]
  52. Pour P. Islet cells as a component of pancreatic ductal neoplasms. I. Experimental study: ductular cells, including islet cell precursors, as primary progenitor cells of tumors. Am J Pathol. 1978 Feb;90(2):295–316. [PMC free article] [PubMed] [Google Scholar]
  53. Pour P., Krüger F. W., Althoff J., Cardesa A., Mohr U. A new approach for induction of pancreatic neoplasms. Cancer Res. 1975 Aug;35(8):2259–2268. [PubMed] [Google Scholar]
  54. Pour P., Krüger F. W., Althoff J., Cardesa A., Mohr U. Cancer of the pancreas induced in the Syrian golden hamster. Am J Pathol. 1974 Aug;76(2):349–358. [PMC free article] [PubMed] [Google Scholar]
  55. Pour P., Krüger F. W., Althoff J., Cardesa A., Mohr U. Effect of beta-oxidized nitrosamines on syrian hamsters. III. 2,2'-Dihydroxydi-n-propylnitrosamine. J Natl Cancer Inst. 1975 Jan;54(1):141–146. doi: 10.1093/jnci/54.1.141. [DOI] [PubMed] [Google Scholar]
  56. Pour P., Mohr U., Cardesa A., Althoff J., Krüger F. W. Pancreatic neoplasms in an animal model: morphological, biological, and comparative studies. Cancer. 1975 Aug;36(2):379–389. doi: 10.1002/1097-0142(197508)36:2<379::aid-cncr2820360213>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  57. Pour P., Salmasi S. Z., Runge R. G. Ductular origin of pancreatic cancer and its multiplicity in man comparable to experimentally induced tumors. A preliminary study. Cancer Lett. 1979 Feb;6(2):89–97. doi: 10.1016/s0304-3835(79)80006-3. [DOI] [PubMed] [Google Scholar]
  58. Rao M. S., Reddy J. K. Histogenesis of pseudo-ductular changes induced in the pancreas of guinea pigs treated with N-methyl-N-nitrosourea. Carcinogenesis. 1980;1(12):1027–1037. doi: 10.1093/carcin/1.12.1027. [DOI] [PubMed] [Google Scholar]
  59. Reddy J. K., Rao M. S. Malignant tumors in rats fed nafenopin, a hepatic peroxisome proliferator. J Natl Cancer Inst. 1977 Dec;59(6):1645–1650. doi: 10.1093/jnci/59.6.1645. [DOI] [PubMed] [Google Scholar]
  60. Reddy J. K., Rao M. S. Pancreatic adenocarcinoma in inbred guinea pigs induced by n-methyl-N-nitrosourea. Cancer Res. 1975 Aug;35(8):2269–2277. [PubMed] [Google Scholar]
  61. Reddy J. K., Svoboda D. J., Rao M. S. Susceptibility of an ibred strain of guinea pigs to the induction of pancreatic adenocarcinoma by N-methyl-N-nitrosourea. J Natl Cancer Inst. 1974 Mar;52(3):991–993. doi: 10.1093/jnci/52.3.991. [DOI] [PubMed] [Google Scholar]
  62. Roberts P. F., Burns J. A histochemical study of mucins in normal and neoplastic human pancreatic tissue. J Pathol. 1972 Jun;107(2):87–94. doi: 10.1002/path.1711070203. [DOI] [PubMed] [Google Scholar]
  63. SOMMERS S. C., MEISSNER W. A. Unusual carcinomas of the pancreas. AMA Arch Pathol. 1954 Aug;58(2):101–111. [PubMed] [Google Scholar]
  64. Scarpelli D. G., Rao M. S. Early changes in regenerating hamster pancreas following a single dose of N-nitrosobis (2-oxopropyl)amine (NBOP) administered at the peak of DNA synthesis. Cancer. 1981 Mar 15;47(6 Suppl):1552–1561. doi: 10.1002/1097-0142(19810315)47:6+<1552::aid-cncr2820471418>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  65. Scarpelli D. G., Rao M. S. Transplantable ductal adenocarcinoma of the Syrian hamster pancreas. Cancer Res. 1979 Feb;39(2 Pt 1):452–458. [PubMed] [Google Scholar]
  66. Shinozuka H., Lee R. E., Dunn J. L., Longnecker D. S. Multiple atypical acinar cell nodules of the pancreas. Hum Pathol. 1980 Jul;11(4):389–391. doi: 10.1016/s0046-8177(80)80037-2. [DOI] [PubMed] [Google Scholar]
  67. Shinozuka H., Popp J. A., Konishi Y. Ultrastructures of atypical acinar cell nodules in rat pancreas induced by 4-hydroxyaminoquinoline-1-oxide. Lab Invest. 1976 May;34(5):501–509. [PubMed] [Google Scholar]
  68. Takahashi M., Pour P., Althoff J., Donnelly T. Sequential alteration of the pancreas during carcinogenesis in Syrian hamsters by N-nitrosobis(2-oxopropyl)amine. Cancer Res. 1977 Dec;37(12):4602–4607. [PubMed] [Google Scholar]
  69. Takahashi M., Pour P. Spontaneous alterations in the pancreas of the aging Syrian golden hamster. J Natl Cancer Inst. 1978 Feb;60(2):355–364. doi: 10.1093/jnci/60.2.355. [DOI] [PubMed] [Google Scholar]
  70. Volk B. W., Wellmann K. F., Lewitan A. The effect of irradiation on the fine structure and enzymes of the dog pancreas. I. Short-term studies. Am J Pathol. 1966 May;48(5):721–753. [PMC free article] [PubMed] [Google Scholar]
  71. WALTERS M. N. GOBLET-CELL METAPLASIA IN DUCTULES AND ACINI OF THE EXOCRINE PANCREAS. J Pathol Bacteriol. 1965 Apr;89:569–572. doi: 10.1002/path.1700890215. [DOI] [PubMed] [Google Scholar]
  72. Wynder E. L. An epidemiological evaluation of the causes of cancer of the pancreas. Cancer Res. 1975 Aug;35(8):2228–2233. [PubMed] [Google Scholar]
  73. Wynder E. L., Mabuchi K., Maruchi N., Fortner J. G. Epidemiology of cancer of the pancreas. J Natl Cancer Inst. 1973 Mar;50(3):645–667. doi: 10.1093/jnci/50.3.645. [DOI] [PubMed] [Google Scholar]