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. 1994 Oct;35(10):1468–1473. doi: 10.1136/gut.35.10.1468

Chronic pancreatitis is associated with increased concentrations of epidermal growth factor receptor, transforming growth factor alpha, and phospholipase C gamma.

M Korc 1, H Friess 1, Y Yamanaka 1, M S Kobrin 1, M Buchler 1, H G Beger 1
PMCID: PMC1375027  PMID: 7959207

Abstract

The epidermal growth factor (EGF) receptor is a transmembrane protein that binds EGF and transforming growth factor alpha (TGF alpha), and that stimulates phospholipase C gamma 1 (PLC gamma 1) activity. In this study the role of the EGF receptor in chronic pancreatitis was studied. By immunohistochemistry, the EGF receptor, TGF alpha, and PLC gamma 1 were found to be expressed at high concentrations in pancreatic ductal and acinar cells from chronic pancreatitis patients. Northern blot analysis showed that, by comparison with normal controls, 19 of 27 chronic pancreatitis tissues exhibited a 5.7-fold increase in EGF receptor mRNA concentrations, and 20 of 27 chronic pancreatitis tissues exhibited a sixfold increase in TGF alpha mRNA concentrations. In situ hybridisation confirmed that overexpression occurred in ductal and acinar cells, and showed that both mRNA moieties colocalised with their respective proteins. These findings suggest that TGF alpha may act through autocrine and paracrine mechanisms to excessively activate the overexpressed EGF receptor in the two major cell types of the exocrine pancreas, thereby contributing to the pathobiology of this disorder.

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Selected References

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  1. Almoguera C., Shibata D., Forrester K., Martin J., Arnheim N., Perucho M. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988 May 20;53(4):549–554. doi: 10.1016/0092-8674(88)90571-5. [DOI] [PubMed] [Google Scholar]
  2. Arteaga C. L., Johnson M. D., Todderud G., Coffey R. J., Carpenter G., Page D. L. Elevated content of the tyrosine kinase substrate phospholipase C-gamma 1 in primary human breast carcinomas. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10435–10439. doi: 10.1073/pnas.88.23.10435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Balmain A., Krumlauf R., Vass J. K., Birnie G. D. Cloning and characterisation of the abundant cytoplasmic 7S RNA from mouse cells. Nucleic Acids Res. 1982 Jul 24;10(14):4259–4277. doi: 10.1093/nar/10.14.4259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barton C. M., Staddon S. L., Hughes C. M., Hall P. A., O'Sullivan C., Klöppel G., Theis B., Russell R. C., Neoptolemos J., Williamson R. C. Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. Br J Cancer. 1991 Dec;64(6):1076–1082. doi: 10.1038/bjc.1991.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Berridge M. J., Irvine R. F. Inositol phosphates and cell signalling. Nature. 1989 Sep 21;341(6239):197–205. doi: 10.1038/341197a0. [DOI] [PubMed] [Google Scholar]
  6. Bockman D. E., Merlino G. Cytological changes in the pancreas of transgenic mice overexpressing transforming growth factor alpha. Gastroenterology. 1992 Dec;103(6):1883–1892. doi: 10.1016/0016-5085(92)91448-d. [DOI] [PubMed] [Google Scholar]
  7. Chang S. C., Brannon P. M., Korc M. Effects of dietary manganese deficiency on rat pancreatic amylase mRNA levels. J Nutr. 1990 Oct;120(10):1228–1234. doi: 10.1093/jn/120.10.1228. [DOI] [PubMed] [Google Scholar]
  8. Derynck R., Roberts A. B., Winkler M. E., Chen E. Y., Goeddel D. V. Human transforming growth factor-alpha: precursor structure and expression in E. coli. Cell. 1984 Aug;38(1):287–297. doi: 10.1016/0092-8674(84)90550-6. [DOI] [PubMed] [Google Scholar]
  9. Di Fiore P. P., Pierce J. H., Fleming T. P., Hazan R., Ullrich A., King C. R., Schlessinger J., Aaronson S. A. Overexpression of the human EGF receptor confers an EGF-dependent transformed phenotype to NIH 3T3 cells. Cell. 1987 Dec 24;51(6):1063–1070. doi: 10.1016/0092-8674(87)90592-7. [DOI] [PubMed] [Google Scholar]
  10. Glinsmann-Gibson B. J., Korc M. Regulation of transforming growth factor-alpha mRNA expression in T3M4 human pancreatic carcinoma cells. Pancreas. 1991 Mar;6(2):142–149. doi: 10.1097/00006676-199103000-00003. [DOI] [PubMed] [Google Scholar]
  11. Grünewald K., Lyons J., Fröhlich A., Feichtinger H., Weger R. A., Schwab G., Janssen J. W., Bartram C. R. High frequency of Ki-ras codon 12 mutations in pancreatic adenocarcinomas. Int J Cancer. 1989 Jun 15;43(6):1037–1041. doi: 10.1002/ijc.2910430614. [DOI] [PubMed] [Google Scholar]
  12. Haas O., Guillard G., Rat P., Friedman S., Favre J. P. Pancreatic carcinoma developing in chronic pancreatitis: a report of four cases. Hepatogastroenterology. 1990 Jun;37(3):350–351. [PubMed] [Google Scholar]
  13. Jhappan C., Stahle C., Harkins R. N., Fausto N., Smith G. H., Merlino G. T. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell. 1990 Jun 15;61(6):1137–1146. doi: 10.1016/0092-8674(90)90076-q. [DOI] [PubMed] [Google Scholar]
  14. Kennedy R. H., Bockman D. E., Uscanga L., Choux R., Grimaud J. A., Sarles H. Pancreatic extracellular matrix alterations in chronic pancreatitis. Pancreas. 1987;2(1):61–72. doi: 10.1097/00006676-198701000-00010. [DOI] [PubMed] [Google Scholar]
  15. Korc M., Chandrasekar B., Yamanaka Y., Friess H., Buchier M., Beger H. G. Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest. 1992 Oct;90(4):1352–1360. doi: 10.1172/JCI116001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  17. Lin J. T., Wang T. H., Chen D. S., How S. W., Lai M. Y., Chen J. C., Sung J. L. Pancreatic carcinoma associated with chronic calcifying pancreatitis in Taiwan: a case report and review of the literature. Pancreas. 1988;3(1):111–114. doi: 10.1097/00006676-198802000-00020. [DOI] [PubMed] [Google Scholar]
  18. Lowenfels A. B., Maisonneuve P., Cavallini G., Ammann R. W., Lankisch P. G., Andersen J. R., Dimagno E. P., Andrén-Sandberg A., Domellöf L. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med. 1993 May 20;328(20):1433–1437. doi: 10.1056/NEJM199305203282001. [DOI] [PubMed] [Google Scholar]
  19. Margolis B., Bellot F., Honegger A. M., Ullrich A., Schlessinger J., Zilberstein A. Tyrosine kinase activity is essential for the association of phospholipase C-gamma with the epidermal growth factor receptor. Mol Cell Biol. 1990 Feb;10(2):435–441. doi: 10.1128/mcb.10.2.435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Meisenhelder J., Suh P. G., Rhee S. G., Hunter T. Phospholipase C-gamma is a substrate for the PDGF and EGF receptor protein-tyrosine kinases in vivo and in vitro. Cell. 1989 Jun 30;57(7):1109–1122. doi: 10.1016/0092-8674(89)90048-2. [DOI] [PubMed] [Google Scholar]
  21. Nanney L. B., Yates R. A., King L. E., Jr Modulation of epidermal growth factor receptors in psoriatic lesions during treatment with topical EGF. J Invest Dermatol. 1992 Mar;98(3):296–301. doi: 10.1111/1523-1747.ep12497963. [DOI] [PubMed] [Google Scholar]
  22. Nishizuka Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature. 1988 Aug 25;334(6184):661–665. doi: 10.1038/334661a0. [DOI] [PubMed] [Google Scholar]
  23. Sandgren E. P., Luetteke N. C., Palmiter R. D., Brinster R. L., Lee D. C. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast. Cell. 1990 Jun 15;61(6):1121–1135. doi: 10.1016/0092-8674(90)90075-p. [DOI] [PubMed] [Google Scholar]
  24. Sarles H., Bernard J. P., Johnson C. Pathogenesis and epidemiology of chronic pancreatitis. Annu Rev Med. 1989;40:453–468. doi: 10.1146/annurev.me.40.020189.002321. [DOI] [PubMed] [Google Scholar]
  25. Schibler U., Tosi M., Pittet A. C., Fabiani L., Wellauer P. K. Tissue-specific expression of mouse alpha-amylase genes. J Mol Biol. 1980 Sep 5;142(1):93–116. doi: 10.1016/0022-2836(80)90208-9. [DOI] [PubMed] [Google Scholar]
  26. Torti M., Lapetina E. G. Role of rap1B and p21ras GTPase-activating protein in the regulation of phospholipase C-gamma 1 in human platelets. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7796–7800. doi: 10.1073/pnas.89.16.7796. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ullrich A., Coussens L., Hayflick J. S., Dull T. J., Gray A., Tam A. W., Lee J., Yarden Y., Libermann T. A., Schlessinger J. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. 1984 May 31-Jun 6Nature. 309(5967):418–425. doi: 10.1038/309418a0. [DOI] [PubMed] [Google Scholar]
  29. Watanabe S., Lazar E., Sporn M. B. Transformation of normal rat kidney (NRK) cells by an infectious retrovirus carrying a synthetic rat type alpha transforming growth factor gene. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1258–1262. doi: 10.1073/pnas.84.5.1258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Wilcox J. N., Smith K. M., Williams L. T., Schwartz S. M., Gordon D. Platelet-derived growth factor mRNA detection in human atherosclerotic plaques by in situ hybridization. J Clin Invest. 1988 Sep;82(3):1134–1143. doi: 10.1172/JCI113671. [DOI] [PMC free article] [PubMed] [Google Scholar]

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