Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / genetics
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Cell Growth Processes / genetics
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Female
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Haploidy
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Pancreatic Neoplasms / enzymology
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / pathology
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Precancerous Conditions / enzymology
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Precancerous Conditions / genetics*
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Precancerous Conditions / pathology
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Protein Serine-Threonine Kinases / genetics*
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins p21(ras) / genetics*
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Transforming Growth Factor beta / genetics*
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Receptors, Transforming Growth Factor beta / metabolism
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Signal Transduction
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Transforming Growth Factor beta / metabolism
Substances
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Receptors, Transforming Growth Factor beta
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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Receptor, Transforming Growth Factor-beta Type II
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Tgfbr1 protein, mouse
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)