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PMID: 14681205 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

The c-myc and PyMT oncogenes induce different tumor types in a somatic mouse model for pancreatic cancer.

Genes & development ·Vol. 17 ·No. 24 ·2003-12-15 ·Pages 3127-38

Lewis BC, Klimstra DS, Varmus HE

Abstract

We have generated a mouse model for pancreatic cancer through the somatic delivery of oncogene-bearing avian retroviruses to mice that express TVA, the receptor for avian leukosis sarcoma virus subgroup A (ALSV-A), under the control of the elastase promoter. Delivery of ALSV-A-based RCAS vectors encoding either mouse polyoma virus middle T antigen (PyMT) or c-Myc to elastase-tv-a transgenic, Ink4a/Arf null mice induced the formation of pancreatic tumors. RCAS-PyMT induced pancreatic tumors with the histologic features of acinar or ductal carcinomas. The induced pancreatic lesions express Pdx1, a marker for pancreas progenitor cells, and many tumors express markers for both exocrine and endocrine cell lineages, suggesting that the tumors may be derived from progenitor cells. In contrast, RCAS-c-myc induced endocrine tumors exclusively, as determined by histology and detection of differentiation markers. Thus, specific oncogenes can induce the formation of different pancreatic tumor types in a single transgenic line, most likely from one or more types of multipotential progenitor cells. Our model appears to be useful for elucidating the genetic alterations, target cells, and signaling pathways that are important in the genesis of different types of pancreatic cancer.

MeSH Terms
Animals Antigens, Polyomavirus Transforming/physiology Avian Leukosis Virus/genetics Avian Proteins Biomarkers, Tumor/analysis Carcinoma in Situ/genetics,metabolism,pathology Carcinoma, Acinar Cell/genetics,metabolism,pathology Carcinoma, Pancreatic Ductal/genetics,metabolism,pathology Cell Transformation, Neoplastic/pathology Cyclin-Dependent Kinase Inhibitor p16/physiology Cystadenocarcinoma/genetics,metabolism,pathology DNA-Binding Proteins/metabolism Genetic Vectors Humans Insulinoma/pathology Mice Mice, Knockout Mice, Transgenic Paired Box Transcription Factors Pancreas/pathology Pancreatic Elastase/metabolism Pancreatic Neoplasms/genetics,metabolism,pathology Plasmids/genetics Proto-Oncogene Proteins c-myc/physiology Receptors, Virus/genetics,metabolism Transcription Factors/metabolism Transfection Tumor Suppressor Protein p14ARF/physiology
Chemicals
Antigens, Polyomavirus Transforming Avian Proteins Biomarkers, Tumor Cyclin-Dependent Kinase Inhibitor p16 DNA-Binding Proteins Paired Box Transcription Factors Proto-Oncogene Proteins c-myc Receptors, Virus Transcription Factors Tumor Suppressor Protein p14ARF Tva receptor PAX1 transcription factor Pancreatic Elastase
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Lewis Brian C
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. brian.lewis@umassmed.edu
Klimstra David S
Varmus Harold E
References (49)
49 references, click to expand
  1. Passage through mitosis is required for oncoretroviruses but not for the human immunodeficiency virus.
    J Virol. 1994 Jan;68(1):510-6 PMID: 8254763
  2. A receptor for subgroup A Rous sarcoma virus is related to the low density lipoprotein receptor.
    Cell. 1993 Sep 24;74(6):1043-51 PMID: 8402880
  3. Murine pancreatic ductal adenocarcinoma produced by in vitro transduction of polyoma middle T oncogene into the islets of Langerhans.
    Am J Pathol. 1994 Sep;145(3):671-84 PMID: 7521578
  4. Insulin-promoter-factor 1 is required for pancreas development in mice.
    Nature. 1994 Oct 13;371(6498):606-9 PMID: 7935793
  5. Role of the INK4a locus in tumor suppression and cell mortality.
    Cell. 1996 Apr 5;85(1):27-37 PMID: 8620534
  6. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.
    Development. 1996 Mar;122(3):983-95 PMID: 8631275
  7. Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables.
    Hum Pathol. 1996 Nov;27(11):1124-34 PMID: 8912819
  8. The DF-1 chicken fibroblast cell line: transformation induced by diverse oncogenes and cell death resulting from infection by avian leukosis viruses.
    Virology. 1998 Sep 1;248(2):295-304 PMID: 9721238
  9. The EV-O-derived cell line DF-1 supports the efficient replication of avian leukosis-sarcoma viruses and vectors.
    Virology. 1998 Sep 1;248(2):305-11 PMID: 9721239
  10. Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice.
    Gastroenterology. 1998 Nov;115(5):1254-62 PMID: 9797382
  11. Transcribing pancreas.
    Diabetes. 1998 Dec;47(12):1817-23 PMID: 9836511
  12. Development of a flexible and specific gene delivery system for production of murine tumor models.
    Oncogene. 1999 Sep 20;18(38):5253-60 PMID: 10498877
  13. Disruption of the ARF-Mdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis.
    Genes Dev. 1999 Oct 15;13(20):2658-69 PMID: 10541552
  14. INK4a/ARF mutations accelerate lymphomagenesis and promote chemoresistance by disabling p53.
    Genes Dev. 1999 Oct 15;13(20):2670-7 PMID: 10541553
  15. Mist1 expression is a common link among serous exocrine cells exhibiting regulated exocytosis.
    Anat Rec. 2000 Jun 1;259(2):157-67 PMID: 10820318
  16. Expression of neurogenin3 reveals an islet cell precursor population in the pancreas.
    Development. 2000 Aug;127(16):3533-42 PMID: 10903178
  17. Astrocytes give rise to oligodendrogliomas and astrocytomas after gene transfer of polyoma virus middle T antigen in vivo.
    Am J Pathol. 2000 Sep;157(3):1031-7 PMID: 10980141
  18. Developmental biology of the pancreas.
    Diabetes. 2001 Feb;50 Suppl 1:S5-9 PMID: 11272202
  19. A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease.
    Genes Dev. 2001 Feb 1;15(3):286-93 PMID: 11159909
  20. Natural biology of polyomavirus middle T antigen.
    Microbiol Mol Biol Rev. 2001 Jun;65(2):288-318 ; second and third pages, table of contents PMID: 11381103
  21. Development of an avian leukosis-sarcoma virus subgroup A pseudotyped lentiviral vector.
    J Virol. 2001 Oct;75(19):9339-44 PMID: 11533197
  22. Cancer statistics, 2002.
    CA Cancer J Clin. 2002 Jan-Feb;52(1):23-47 PMID: 11814064
  23. Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway.
    Am J Pathol. 2002 Mar;160(3):953-62 PMID: 11891193
  24. MYC expression promotes the proliferation of neural progenitor cells in culture and in vivo.
    Neoplasia. 2002 Jan-Feb;4(1):32-9 PMID: 11922389
  25. Direct evidence for the pancreatic lineage: NGN3+ cells are islet progenitors and are distinct from duct progenitors.
    Development. 2002 May;129(10):2447-57 PMID: 11973276
  26. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression.
    Cell. 2002 May 3;109(3):321-34 PMID: 12015982
  27. Acinar-to-ductal metaplasia in pancreatic cancer development.
    J Clin Invest. 2002 Jun;109(11):1403-4 PMID: 12045253
  28. Induction of ovarian cancer by defined multiple genetic changes in a mouse model system.
    Cancer Cell. 2002 Feb;1(1):53-62 PMID: 12086888
  29. Pancreatic organogenesis--developmental mechanisms and implications for therapy.
    Nat Rev Genet. 2002 Jul;3(7):524-32 PMID: 12094230
  30. Focus on pancreas cancer.
    Cancer Cell. 2002 Jul;2(1):25-8 PMID: 12150822
  31. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors.
    Nat Genet. 2002 Sep;32(1):128-34 PMID: 12185368
  32. An RCAS-TVA-based approach to designer mouse models.
    Mamm Genome. 2002 Oct;13(10):543-7 PMID: 12420130
  33. Pancreatic cancer biology and genetics.
    Nat Rev Cancer. 2002 Dec;2(12):897-909 PMID: 12459728
  34. Gene expression cascades in pancreatic development.
    Mech Dev. 2003 Jan;120(1):65-80 PMID: 12490297
  35. Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice.
    Cancer Res. 2003 May 1;63(9):2016-9 PMID: 12727811
  36. Specific expression of an elastase-human growth hormone fusion gene in pancreatic acinar cells of transgenic mice.
    Nature. 1985 Feb 14-20;313(6003):600-2 PMID: 3844051
  37. Pancreatic neoplasia induced by ras expression in acinar cells of transgenic mice.
    Cell. 1987 Mar 27;48(6):1023-34 PMID: 3470144
  38. Expression of the proto-oncogene int-1 is restricted to specific neural cells in the developing mouse embryo.
    Cell. 1987 Jul 3;50(1):79-88 PMID: 3594565
  39. Endocrine tumors--special problems in diagnosis and management.
    Semin Oncol. 1987 Sep;14(3):235-6 PMID: 3629264
  40. Pancreatic neoplasia induced by SV40 T-antigen expression in acinar cells of transgenic mice.
    Science. 1987 Oct 9;238(4824):188-93 PMID: 2821617
  41. Embryonic expression pattern of TGF beta type-1 RNA suggests both paracrine and autocrine mechanisms of action.
    Development. 1988 Oct;104(2):263-73 PMID: 2474426
  42. Pancreatic acinar cells in culture: expression of acinar and ductal antigens in a growth-related manner.
    Eur J Cell Biol. 1990 Feb;51(1):64-75 PMID: 2184038
  43. Overexpression of TGF alpha in transgenic mice: induction of epithelial hyperplasia, pancreatic metaplasia, and carcinoma of the breast.
    Cell. 1990 Jun 15;61(6):1121-35 PMID: 1693546
  44. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas.
    Cell. 1990 Jun 15;61(6):1137-46 PMID: 2350785
  45. Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection.
    Mol Cell Biol. 1990 Aug;10(8):4239-42 PMID: 2370865
  46. Pancreatic tumor pathogenesis reflects the causative genetic lesion.
    Proc Natl Acad Sci U S A. 1991 Jan 1;88(1):93-7 PMID: 1986386
  47. Integration of murine leukemia virus DNA depends on mitosis.
    EMBO J. 1993 May;12(5):2099-108 PMID: 8491198
  48. An endocrine-specific element is an integral component of an exocrine-specific pancreatic enhancer.
    Genes Dev. 1993 May;7(5):774-86 PMID: 7684006
  49. Mixed acinar-endocrine carcinomas of the pancreas.
    Am J Surg Pathol. 1994 Aug;18(8):765-78 PMID: 8037290
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
0890-9369
DOI
10.1101/gad.1140403
Email
brian.lewis@umassmed.edu
Published
2003-12-15
Epub
2003-00-17
Pages
3127-38
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC305263
Subset
IM
External Links
PubMed source DOI: 10.1101/gad.1140403 PMC Full Text View journal details
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