Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Mucinous cystic carcinoma of the pancreas: a unique cell line and xenograft model of a preinvasive lesion

Abstract

Pancreatic mucinous cystic tumors (MCT) are proliferations of mucin-producing epithelia supported by an ovarian-like stroma. They are classified into adenomas (MCA), borderline (MCB) and noninvasive or invasive carcinomas (MCC). The molecular mechanisms underlying their clinical behavior are poorly understood, partly due to the lack of cellular models. We report the establishment of MCC1, the first cell line from a pancreatic MCT, deriving from the highly dysplastic cell component of a noninvasive MCC. MCC1 has mutations in codon 12 of K-RAS (GGT>GAT), codon 58 of P16 (CGA>TGA) and codon 132 of P53 (AAG>AGG). The FHIT and DPC4 genes are unaltered. Immunohistochemistry shows abnormal expression of MUC1 and p53, loss of p16 and retention of Fhit and Dpc4 in both the cell line and the highly dysplastic cells of the primary lesion. The morphological and molecular features of MCC1 and its corresponding primary tumor are consistent with a model for non-invasive MCC, where K-RAS, P16, P53 and MUC1 alterations are pre-invasive changes associated with progression of malignancy of MCT from adenoma to carcinoma. MCC1 is sensitive to 5-fluorouracil, representing the first assessment of drug sensitivity for MCC. Finally, MCC1 is a suitable model for preclinical studies, as it grows in immunodeficient mice.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2

References

  1. 1.

    Adsay NV, Merati K, Basturk O, Iacobuzio-Donahue C, Levi E, Cheng JD, Sarkar FH, Hruban RH, Klimstra DS (2004) Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an “intestinal” pathway of carcinogenesis in the pancreas. Am J Surg Pathol 28:839–848

  2. 2.

    Agrawal B, Krantz MJ, Reddish MA, Longenecker BM (1998) Cancer-associated MUC1 mucin inhibits human T-cell proliferation, which is reversible by IL-2. Nat Med 4:43–49

  3. 3.

    Bartsch D, Bastian D, Barth P, Schudy A, Nies C, Kisker O, Wagner HJ, Rothmund M (1998) K-ras oncogene mutations indicate malignancy in cystic tumors of the pancreas. Ann Surg 228:79–86

  4. 4.

    Caduff RF, Svoboda-Newman SM, Ferguson AW, Johnston CM, Frank TS (1999) Comparison of mutations of Ki-RAS and p53 immunoreactivity in borderline and malignant epithelial ovarian tumors. Am J Surg Pathol 23:323–328

  5. 5.

    Fujita M, Enomoto T, Murata Y (2003) Genetic alterations in ovarian carcinoma: with specific reference to histological subtypes. Mol Cell Endocrinol 202:97–99

  6. 6.

    Gerdes B, Wild A, Wittenberg J, Barth P, Ramaswamy A, Kersting M, Luttges J, Kloppel G, Bartsch DK (2003) Tumor-suppressing pathways in cystic pancreatic tumors. Pancreas 26:42–48

  7. 7.

    Hahn SA, Bartsch D, Schroers A, Galehdari H, Becker M, Ramaswamy A, Schwarte-Waldhoff I, Maschek H, Schmiegel W (1998) Mutations of the DPC4/Smad4 gene in biliary tract carcinoma. Cancer Res 58:1124–1126

  8. 8.

    Hanski C, Hofmeier M, Schmitt-Graff A, Riede E, Hanski ML, Borchard F, Sieber E, Niedobitek F, Foss HD, Stein H, Riecken EO (1997) Overexpression or ectopic expression of MUC2 is the common property of mucinous carcinomas of the colon, pancreas, breast, and ovary. J Pathol 182:385–391

  9. 9.

    Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci U S A 93:9821–9826

  10. 10.

    Iacobuzio-Donahue CA, Wilentz RE, Argani P, Yeo CJ, Cameron JL, Kern SE, Hruban RH (2000) Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol 24:1544–1548

  11. 11.

    Jimenez RE, Warshaw AL, Z’Graggen K, Hartwig W, Taylor DZ, Compton CC, Fernandez-del Castillo C (1999) Sequential accumulation of K-ras mutations and p53 overexpression in the progression of pancreatic mucinous cystic neoplasms to malignancy. Ann Surg 230:501–511

  12. 12.

    Jimenez RE, Z’Graggen K, Hartwig W, Graeme-Cook F, Warshaw AL, Fernandez-del Castillo C (1999) Immunohistochemical characterization of pancreatic tumors induced by dimethylbenzanthracene in rats. Am J Pathol 154:1223–1229

  13. 13.

    Luttges J, Zamboni G, Longnecker D, Kloppel G (2001) The immunohistochemical mucin expression pattern distinguishes different types of intraductal papillary mucinous neoplasms of the pancreas and determines their relationship to mucinous noncystic carcinoma and ductal adenocarcinoma. Am J Surg Pathol 25:942–948

  14. 14.

    Luttges J, Feyerabend B, Buchelt T, Pacena M, Kloppel G (2002) The mucin profile of noninvasive and invasive mucinous cystic neoplasms of the pancreas. Am J Surg Pathol 26:466–471

  15. 15.

    Milde-Langosch K, Ocon E, Becker G, Loning T (1998) p16/MTS1 inactivation in ovarian carcinomas: high frequency of reduced protein expression associated with hyper-methylation or mutation in endometrioid and mucinous tumors. Int J Cancer 79:61–65

  16. 16.

    Moore P, Sipos B, Orlandini S, Sorio C, Real F, Lemoine N, Gress T, Bassi C, Klöppel G, Kalthoff H, Löhr M, Scarpa A (2001) Genetic profile of 22 pancreatic carcinoma cell lines: analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch 439:798–802

  17. 17.

    Scarpa A, Capelli P, Zamboni G, Oda T, Mukai K, Bonetti F, Martignoni G, Iacono C, Serio G, Hirohashi S (1993) Neoplasia of the ampulla of Vater. Ki-ras and p53 mutations. Am J Pathol 142:1163–1172

  18. 18.

    Scarpa A, Zamboni G, Achille A, Capelli P, Bogina G, Iacono C, Serio G, Accolla RS (1994) Ras-family gene mutations in neoplasia of the ampulla of Vater. Int J Cancer 59:39–42

  19. 19.

    Sipos B, Moser S, Kalthoff H, Torok V, Lohr M, Kloppel G (2003) A comprehensive characterization of pancreatic ductal carcinoma cell lines: towards the establishment of an in vitro research platform. Virchows Arch 442:444–452

  20. 20.

    Terada T, Ohta T, Sasaki M, Nakanuma Y, Kim YS (1996) Expression of MUC apomucins in normal pancreas and pancreatic tumours. J Pathol 180:160–165

  21. 21.

    Wilentz RE, Albores-Saavedra J, Zahurak M, Talamini MA, Yeo CJ, Cameron JL, Hruban RH (1999) Pathologic examination accurately predicts prognosis in mucinous cystic neoplasms of the pancreas. Am J Surg Pathol 23:1320–1327

  22. 22.

    Wilentz RE, Albores-Saavedra J, Hruban RH (2000) Mucinous cystic neoplasms of the pancreas. Semin Diagn Pathol 17:31–42

  23. 23.

    Yonezawa S, Taira M, Osako M, Kubo M, Tanaka S, Sakoda K, Takao S, Aiko T, Yamamoto M, Irimura T, Kim YS, Sato E (1998) MUC-1 mucin expression in invasive areas of intraductal papillary mucinous tumors of the pancreas. Pathol Int 48:319–322

  24. 24.

    Zamboni G, Scarpa A, Bogina G, Iacono C, Bassi C, Talamini G, Sessa F, Capella C, Solcia E, Rickaert F, Mariuzzi GM, Kloppel G (1999) Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors. Am J Surg Pathol 23:410–422

  25. 25.

    Zamboni G, Klöppel G, Hruban R, Longnecker D, Adler G (2000) Mucinous cystic neoplasms of the pancreas. In: Hamilton S, Aaltonen L (eds) Tumours of the digestive system, 2nd edn. Oxford University Press, Berlin

  26. 26.

    Zhang SY, Klein-Szanto AJ, Sauter ER, Shafarenko M, Mitsunaga S, Nobori T, Carson DA, Ridge JA, Goodrow TL (1994) Higher frequency of alterations in the p16/CDKN2 gene in squamous cell carcinoma cell lines than in primary tumors of the head and neck. Cancer Res 54:5050–5053

Download references

Acknowledgements

This work was supported by: Associazione Italiana Ricerca Cancro, Milan, Italy; Fondazione Cassa di Risparmio (Bando 2001), Verona, Italy; CNR-diagnostica molecolare, Ministero Università and Ministero Sanita’, Rome, Italy; and European Community Grant QLG1-CT-2002–01196.

Author information

Correspondence to Aldo Scarpa.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sorio, C., Capelli, P., Lissandrini, D. et al. Mucinous cystic carcinoma of the pancreas: a unique cell line and xenograft model of a preinvasive lesion. Virchows Arch 446, 239–245 (2005). https://doi.org/10.1007/s00428-004-1167-1

Download citation

Keywords

  • Pancreas
  • Mucinous cystic tumor
  • Carcinoma
  • Cell line
  • Xenograft