Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Pancreatic cancer biology and genetics

Nature Reviews Cancer volume 2, pages 897–909 (2002)Cite this article

Key Points

  • Pancreatic adenocarcinoma is a highly aggressive malignancy that shows profound resistance to extant treatments.

  • Genetic studies identified a signature molecular profile of this malignancy, consisting of mutations in KRAS, CDKN2A, TP53 and SMAD4/DPC4.

  • Pancreatic adenocarcinomas seem to arise from the progression of lesions that occur in the pancreatic ducts (pancreatic intraepithelial neoplasia, PanIN). Although the mutations listed above seem to occur in a temporal sequence in progressive PanIN stages, the specific biochemical and cellular events resulting from the mutations are not known.

  • This tumour type shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in TP53 and BRCA2 are likely to contribute to these phenotypes.

  • There is ongoing study of the cell of origin in pancreatic adenocarcinoma. Although there is general agreement that the pancreatic ductal epithelial cell gives rise to this malignancy, there is evidence that transdifferentiation of other pancreatic cell types, such as acinar cells, might serve as an alternative route to pancreatic adenocarcinoma.

  • These tumours show an extensive proliferation of stromal fibroblasts and deposition of extracellular-matrix components (desmoplasia) that seem to promote growth and invasiveness. The molecular basis of this phenotype is not resolved, although TGF-β is thought to have a role.

  • Engineered mouse models have recapitulated some of the genetic and histological features of the human disease. The use of refined methodologies, such as tissue-specific mouse knockouts, should give insight into the biological and biochemical impact of tumour-suppressor gene loss or oncogene activation in pancreatic neoplasia.

Abstract

Pancreatic ductal adenocarcinoma is an aggressive and devastating disease, which is characterized by invasiveness, rapid progression and profound resistance to treatment. Advances in pathological classification and cancer genetics have improved our descriptive understanding of this disease; however, important aspects of pancreatic cancer biology remain poorly understood. What is the pathogenic role of specific gene mutations? What is the cell of origin? And how does the stroma contribute to tumorigenesis? A better understanding of pancreatic cancer biology should lead the way to more effective treatments.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Anatomy of the pancreas.
Figure 2: Genetic progression model of pancreatic adenocarcinoma.
Figure 3: Telomere attrition and genomic instability.
Figure 4: Model of relationship of pancreatic regeneration and tumorigenesis.

Similar content being viewed by others

References

  1. Niederhuber, J. E., Brennan, M. F. & Menck, H. R. The National Cancer Data Base report on pancreatic cancer. Cancer 76, 1671–1677 (1995).

    Article  CAS  PubMed  Google Scholar 

  2. Warshaw, A. L. & Fernandez-del Castillo, C. Pancreatic carcinoma. N. Engl. J. Med. 326, 455–465 (1992).

    Article  CAS  PubMed  Google Scholar 

  3. Ahrendt, S. A. & Pitt, H. A. Surgical management of pancreatic cancer. Oncology 16, 725–734; discussion 734, 736–738, 740, 743 (2002).

    PubMed  Google Scholar 

  4. Kern, S. et al. A white paper: the product of a pancreas cancer think tank. Cancer Res. 61, 4923–4932 (2001).

    CAS  PubMed  Google Scholar 

  5. Anderson, K. E., Potter, J. D. & Mack, T. M. in Cancer Epidemiology and Prevention (eds Schottenfeld, D. & Fraumeni, J. J.) 725–771 (Oxford University Press, New York, 1996).

    Google Scholar 

  6. Lynch, H. T. et al. Familial pancreatic cancer: a review. Semin. Oncol. 23, 251–275 (1996).

    CAS  PubMed  Google Scholar 

  7. Jaffee, E. M., Hruban, R. H., Canto, M. & Kern, S. E. Focus on pancreas cancer. Cancer Cell 2, 25–28 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Eberle, M. A. et al. A new susceptibility locus for autosomal dominant pancreatic cancer maps to chromosome 4q32-34. Am. J. Hum. Genet. 70, 1044–1048 (2002). Linkage mapping of a new familial pancreatic cancer gene.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lowenfels, A. B. et al. Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J. Natl Cancer Inst. 89, 442–446 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Whitcomb, D. C. et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nature Genet. 14, 141–145 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Kinzler, K. W. & Vogelstein, B. Lessons from hereditary colorectal cancer. Cell 87, 159–170 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Cubilla, A. L. & Fitzgerald, P. J. Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res. 36, 2690–2698 (1976). A landmark study providing histological evidence for a ductal cell of origin for pancreatic adenocarcinoma.

    CAS  PubMed  Google Scholar 

  13. Klimstra, D. S. & Longnecker, D. S. K-ras mutations in pancreatic ductal proliferative lesions. Am. J. Pathol. 145, 1547–1550 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Hruban, R. H. et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am. J. Surg. Pathol. 25, 579–586 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Klein, W. M., Hruban, R. H., Klein-Szanto, A. J. & Wilentz, R. E. Direct correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression. Mod. Pathol. 15, 441–447 (2002).

    Article  PubMed  Google Scholar 

  16. Moskaluk, C. A., Hruban, R. H. & Kern, S. E. p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res. 57, 2140–2143 (1997).

    CAS  PubMed  Google Scholar 

  17. Yamano, M. et al. Genetic progression and divergence in pancreatic carcinoma. Am. J. Pathol. 156, 2123–2133 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Luttges, J. et al. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am. J. Pathol. 158, 1677–1683 (2001). References 16–18 document common mutational profiles in PanINs and pancreatic adenocarcinomas occurring in the same patient, providing genetic evidence that PanINs are progenitors of adenocarcinomas.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wilentz, R. E. et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 60, 2002–2006 (2000).

    CAS  PubMed  Google Scholar 

  20. Heinmoller, E. et al. Molecular analysis of microdissected tumors and preneoplastic intraductal lesions in pancreatic carcinoma. Am. J. Pathol. 157, 83–92 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rozenblum, E. et al. Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 57, 1731–1734 (1997). Mutational profile of a large series of pancreatic adenocarcinomas.

    CAS  PubMed  Google Scholar 

  22. Biankin, A. V. et al. Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. Cancer Res. 61, 8830–8837 (2001).

    CAS  PubMed  Google Scholar 

  23. Shields, J. M., Pruitt, K., McFall, A., Shaub, A. & Der, C. J. Understanding Ras: 'it ain't over 'til it's over'. Trends Cell Biol. 10, 147–154 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Korc, M. et al. 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. 90, 1352–1360 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Barton, C. M., Hall, P. A., Hughes, C. M., Gullick, W. J. & Lemoine, N. R. Transforming growth factor alpha and epidermal growth factor in human pancreatic cancer. J. Pathol. 163, 111–116 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. Friess, H. et al. Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. J. Mol. Med. 74, 35–42 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Watanabe, M., Nobuta, A., Tanaka, J. & Asaka, M. An effect of K-ras gene mutation on epidermal growth factor receptor signal transduction in PANC-1 pancreatic carcinoma cells. Int. J. Cancer 67, 264–268 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Sibilia, M. et al. The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. Cell 102, 211–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Day, J. D. et al. Immunohistochemical evaluation of HER-2/ neu expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasms. Hum. Pathol. 27, 119–124 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Wagner, M. et al. Expression of a truncated EGF receptor is associated with inhibition of pancreatic cancer cell growth and enhanced sensitivity to cisplatinum. Int. J. Cancer 68, 782–787 (1996).

    Article  CAS  PubMed  Google Scholar 

  31. Overholser, J. P., Prewett, M. C., Hooper, A. T., Waksal, H. W. & Hicklin, D. J. Epidermal growth factor receptor blockade by antibody IMC-C225 inhibits growth of a human pancreatic carcinoma xenograft in nude mice. Cancer 89, 74–82 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Whelan, A. J., Bartsch, D. & Goodfellow, P. J. Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N. Engl. J. Med. 333, 975–977 (1995).

    Article  CAS  PubMed  Google Scholar 

  33. Goldstein, A. M. et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N. Engl. J. Med. 333, 970–974 (1995).

    Article  CAS  PubMed  Google Scholar 

  34. Goldstein, A. M., Struewing, J. P., Chidambaram, A., Fraser, M. C. & Tucker, M. A. Genotype-phenotype relationships in U. S. melanoma-prone families with CDKN2A and CDK4 mutations. J. Natl Cancer Inst. 92, 1006–1010 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Lynch, H. T. et al. Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome. Cancer 94, 84–96 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Borg, A. et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J. Natl Cancer Inst. 92, 1260–1266 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Sherr, C. J. The INK4A/ARF network in tumour suppression. Nature Rev. Mol. Cell Biol. 2, 731–737 (2001).

    Article  CAS  Google Scholar 

  38. Liu, L. et al. Mutation of the CDKN2A 5′ UTR creates an aberrant initiation codon and predisposes to melanoma. Nature Genet. 21, 128–132 (1999).

    Article  PubMed  CAS  Google Scholar 

  39. Lal, G. et al. Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. Genes Chromosom. Cancer 27, 358–361 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Krimpenfort, P., Quon, K. C., Mooi, W. J., Loonstra, A. & Berns, A. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature 413, 83–86 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Sharpless, N. E. et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413, 86–91 (2001). References 40 and 41 report the phenotypes of Ink4a-knockout mice.

    Article  CAS  PubMed  Google Scholar 

  42. Zindy, F., Quelle, D. E., Roussel, M. F. & Sherr, C. J. Expression of the p16INK4a tumor suppressor versus other INK4 family members during mouse development and aging. Oncogene 15, 203–211 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Nielsen, G. P. et al. Immunohistochemical survey of p16INK4A expression in normal human adult and infant tissues. Lab. Invest. 79, 1137–1143 (1999).

    CAS  PubMed  Google Scholar 

  44. Sherr, C. J. & DePinho, R. A. Cellular senescence: mitotic clock or culture shock? Cell 102, 407–410 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Ramirez, R. D. et al. Putative telomere-independent mechanisms of replicative aging reflect inadequate growth conditions. Genes Dev. 15, 398–403 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Schmitt, C. A. et al. A senescence program controlled by p53 and p16(INK4a) contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Zhu, J., Woods, D., McMahon, M. & Bishop, J. M. Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev. 12, 2997–3007 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Brookes, S. et al. INK4A-deficient human diploid fibroblasts are resistant to RAS-induced senescence. EMBO J. 21, 2936–2945 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997). References 47–49 provide an explanation for the oncogenic cooperation of activated RAS genes and loss of the INK4A /ARF locus.

    Article  CAS  PubMed  Google Scholar 

  50. Luttges, J. et al. The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplastic, and metaplastic ductal epithelium. Cancer 85, 1703–1710 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Laghi, L. et al. Common occurrence of multiple K-RAS mutations in pancreatic cancers with associated precursor lesions and in biliary cancers. Oncogene 21, 4301–4306 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chin, L. et al. Cooperative effects of INK4A and RAS in melanoma susceptibility in vivo. Genes Dev. 11, 2822–2834 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev. 15, 3249–3262 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sharpless, N. E. & DePinho, R. A. The INK4A/ARF locus and its two gene products. Curr. Opin. Genet. Dev. 9, 22–30 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Maser, R. S. & DePinho, R. A. Connecting chromosomes, crisis, and cancer. Science 297, 565–569 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Gorunova, L. et al. Cytogenetic analysis of pancreatic carcinomas: intratumor heterogeneity and nonrandom pattern of chromosome aberrations. Genes Chromosom. Cancer 23, 81–99 (1998).

    Article  CAS  PubMed  Google Scholar 

  58. Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999).

    Article  CAS  PubMed  Google Scholar 

  60. Gisselsson, D. et al. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity. Proc. Natl Acad. Sci. USA 97, 5357–5362 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Gisselsson, D. et al. Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors. Proc. Natl Acad. Sci. USA 98, 12683–12688 (2001). Evidence for a role of telomere attrition in promoting chromosomal instability in the progression of pancreatic adenocarcinoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Suehara, N. et al. Telomerase elevation in pancreatic ductal carcinoma compared to nonmalignant pathological states. Clin. Cancer Res. 3, 993–998 (1997).

    CAS  PubMed  Google Scholar 

  63. Venkitaraman, A. R. Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108, 171–182 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Cancer risks in BRCA2 mutation carriers. The Breast Cancer Linkage Consortium. J. Natl Cancer Inst. 91, 1310–1316 (1999).

  65. Goggins, M., Hruban, R. H. & Kern, S. E. BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications. Am. J. Pathol. 156, 1767–1771 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sato, N. et al. Correlation between centrosome abnormalities and chromosomal instability in human pancreatic cancer cells. Cancer Genet. Cytogenet. 126, 13–19 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Aarnio, M., Mecklin, J. P., Aaltonen, L. A., Nystrom-Lahti, M. & Jarvinen, H. J. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int. J. Cancer 64, 430–433 (1995).

    Article  CAS  PubMed  Google Scholar 

  68. Goggins, M. et al. Pancreatic adenocarcinomas with DNA replication errors (RER+) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am. J. Pathol. 152, 1501–1507 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Mahlamaki, E. H. et al. Comparative genomic hybridization reveals frequent gains of 20q, 8q, 11q, 12p, and 17q, and losses of 18q, 9p, and 15q in pancreatic cancer. Genes Chromosom. Cancer 20, 383–391 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Peltomaki, P. & de la Chapelle, A. Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv. Cancer Res. 71, 93–119 (1997).

    Article  CAS  PubMed  Google Scholar 

  71. Lynch, H. T., Voorhees, G. J., Lanspa, S. J., McGreevy, P. S. & Lynch, J. F. Pancreatic carcinoma and hereditary nonpolyposis colorectal cancer: a family study. Br. J. Cancer 52, 271–273 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Yamamoto, H. et al. Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res. 61, 3139–3144 (2001).

    CAS  PubMed  Google Scholar 

  73. Wilentz, R. E. et al. Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity. Am. J. Pathol. 156, 1641–1651 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Hahn, S. A. et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271, 350–353 (1996). Identification of SMAD4/DPC4.

    Article  CAS  PubMed  Google Scholar 

  75. Massague, J., Blain, S. W. & Lo, R. S. TGF-β signaling in growth control, cancer, and heritable disorders. Cell 103, 295–309 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Sirard, C. et al. Targeted disruption in murine cells reveals variable requirement for Smad4 in transforming growth factor beta-related signaling. J. Biol. Chem. 275, 2063–2070 (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Jonson, T. et al. Altered expression of TGF-β receptors and mitogenic effects of TGF-β in pancreatic carcinomas. Int. J. Oncol. 19, 71–81 (2001).

    CAS  PubMed  Google Scholar 

  78. Dai, J. L. et al. Transforming growth factor-beta responsiveness in DPC4/SMAD4-null cancer cells. Mol. Carcinog. 26, 37–43 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Giehl, K., Seidel, B., Gierschik, P., Adler, G. & Menke, A. TGF-β1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation. Oncogene 19, 4531–4541 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Rowland-Goldsmith, M. A., Maruyama, H., Kusama, T., Ralli, S. & Korc, M. Soluble type II transforming growth factor-beta (TGF-beta) receptor inhibits TGF-beta signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor formation. Clin. Cancer Res. 7, 2931–2940 (2001).

    CAS  PubMed  Google Scholar 

  81. Hemminki, A. et al. A serine/threonine kinase gene defective in Peutz–Jeghers syndrome. Nature 391, 184–187 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Solcia, E., Capella, C. & Kloppel, G. Tumors of the Pancreas (ed. Rosai, J.) (Armed Forces Institute for Pathology, Washington DC, 1995).

    Google Scholar 

  83. Pour, P. M. The role of langerhans islets in pancreatic ductal adenocarcinoma. Front Biosci. 2, d271–282 (1997).

    Article  CAS  PubMed  Google Scholar 

  84. Boardman, L. A. et al. Genetic heterogeneity in Peutz–Jeghers syndrome. Hum. Mutat. 16, 23–30 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Cooper, H. S. in Pathology of the Gastrointestinal Tract (eds Ming, S.-C. & Goldman, H.) 819–853 (Wiliams & Wilkens, Baltimore, 1998).

    Google Scholar 

  86. Olschwang, S. et al. Peutz–Jeghers disease: most, but not all, families are compatible with linkage to 19p13.3. J. Med. Genet. 35, 42–44 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Olschwang, S., Boisson, C. & Thomas, G. Peutz–Jeghers families unlinked to STK11/LKB1 gene mutations are highly predisposed to primitive biliary adenocarcinoma. J. Med. Genet. 38, 356–360 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Klimstra, D. S. in Pancreatic Cancer: Advances in Molecular Pathology, Diagnosis and Clinical Management (eds Sarkar, F. S. & Duggan, M. C.) 21–48 (Eaton Publishing, Natick, Massachusetts, 1998).

    Google Scholar 

  89. Jimenez, R. E. et al. Immunohistochemical characterization of pancreatic tumors induced by dimethylbenzanthracene in rats. Am. J. Pathol. 154, 1223–1229 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wagner, M. et al. A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Genes Dev. 15, 286–293 (2001). The first description of a genetically defined mouse model of pancreatic adenocarcinoma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Yoshida, T. & Hanahan, D. Murine pancreatic ductal adenocarcinoma produced by in vitro transduction of polyoma middle T oncogene into the islets of Langerhans. Am. J. Pathol. 145, 671–684 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Tosh, D. & Slack, J. M. How cells change their phenotype. Nature Rev. Mol. Cell Biol. 3, 187–194 (2002).

    Article  CAS  Google Scholar 

  93. Blau, H. M., Brazelton, T. R. & Weimann, J. M. The evolving concept of a stem cell: entity or function? Cell 105, 829–841 (2001).

    Article  CAS  PubMed  Google Scholar 

  94. Bonner–Weir, S. & Sharma, A. Pancreatic stem cells. J. Pathol. 197, 519–526 (2002).

    Article  PubMed  Google Scholar 

  95. Elsasser, H.-P., Adler, G. & Kern, H. F. in The Pancreas: Biology, Pathobiology and Disease (Raven Press Ltd, New York, 1993).

    Google Scholar 

  96. Bonner–Weir, S., Stubbs, M., Reitz, P., Taneja, M. & Smith, F. E. in Pancreatic Growth and Regeneration (ed. Sarvetnick, N.) (Karger Landes Systems, Basel, Switzerland, 1997).

    Google Scholar 

  97. Sharma, A. et al. The homeodomain protein IDX-1 increases after an early burst of proliferation during pancreatic regeneration. Diabetes 48, 507–513 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Vinik, A. I., Pittenger, G. L., Rafaeloff, R., Rosenberg, L. & Duguid, W. in Pancreatic Growth and Regeneration. (ed. Sarvetnick, N.) 183–217 (Karger Landes Systems, Basel, 1997).

    Google Scholar 

  99. Scoggins, C. R. et al. p53-dependent acinar cell apoptosis triggers epithelial proliferation in duct-ligated murine pancreas. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G827–G836 (2000).

    Article  CAS  PubMed  Google Scholar 

  100. Kritzik, M. R. et al. PDX-1 and Msx-2 expression in the regenerating and developing pancreas. J. Endocrinol. 163, 523–530 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Arnush, M. et al. Growth factors in the regenerating pancreas of γ-interferon transgenic mice. Lab. Invest. 74, 985–990 (1996).

    CAS  PubMed  Google Scholar 

  102. Rooman, I., Heremans, Y., Heimberg, H. & Bouwens, L. Modulation of rat pancreatic acinoductal transdifferentiation and expression of PDX-1 in vitro. Diabetologia 43, 907–914 (2000).

    Article  CAS  PubMed  Google Scholar 

  103. Bachoo, R. M. et al. Epidermal growth factor receptor and Ink4a/Arf. Convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell 1, 269–277 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Lohr, M. et al. Transforming growth factor-β1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 61, 550–555 (2001).

    CAS  PubMed  Google Scholar 

  105. Schwarte-Waldhoff, I. et al. Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc. Natl Acad. Sci. USA 97, 9624–9629 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Bissell, M. J. & Radisky, D. Putting tumours in context. Nature Rev. Cancer 1, 46–54 (2001).

    CAS  Google Scholar 

  107. Olumi, A. F. et al. Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59, 5002–5011 (1999).

    CAS  PubMed  Google Scholar 

  108. Van Dyke, T. & Jacks, T. Cancer modeling in the modern era: progress and challenges. Cell 108, 135–144 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Ornitz, D. M., Hammer, R. E., Messing, A., Palmiter, R. D. & Brinster, R. L. Pancreatic neoplasia induced by SV40 T-antigen expression in acinar cells of transgenic mice. Science 238, 188–193 (1987).

    Article  CAS  PubMed  Google Scholar 

  110. Glasner, S., Memoli, V. & Longnecker, D. S. Characterization of the ELSV transgenic mouse model of pancreatic carcinoma. Histologic type of large and small tumors. Am. J. Pathol. 140, 1237–1245 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Quaife, C. J., Pinkert, C. A., Ornitz, D. M., Palmiter, R. D. & Brinster, R. L. Pancreatic neoplasia induced by Ras expression in acinar cells of transgenic mice. Cell 48, 1023–1034 (1987).

    Article  CAS  PubMed  Google Scholar 

  112. Sandgren, E. P., Quaife, C. J., Paulovich, A. G., Palmiter, R. D. & Brinster, R. L. Pancreatic tumor pathogenesis reflects the causative genetic lesion. Proc Natl Acad Sci USA 88, 93–97 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sandgren, E. P. et al. Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol. Cell Biol. 13, 320–330 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Bardeesy, N. et al. Obligate roles for p16(Ink4a) and p19(Arf)-p53 in the suppression of murine pancreatic neoplasia. Mol. Cell Biol. 22, 635–643 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Sotillo, R. et al. Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. EMBO J. 20, 6637–6647 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Rane, S. G. et al. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nature Genet. 22, 44–52 (1999).

    Article  CAS  PubMed  Google Scholar 

  117. Xu, X. et al. Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. Oncogene 19, 1868–1874 (2000).

    Article  CAS  PubMed  Google Scholar 

  118. Takaku, K. et al. Gastric and duodenal polyps in Smad4 (Dpc4) knockout mice. Cancer Res. 59, 6113–6117 (1999).

    CAS  PubMed  Google Scholar 

  119. Jishage, K. et al. Role of Lkb1, the causative gene of Peutz–Jegher's syndrome, in embryogenesis and polyposis. Proc. Natl Acad. Sci. USA 99, 8903–8908 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Miyoshi, H. et al. Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 62, 2261–2266 (2002).

    CAS  PubMed  Google Scholar 

  121. Bardeesy, N. et al. Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature 419, 162–167 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Robanus-Maandag, E. et al. p107 is a suppressor of retinoblastoma development in pRb-deficient mice. Genes Dev. 12, 1599–1609 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Jonkers, J. & Berns, A. Conditional mouse models of sporadic cancer. Nature Rev. Cancer 2, 251–265 (2002).

    Article  CAS  Google Scholar 

  124. Gu, G., Dubauskaite, J. & Melton, D. A. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors. Development 129, 2447–2457 (2002).

    Article  CAS  PubMed  Google Scholar 

  125. Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Hennig, R. et al. 5-lipoxygenase and leukotriene b(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am. J. Pathol. 161, 421–428 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Maitra, A. et al. Cyclooxygenase 2 expression in pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia: an immunohistochemical analysis with automated cellular imaging. Am. J. Clin. Pathol. 118, 194–201 (2002).

    Article  CAS  PubMed  Google Scholar 

  128. Tucker, O. N. et al. Cyclooxygenase-2 expression is up-regulated in human pancreatic cancer. Cancer Res. 59, 987–990 (1999).

    CAS  PubMed  Google Scholar 

  129. Anderson, K. E., Johnson, T. W., Lazovich, D. & Folsom, A. R. Association between nonsteroidal anti-inflammatory drug use and the incidence of pancreatic cancer. J. Natl Cancer Inst. 94, 1168–1171 (2002).

    Article  PubMed  Google Scholar 

  130. Oshima, M. & Taketo, M. M. COX selectivity and animal models for colon cancer. Curr. Pharm. Des. 8, 1021–1034 (2002).

    Article  CAS  PubMed  Google Scholar 

  131. Ramaswamy, S. & Golub, T. R. DNA microarrays in clinical oncology. J. Clin. Oncol. 20, 1932–1941 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Argani, P. et al. Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma. Cancer Res. 61, 4320–4324 (2001).

    CAS  PubMed  Google Scholar 

  133. Iacobuzio-Donahue, C. A. et al. Discovery of novel tumor markers of pancreatic cancer using global gene expression technology. Am. J. Pathol. 160, 1239–1249 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rosty, C. et al. Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein I as a biomarker for pancreatic ductal adenocarcinoma by protein biochip technology. Cancer Res. 62, 1868–1875 (2002).

    CAS  PubMed  Google Scholar 

  135. Han, H. et al. Identification of differentially expressed genes in pancreatic cancer cells using cDNA microarray. Cancer Res. 62, 2890–2896 (2002).

    CAS  PubMed  Google Scholar 

  136. Githens, S. in The Pancreas: Biology, Pathobiology and Disease (eds Liang, V. & Go, W.) 21–55 (Raven Press Ltd, New York, 1993).

    Google Scholar 

  137. Slack, J. M. Developmental biology of the pancreas. Development 121, 1569–1580 (1995).

    Article  CAS  PubMed  Google Scholar 

  138. Kim, S. K. & Hebrok, M. Intercellular signals regulating pancreas development and function. Genes Dev. 15, 111–127 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Kobitsu, K. et al. Shortened telomere length and increased telomerase activity in hamster pancreatic duct adenocarcinomas and cell lines. Mol. Carcinog. 18, 153–159 (1997).

    Article  CAS  PubMed  Google Scholar 

  140. Edlund, H. Organogenesis: pancreatic organogenesis developmental mechanisms and implications for therapy. Nature Rev. Genet. 3, 524–532 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Hebrok, M., Kim, S. K. & Melton, D. A. Notochord repression of endodermal Sonic hedgehog permits pancreas development. Genes Dev. 12, 1705–1713 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Wells, J. M. & Melton, D. A. Vertebrate endoderm development. Annu. Rev. Cell Dev. Biol. 15, 393–410 (1999).

    Article  CAS  PubMed  Google Scholar 

  143. Shen, C. N., Slack, J. M. & Tosh, D. Molecular basis of transdifferentiation of pancreas to liver. Nature Cell Biol. 2, 879–887 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Harada, T. et al. Interglandular cytogenetic heterogeneity detected by comparative genomic hybridization in pancreatic cancer. Cancer Res 62, 835–839 (2002).

    CAS  PubMed  Google Scholar 

  145. Giardiello, F. M. et al. Very high risk of cancer in familial Peutz–Jeghers syndrome. Gastroenterology 119, 1447–1453 (2000).

    Article  CAS  PubMed  Google Scholar 

  146. Clarke, A. R., Cummings, M. C. & Harrison, D. J. Interaction between murine germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to increased intestinal malignancy. Oncogene 11, 1913–1920 (1995).

    CAS  PubMed  Google Scholar 

  147. Meszoely, I. M., Means, A. L., Scoggins, C. R. & Leach, S. D. Developmental aspects of early pancreatic cancer. Cancer J. 7, 242–250 (2001).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Adult Oncology, Dana–Farber Cancer Institute and Departments of Medicine and Genetics, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Nabeel Bardeesy & Ronald A. DePinho

Authors
  1. Nabeel Bardeesy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronald A. DePinho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ronald A. DePinho.

Related links

Related links

DATABASES

Cancer.gov

pancreatic adenocarcinoma

LocusLink

BRCA2

CDK4

CDK6

CDKN2A

EGF

EGFR

ERBB2

ERBB3

KRAS

LKB1

MDM2

MLH1

MSH2

MSH6

Pdx1

PRSS1

RB

SMAD4

TGF-α

TP53

WAF1

OMIM

FAMMM syndrome

hereditary pancreatitis

HNPCC syndrome

Peutz–Jeghers syndrome

FURTHER INFORMATION

Pancreatic Cancer Agenda for Action

Glossary

PANCREATIC ADENOCARCINOMA

The most common type of cancer of the pancreas, accounting for greater than 85% of pancreatic neoplasms. These tumours show histological resemblance to the pancreatic ducts and are also referred to as pancreatic ductal adenocarcinoma, or simply pancreatic cancer.

PANCREATICODUODENECTOMY

A surgical resection of the distal stomach, duodenum, common duct, and head of the pancreas, containing the pancreatic neoplasm.

INK4A

A cyclin-dependent kinase inhibitor that acts on cyclin-D–CDK4/6. It prevents hyperphosphorylation and inactivation of RB, so cells can not enter S phase.

ARF

A regulator of p53 that functions by inhibiting MDM2-dependent proteolysis of p53.

LOSS OF HETEROZYGOSITY

(LOH). In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with high frequency of LOH are believed to harbour tumour-suppressor genes.

MAPK PATHWAY

A signal-transduction pathway that is crucial for the integration of mitogenic signals mediated by various growth factors. Activation of this pathway is involved in many cellular processes, including cell-cycle progression.

AUTOCRINE SIGNALLING

A signal-transduction mechanism in which both a secreted ligand and corresponding cell-surface receptor are expressed by the same cell.

PI3K PATHWAY

The phosphatidylinositol 3-kinase (PI3K) family of enzymes are activated in response to various stimuli and catalyse the phophorylation of inositol lipids at the d-3 position of the inositol ring. These phosphoinositides act as second messengers; a primary target is the serine/threonine kinase AKT (protein kinase B). Activated AKT phosphorylates several cellular targets, including proteins that are involved in cell survival, proliferation and migration.

FIELD DEFECT

The independent transformation of different epithelial cells following exposure of an area of tissue to carcinogenic insults.

COMPARATIVE GENOMIC HYBRIDIZATION

A method that is used to detect chromosome copy-number alterations. Tumour and control DNA are labelled with different coloured fluorescent dyes and hybridized to metaphase chromosomes. Deletions/amplifications are visualized by changes in the fluorescent spectrum at specific chromosomal regions. Array-CGH allows higher resolution and accuracy as it uses hybridization to small DNA fragments that are arranged on microchips.

TRANSFORMING GROWTH FACTOR-β FAMILY

Secreted growth factors, comprising the TGF-β, bone morphogenic protein and activin families, which transduce signals through specific cell-surface receptors. These signalling pathways control many morphogenic and homeostatic processes. SMAD4 mediates TGF-β-family signalling, linking receptor stimulation to transcriptional responses by complexing with specific receptor-activated SMADs and other transcriptional components.

STROMA

The non-transformed component of epithelial tumours, comprised of fibroblasts, blood-vessel elements and immune cells. The stromal cells do not show the same clonal genetic changes as the malignant tumour cells, yet are altered by molecular events in the tumour cells and, in turn, modulate biological features of the tumour compartment. These heterotypic interactions are fundamental to tumour genesis and progression.

CELL OF ORIGIN

The cell type and specific developmental stage from which a tumour type evolves. Although epithelial tumours are classified by their histological resemblance to normal cellular counterparts, this might not strictly indicate a cell-lineage relationship, given the known developmental plasticity of malignant cells. Understanding the cell of origin in pancreatic adenocarcinoma might help in prevention, diagnosis and treatment.

TRANSDIFFERENTIATION

The conversion of one differentiated cell type into another. Transdifferentiation and the conversion between undifferentiated stem cells of different tissue are subclasses of metaplasia.

APC Min/+

A mouse strain that is prone to the development of multiple intestinal polyps, due to mutations in the Apc gene — the homologue of the human familial colon cancer gene.

CRE RECOMBINASE

An enzyme that is derived from the P1 bacteriophage that binds to a 34-base-pair DNA sequence (loxP site). Sequences flanked by loxP sites can be excised by Cre recombinase expression. The Cre–Lox system is a technology that allows genes to be ablated in a tissue-selective and inducible manner.

AVIAN RETROVIRAL RECEPTOR

An avian cell-surface protein that is required for infection by the avian sarcoma and leukosis virus (ASLV). Tissue-specific expression of the gene encoding this receptor in transgenic mice enables infection of these tissues with ASLV, allowing somatically targeted gene transfer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bardeesy, N., DePinho, R. Pancreatic cancer biology and genetics. Nat Rev Cancer 2, 897–909 (2002). https://doi.org/10.1038/nrc949

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc949

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing