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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, Polyomavirus Transforming / physiology*
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Avian Leukosis Virus / genetics
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Avian Proteins
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Biomarkers, Tumor / analysis
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Carcinoma in Situ / genetics
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Carcinoma in Situ / metabolism
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Carcinoma in Situ / pathology
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Carcinoma, Acinar Cell / genetics
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Carcinoma, Acinar Cell / metabolism
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Carcinoma, Acinar Cell / pathology*
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Carcinoma, Pancreatic Ductal / genetics
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Carcinoma, Pancreatic Ductal / metabolism
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Carcinoma, Pancreatic Ductal / pathology*
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Cell Transformation, Neoplastic / pathology
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Cyclin-Dependent Kinase Inhibitor p16 / physiology
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Cystadenocarcinoma / genetics
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Cystadenocarcinoma / metabolism
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Cystadenocarcinoma / pathology
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DNA-Binding Proteins / metabolism
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Genetic Vectors*
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Humans
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Insulinoma / pathology
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Mice
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Mice, Knockout
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Mice, Transgenic
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Paired Box Transcription Factors
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Pancreas / pathology
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Pancreatic Elastase / metabolism
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology*
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Plasmids / genetics
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Proto-Oncogene Proteins c-myc / physiology*
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Receptors, Virus / genetics
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Receptors, Virus / metabolism
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Transcription Factors / metabolism
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Transfection
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Tumor Suppressor Protein p14ARF / physiology
Substances
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Antigens, Polyomavirus Transforming
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Avian Proteins
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Biomarkers, Tumor
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Cyclin-Dependent Kinase Inhibitor p16
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DNA-Binding Proteins
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Paired Box Transcription Factors
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Proto-Oncogene Proteins c-myc
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Receptors, Virus
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Transcription Factors
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Tumor Suppressor Protein p14ARF
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Tva receptor
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PAX1 transcription factor
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Pancreatic Elastase