Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer
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.
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ABSTRACT: With the advent of mouse models that recapitulate the cellular and molecular pathology of pancreatic neoplasia and cancer, it is now feasible to recruit and deploy these models for the evaluation of various chemopreventive and/or anticancer regimens. The highly lethal nature of pancreatic ductal adenocarcinoma (PDAC) makes multiple areas of research a priority, including assessment of compounds that prevent or suppress the development of early lesions that can transform into PDAC. Currently, there are over a dozen models available, which range from homogeneous preneoplastic lesions with remarkable similarity to human pancreatic intraepithelial neoplasms to models with a more heterogeneous population of lesions including cystic papillary and mucinous lesions. The molecular features of these models may also vary in a manner comparable with the differences observed in lesion morphology, and so, navigating the route of model selection is not trivial. Yet, arming the community of cancer investigators with a repertoire of models and the guidance to select relevant models that fit their research themes promises to produce findings that will have clinical relevance.Cancer Prevention Research 11/2010; 3(11):1382-7. DOI:10.1158/1940-6207.CAPR-10-0258 · 5.27 Impact Factor
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ABSTRACT: Human cell-free circulating DNA (cf-DNA) derived mainly from cell apoptosis and necrosis can be measured by a variety of laboratory techniques, but almost all of these methods require sample preparation. We have developed a branched DNA (bDNA)-based Alu assay for quantifying cf-DNA in myocardial infarction (MI) patients. A total of 82 individuals were included in the study; 22 MI and 60 normal controls. cf-DNA was quantified using a bDNA-based Alu assay. cf-DNA was higher in serum compared to plasma and there was a difference between genders. cf-DNA was significantly higher in MI patients compared to the controls. There was no correlation between cf-DNA and creatine kinase-MB (CK-MB), troponin I (cTnI) or myoglobin (MYO). In serial specimens, cf-DNA was sensitive and peaked earlier than cTnI. The bDNA-based Alu assay is a novel method for quantifying human cf-DNA. Increased cf-DNA in MI patients might complement cTnI, CK-MB and MYO in a multiple marker format.Clinical biochemistry 06/2011; 44(13):1074-9. DOI:10.1016/j.clinbiochem.2011.06.083 · 2.28 Impact Factor
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ABSTRACT: One of the major signaling pathways that determine the tumor aggression and patient outcome in pancreatic cancer is the transforming growth factor-beta (TGF-ß) pathway. It is inactivated at various levels in pancreatic cancer and plays a dual role in tumor initiation and progression. The Smad family of proteins transduce signals from the TGF-ß superfamily ligands that regulate cell proliferation, differentiation and death through activation of receptor serine/threonine kinases. This review discusses the structure, function and regulation of various participating Smad family members, and their individual roles in determining the progression and outcome of pancreatic cancer patients, with a special emphasis on Smad4.Indian Journal of Cancer 07/2011; 48(3):351-60. DOI:10.4103/0019-509X.84939 · 1.13 Impact Factor