A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease.
This study describes a tumor progression model for ductal pancreatic cancer in mice overexpressing TGF-alpha. Activation of Ras and Erk causes induction of cyclin D1-Cdk4 without increase of cyclin E or PCNA in ductal lesions. Thus, TGF-alpha is able to promote progression throughout G1, but not S phase. Crossbreeding with p53 null mice accelerates tumor development in TGF-alpha transgenic mice dramatically. In tumors developing in these mice, biallelic deletion of Ink4a/Arf or LOH of the Smad4 locus is found suggesting that loci in addition to p53 are involved in antitumor activities. We conclude that these genetic events are critical for pancreatic tumor formation in mice. This model recapitulates pathomorphological features and genetic alterations of the human disease.
Wagner
M
M
Department of Internal Medicine I, University of Ulm, 89081 Ulm, Germany.
Greten
F R
FR
Weber
C K
CK
Koschnick
S
S
Mattfeldt
T
T
Deppert
W
W
Kern
H
H
Adler
G
G
Schmid
R M
RM
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D011518:Proto-Oncogene Proteins; D016196:S Phase / Q000502:physiology; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; D016211:Transforming Growth Factor alpha; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins