Tgfbr1 haploinsufficiency inhibits the development of murine mutant Kras-induced pancreatic precancer.
To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed Elastase-Kras(G12D) (EL-Kras) mice with Tgfbr1 haploinsufficient mice to generate EL-Kras/Tgfbr1(+/-) mice. Mice were euthanized at 6 to 9 months to compare the incidence, frequency, and size of precancerous lesions in the pancreas. Only 50% of all EL-Kras/Tgfbr1(+/-) mice developed preinvasive lesions compared with 100% of EL-Kras (wild-type Tgfbr1) mice. The frequency of precancerous lesions was 4-fold lower in haploinsufficient than in control mice. Paradoxically, the precancerous lesions of EL-Kras/Tgfbr1(+/-) mice were considerably larger than those in EL-Kras mice. Yet, the mitotic index of precancerous cells and the observable levels of fibrosis, lipoatrophy, and lymphocytic infiltration were reduced in EL-Kras/Tgfbr1(+/-) mice. We conclude that Tgfbr1 signaling promotes the development of precancerous lesions in mice. These findings suggest that individuals with constitutively decreased TGFBR1 expression may have a decreased risk of pancreatic cancer.
Adrian
Kevin
K
Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
Strouch
Matthew J
MJ
Zeng
Qinghua
Q
Barron
Morgan R
MR
Cheon
Eric C
EC
Honasoge
Akilesh
A
Xu
Yanfei
Y
Phukan
Sharbani
S
Sadim
Maureen
M
Bentrem
David J
DJ
Pasche
Boris
B
Grippo
Paul J
PJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D005260:Female; D006238:Haploidy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625842:Tgfbr1 protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)