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. 1993 Jul;143(1):283–291.

Immunoreactivity and expression of amylin in gastroenteropancreatic endocrine tumors.

R Eissele 1, C Neuhaus 1, M E Trautmann 1, A Funk 1, R Arnold 1, H Höfler 1
PMCID: PMC1886962  PMID: 8317551

Abstract

Amylin was isolated from human insulinomas, but there has been only preliminary data regarding whether this peptide can also be detected in other types of gastroenteropancreatic endocrine tumors. In the present study, immunohistochemical staining of 87 gastroenteropancreatic endocrine tumors demonstrated amylin immunoreactivity in 21.8% of the neoplasmas. Thirteen of 15 insulinomas, three of 21 gastrinomas, two of 29 nonfunctioning tumors, and one of 18 carcinoids were amylin-immunoreactive. Seventeen of the 19 amylin-immunoreactive tumors were primarily located in the pancreas, but two tumors were found in the intestine. Measurements of amylin messenger RNA expression in a few tumors revealed amylin synthesis in these tumors. Amylin immunoreactivity did not correlate with invasion and metastasis. However, the rate of curative resections was significantly higher in amylin-immunoreactive tumors. These results demonstrate for the first time that amylin immunoreactivity is not restricted to insulinomas and can also occur rarely in endocrine tumors of the intestine.

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Selected References

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  1. Alpert S., Hanahan D., Teitelman G. Hybrid insulin genes reveal a developmental lineage for pancreatic endocrine cells and imply a relationship with neurons. Cell. 1988 Apr 22;53(2):295–308. doi: 10.1016/0092-8674(88)90391-1. [DOI] [PubMed] [Google Scholar]
  2. BELL E. T. Hyalinization of the islets of Langerhans in nondiabetic individuals. Am J Pathol. 1959 Jul-Aug;35(4):801–805. [PMC free article] [PubMed] [Google Scholar]
  3. Bell G. I. Lilly lecture 1990. Molecular defects in diabetes mellitus. Diabetes. 1991 Apr;40(4):413–422. doi: 10.2337/diab.40.4.413. [DOI] [PubMed] [Google Scholar]
  4. Betsholtz C., Svensson V., Rorsman F., Engström U., Westermark G. T., Wilander E., Johnson K., Westermark P. Islet amyloid polypeptide (IAPP):cDNA cloning and identification of an amyloidogenic region associated with the species-specific occurrence of age-related diabetes mellitus. Exp Cell Res. 1989 Aug;183(2):484–493. doi: 10.1016/0014-4827(89)90407-2. [DOI] [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Christmanson L., Rorsman F., Stenman G., Westermark P., Betsholtz C. The human islet amyloid polypeptide (IAPP) gene. Organization, chromosomal localization and functional identification of a promoter region. FEBS Lett. 1990 Jul 2;267(1):160–166. doi: 10.1016/0014-5793(90)80314-9. [DOI] [PubMed] [Google Scholar]
  7. Clark A., Edwards C. A., Ostle L. R., Sutton R., Rothbard J. B., Morris J. F., Turner R. C. Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects. Cell Tissue Res. 1989 Jul;257(1):179–185. doi: 10.1007/BF00221649. [DOI] [PubMed] [Google Scholar]
  8. Cooper G. J., Day A. J., Willis A. C., Roberts A. N., Reid K. B., Leighton B. Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus. Biochim Biophys Acta. 1989 Dec 14;1014(3):247–258. doi: 10.1016/0167-4889(89)90220-6. [DOI] [PubMed] [Google Scholar]
  9. Cooper G. J., Willis A. C., Clark A., Turner R. C., Sim R. B., Reid K. B. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci U S A. 1987 Dec;84(23):8628–8632. doi: 10.1073/pnas.84.23.8628. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Denijn M., De Weger R. A., Van Mansfeld A. D., van Unnik J. A., Lips C. J. Islet amyloid polypeptide (IAPP) is synthesized in the islets of Langerhans. Detection of IAPP polypeptide and IAPP mRNA by combined in situ hybridization and immunohistochemistry in rat pancreas. Histochemistry. 1992;97(1):33–37. doi: 10.1007/BF00271279. [DOI] [PubMed] [Google Scholar]
  11. EHRLICH J. C., RATNER I. M. Amyloidosis of the islets of Langerhans. A restudy of islet hyalin in diabetic and non-diabetic individuals. Am J Pathol. 1961 Jan;38:49–59. [PMC free article] [PubMed] [Google Scholar]
  12. Fehmann H. C., Weber V., Göke R., Göke B., Arnold R. Cosecretion of amylin and insulin from isolated rat pancreas. FEBS Lett. 1990 Mar 26;262(2):279–281. doi: 10.1016/0014-5793(90)80210-a. [DOI] [PubMed] [Google Scholar]
  13. Hoefler H., Childers H., Montminy M. R., Lechan R. M., Goodman R. H., Wolfe H. J. In situ hybridization methods for the detection of somatostatin mRNA in tissue sections using antisense RNA probes. Histochem J. 1986 Nov-Dec;18(11-12):597–604. doi: 10.1007/BF01675295. [DOI] [PubMed] [Google Scholar]
  14. Hsu S. M., Raine L., Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981 Apr;29(4):577–580. doi: 10.1177/29.4.6166661. [DOI] [PubMed] [Google Scholar]
  15. Johnson K. H., O'Brien T. D., Betsholtz C., Westermark P. Islet amyloid, islet-amyloid polypeptide, and diabetes mellitus. N Engl J Med. 1989 Aug 24;321(8):513–518. doi: 10.1056/NEJM198908243210806. [DOI] [PubMed] [Google Scholar]
  16. Johnson K. H., O'Brien T. D., Hayden D. W., Jordan K., Ghobrial H. K., Mahoney W. C., Westermark P. Immunolocalization of islet amyloid polypeptide (IAPP) in pancreatic beta cells by means of peroxidase-antiperoxidase (PAP) and protein A-gold techniques. Am J Pathol. 1988 Jan;130(1):1–8. [PMC free article] [PubMed] [Google Scholar]
  17. Johnson K. H., O'Brien T. D., Westermark P. Newly identified pancreatic protein islet amyloid polypeptide. What is its relationship to diabetes? Diabetes. 1991 Mar;40(3):310–314. doi: 10.2337/diab.40.3.310. [DOI] [PubMed] [Google Scholar]
  18. Kahn S. E., D'Alessio D. A., Schwartz M. W., Fujimoto W. Y., Ensinck J. W., Taborsky G. J., Jr, Porte D., Jr Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells. Diabetes. 1990 May;39(5):634–638. doi: 10.2337/diab.39.5.634. [DOI] [PubMed] [Google Scholar]
  19. Kanatsuka A., Makino H., Ohsawa H., Tokuyama Y., Yamaguchi T., Yoshida S., Adachi M. Secretion of islet amyloid polypeptide in response to glucose. FEBS Lett. 1989 Dec 18;259(1):199–201. doi: 10.1016/0014-5793(89)81527-3. [DOI] [PubMed] [Google Scholar]
  20. Klöppel G., Heitz P. U. Pancreatic endocrine tumors. Pathol Res Pract. 1988 Apr;183(2):155–168. doi: 10.1016/S0344-0338(88)80043-8. [DOI] [PubMed] [Google Scholar]
  21. Leffert J. D., Newgard C. B., Okamoto H., Milburn J. L., Luskey K. L. Rat amylin: cloning and tissue-specific expression in pancreatic islets. Proc Natl Acad Sci U S A. 1989 May;86(9):3127–3130. doi: 10.1073/pnas.86.9.3127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lukinius A., Wilander E., Westermark G. T., Engström U., Westermark P. Co-localization of islet amyloid polypeptide and insulin in the B cell secretory granules of the human pancreatic islets. Diabetologia. 1989 Apr;32(4):240–244. doi: 10.1007/BF00285291. [DOI] [PubMed] [Google Scholar]
  23. Mitsukawa T., Takemura J., Asai J., Nakazato M., Kangawa K., Matsuo H., Matsukura S. Islet amyloid polypeptide response to glucose, insulin, and somatostatin analogue administration. Diabetes. 1990 May;39(5):639–642. doi: 10.2337/diab.39.5.639. [DOI] [PubMed] [Google Scholar]
  24. Miyazato M., Nakazato M., Shiomi K., Aburaya J., Toshimori H., Kangawa K., Matsuo H., Matsukura S. Identification and characterization of islet amyloid polypeptide in mammalian gastrointestinal tract. Biochem Biophys Res Commun. 1991 Nov 27;181(1):293–300. doi: 10.1016/s0006-291x(05)81416-0. [DOI] [PubMed] [Google Scholar]
  25. Mosselman S., Höppener J. W., Lips C. J., Jansz H. S. The complete islet amyloid polypeptide precursor is encoded by two exons. FEBS Lett. 1989 Apr 10;247(1):154–158. doi: 10.1016/0014-5793(89)81260-8. [DOI] [PubMed] [Google Scholar]
  26. Mosselman S., Höppener J. W., Zandberg J., van Mansfeld A. D., Geurts van Kessel A. H., Lips C. J., Jansz H. S. Islet amyloid polypeptide: identification and chromosomal localization of the human gene. FEBS Lett. 1988 Nov 7;239(2):227–232. doi: 10.1016/0014-5793(88)80922-0. [DOI] [PubMed] [Google Scholar]
  27. Nagamatsu S., Nishi M., Steiner D. F. Biosynthesis of islet amyloid polypeptide. Elevated expression in mouse beta TC3 cells. J Biol Chem. 1991 Jul 25;266(21):13737–13741. [PubMed] [Google Scholar]
  28. Nagamatsu S., Nishi M., Steiner D. F. Biosynthesis of islet amyloid polypeptide. Elevated expression in mouse beta TC3 cells. J Biol Chem. 1991 Jul 25;266(21):13737–13741. [PubMed] [Google Scholar]
  29. Nakazato M., Asai J., Kangawa K., Matsukura S., Matsuo H. Establishment of radioimmunoassay for human islet amyloid polypeptide and its tissue content and plasma concentration. Biochem Biophys Res Commun. 1989 Oct 16;164(1):394–399. doi: 10.1016/0006-291x(89)91732-4. [DOI] [PubMed] [Google Scholar]
  30. Nishi M., Chan S. J., Nagamatsu S., Bell G. I., Steiner D. F. Conservation of the sequence of islet amyloid polypeptide in five mammals is consistent with its putative role as an islet hormone. Proc Natl Acad Sci U S A. 1989 Aug;86(15):5738–5742. doi: 10.1073/pnas.86.15.5738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nishi M., Sanke T., Seino S., Eddy R. L., Fan Y. S., Byers M. G., Shows T. B., Bell G. I., Steiner D. F. Human islet amyloid polypeptide gene: complete nucleotide sequence, chromosomal localization, and evolutionary history. Mol Endocrinol. 1989 Nov;3(11):1775–1781. doi: 10.1210/mend-3-11-1775. [DOI] [PubMed] [Google Scholar]
  32. O'Brien T. D., Westermark P., Johnson K. H. Islet amyloid polypeptide and calcitonin gene-related peptide immunoreactivity in amyloid and tumor cells of canine pancreatic endocrine tumors. Vet Pathol. 1990 May;27(3):194–198. doi: 10.1177/030098589002700307. [DOI] [PubMed] [Google Scholar]
  33. Ogawa A., Harris V., McCorkle S. K., Unger R. H., Luskey K. L. Amylin secretion from the rat pancreas and its selective loss after streptozotocin treatment. J Clin Invest. 1990 Mar;85(3):973–976. doi: 10.1172/JCI114528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Ohsawa H., Kanatsuka A., Tokuyama Y., Yamaguchi T., Makino H., Yoshida S., Horie H., Mikata A., Kohen Y. Amyloid protein in somatostatinoma differs from human islet amyloid polypeptide. Acta Endocrinol (Copenh) 1991 Jan;124(1):45–53. doi: 10.1530/acta.0.1240045. [DOI] [PubMed] [Google Scholar]
  35. Roberts A. N., Leighton B., Todd J. A., Cockburn D., Schofield P. N., Sutton R., Holt S., Boyd Y., Day A. J., Foot E. A. Molecular and functional characterization of amylin, a peptide associated with type 2 diabetes mellitus. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9662–9666. doi: 10.1073/pnas.86.24.9662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Rothmund M., Angelini L., Brunt L. M., Farndon J. R., Geelhoed G., Grama D., Herfarth C., Kaplan E. L., Largiader F., Morino F. Surgery for benign insulinoma: an international review. World J Surg. 1990 May-Jun;14(3):393–399. doi: 10.1007/BF01658536. [DOI] [PubMed] [Google Scholar]
  37. Sanke T., Bell G. I., Sample C., Rubenstein A. H., Steiner D. F. An islet amyloid peptide is derived from an 89-amino acid precursor by proteolytic processing. J Biol Chem. 1988 Nov 25;263(33):17243–17246. [PubMed] [Google Scholar]
  38. Sletten K., Westermark P., Natvig J. B. Characterization of amyloid fibril proteins from medullary carcinoma of the thyroid. J Exp Med. 1976 Apr 1;143(4):993–998. doi: 10.1084/jem.143.4.993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Steiner D. F., Ohagi S., Nagamatsu S., Bell G. I., Nishi M. Is islet amyloid polypeptide a significant factor in pathogenesis or pathophysiology of diabetes? Diabetes. 1991 Mar;40(3):305–309. doi: 10.2337/diab.40.3.305. [DOI] [PubMed] [Google Scholar]
  40. Stridsberg M., Wilander E. Islet amyloid polypeptide (IAPP). A short review. Acta Oncol. 1991;30(4):451–456. doi: 10.3109/02841869109092400. [DOI] [PubMed] [Google Scholar]
  41. Toshimori H., Narita R., Nakazato M., Asai J., Mitsukawa T., Kangawa K., Matsuo H., Matsukura S. Islet amyloid polypeptide (IAPP) in the gastrointestinal tract and pancreas of man and rat. Cell Tissue Res. 1990 Dec;262(3):401–406. doi: 10.1007/BF00305236. [DOI] [PubMed] [Google Scholar]
  42. Toshimori H., Narita R., Nakazato M., Asai J., Mitsukawa T., Kangawa K., Matsuo H., Takahashi K., Matsukura S. Islet amyloid polypeptide in insulinoma and in the islets of the pancreas of non-diabetic and diabetic subjects. Virchows Arch A Pathol Anat Histopathol. 1991;418(5):411–417. doi: 10.1007/BF01605927. [DOI] [PubMed] [Google Scholar]
  43. Westermark P., Grimelius L., Polak J. M., Larsson L. I., Van Noorden S., Wilander E., Pearse A. G. Amyloid in polypeptide hormone-producing tumors. Lab Invest. 1977 Aug;37(2):212–215. [PubMed] [Google Scholar]
  44. Westermark P., Grimelius L. The pancreatic islet cells in insular amyloidosis in human diabetic and non-diabetic adults. Acta Pathol Microbiol Scand A. 1973 May;81(3):291–300. doi: 10.1111/j.1699-0463.1973.tb03538.x. [DOI] [PubMed] [Google Scholar]
  45. Westermark P. Quantitative studies on amyloid in the islets of Langerhans. Ups J Med Sci. 1972;77(2):91–94. doi: 10.1517/03009734000000014. [DOI] [PubMed] [Google Scholar]
  46. Westermark P., Wernstedt C., O'Brien T. D., Hayden D. W., Johnson K. H. Islet amyloid in type 2 human diabetes mellitus and adult diabetic cats contains a novel putative polypeptide hormone. Am J Pathol. 1987 Jun;127(3):414–417. [PMC free article] [PubMed] [Google Scholar]
  47. Westermark P., Wernstedt C., Wilander E., Hayden D. W., O'Brien T. D., Johnson K. H. Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3881–3885. doi: 10.1073/pnas.84.11.3881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Westermark P., Wernstedt C., Wilander E., Sletten K. A novel peptide in the calcitonin gene related peptide family as an amyloid fibril protein in the endocrine pancreas. Biochem Biophys Res Commun. 1986 Nov 14;140(3):827–831. doi: 10.1016/0006-291x(86)90708-4. [DOI] [PubMed] [Google Scholar]
  49. Wilander E. Diagnostic pathology of gastrointestinal and pancreatic neuroendocrine tumours. Acta Oncol. 1989;28(3):363–369. doi: 10.3109/02841868909111207. [DOI] [PubMed] [Google Scholar]
  50. van Mansfeld A. D., Mosselman S., Höppener J. W., Zandberg J., van Teeffelen H. A., Baas P. D., Lips C. J., Jansz H. S. Islet amyloid polypeptide: structure and upstream sequences of the IAPP gene in rat and man. Biochim Biophys Acta. 1990 Oct 23;1087(2):235–240. doi: 10.1016/0167-4781(90)90210-s. [DOI] [PubMed] [Google Scholar]

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