TY - JOUR
T1 - Obligate roles for p16Ink4a and p19Arf-p53 in the suppression of murine pancreatic neoplasia
AU - Bardeesy, N.
AU - Morgan, J.
AU - Sinha, M.
AU - Signoretti, S.
AU - Srivastava, S.
AU - Loda, M.
AU - Merlino, G.
AU - DePinho, R. A.
PY - 2002
Y1 - 2002
N2 - Epithelial tumors of the pancreas exhibit a wide spectrum of histologies with varying propensities for metastasis and tissue invasion. The histogenic relationship among these tumor types is not well established; moreover, the specific role of genetic lesions in the progression of these malignancies is largely undefined. Transgenic mice with ectopic expression of transforming growth factor alpha (TGF-α) in the pancreatic acinar cells develop tubular metaplasia, a potential premalignant lesion of the pancreatic ductal epithelium. To evaluate the cooperative interactions between TGF-α and signature mutations in pancreatic tumor genesis and progression, TGFα transgenic mice were crossed onto Ink4a/Arf and/or p53 mutant backgrounds. These compound mutant mice developed a novel pancreatic neoplasm, serous cystadenoma (SCA), presenting as large epithelial tumors bearing conspicuous gross and histological resemblances to their human counterpart. TGFα animals heterozygous for both the Ink4a/Arf and the p53 mutation showed a dramatically increased incidence of SCA, indicating synergistic interaction of these alleles. Inactivation of p16Ink4a by loss of heterozygosity, intragenic mutation, or promoter hypermethylation was a common feature in these SCAs, and correspondingly, none of the tumors expressed wild-type p16Ink4a. All tumors sustained loss of p53 or Arf, generally in a mutually exclusive fashion. The tumor incidence data and molecular profiles establish a pathogenic role for the dual inactivation of p16Ink4a and p19Arf-p53 in the development of SCA in mice, demonstrating that p16Ink4a is a murine tumor suppressor. This genetically defined model provides insights into the molecular pathogenesis of SCA and serves as a platform for dissection of cell-specific programs of epithelial tumor suppression.
AB - Epithelial tumors of the pancreas exhibit a wide spectrum of histologies with varying propensities for metastasis and tissue invasion. The histogenic relationship among these tumor types is not well established; moreover, the specific role of genetic lesions in the progression of these malignancies is largely undefined. Transgenic mice with ectopic expression of transforming growth factor alpha (TGF-α) in the pancreatic acinar cells develop tubular metaplasia, a potential premalignant lesion of the pancreatic ductal epithelium. To evaluate the cooperative interactions between TGF-α and signature mutations in pancreatic tumor genesis and progression, TGFα transgenic mice were crossed onto Ink4a/Arf and/or p53 mutant backgrounds. These compound mutant mice developed a novel pancreatic neoplasm, serous cystadenoma (SCA), presenting as large epithelial tumors bearing conspicuous gross and histological resemblances to their human counterpart. TGFα animals heterozygous for both the Ink4a/Arf and the p53 mutation showed a dramatically increased incidence of SCA, indicating synergistic interaction of these alleles. Inactivation of p16Ink4a by loss of heterozygosity, intragenic mutation, or promoter hypermethylation was a common feature in these SCAs, and correspondingly, none of the tumors expressed wild-type p16Ink4a. All tumors sustained loss of p53 or Arf, generally in a mutually exclusive fashion. The tumor incidence data and molecular profiles establish a pathogenic role for the dual inactivation of p16Ink4a and p19Arf-p53 in the development of SCA in mice, demonstrating that p16Ink4a is a murine tumor suppressor. This genetically defined model provides insights into the molecular pathogenesis of SCA and serves as a platform for dissection of cell-specific programs of epithelial tumor suppression.
UR - http://www.scopus.com/inward/record.url?scp=0036134968&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036134968&partnerID=8YFLogxK
U2 - 10.1128/MCB.22.2.635-643.2002
DO - 10.1128/MCB.22.2.635-643.2002
M3 - Article
C2 - 11756558
AN - SCOPUS:0036134968
SN - 0270-7306
VL - 22
SP - 635
EP - 643
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 2
ER -