Altered expression of TGFB receptors and mitogenic effects of TGFB in pancreatic carcinomas

Jonson, Tord; Albrechtsson, Elin; Axelson, Jan; Heidenblad, Markus; Gorunova, Ludmila; Johansson, Bertil; Höglund, Mattias

doi:10.3892/ijo.19.1.71

Cited by 37 publications

(48 citation statements)

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“…Findings in human PC are less clear, as reports vary regarding the expression of TGFBR1 and TGFBR2 in cancer cells. In 12 PC cell lines, an increase in TGFBR1 expression has been observed (22). In human cancer samples, initial reports indicated high levels of TGFBR1 in normal duct cells with low or nondetectable levels in cancer cells; the converse was true for TGFBR2 (7).…”

Section: Discussionmentioning

confidence: 89%

Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

et al. 2009

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To dissect the role of constitutively altered Tgfbr1 signaling in pancreatic cancer development, we crossed ElastaseKras 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. [Cancer Res 2009;69(24):9169-74]

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Section: Discussionmentioning

confidence: 89%

Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

et al. 2009

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“…27,28). Concomitant with increased secretion of TGF-h1 by cancer cells is an observed decrease in expression of receptors for TGF-h1 such as TGF-hR1, which has been shown to lead to increased cancer risk, tumorigenicity, and metastasis in several human cancers to include cancers of the kidney and bladder (47), colon (48), pancreas (49) and prostate (50). The decrease or loss of expression of a TGF-hR is often through mutations that alter its signaling functions (43).…”

Section: Discussionmentioning

confidence: 99%

Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52

Lewis

Payton

Whitford

et al. 2007

Molecular Cancer Research

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Expression studies have consistently identified tumor protein D52 (TPD52) overexpression in tumor cells. Murine TPD52 (mD52) shares 86% identity with the human orthologue. To study a possible role for TPD52 in transformation, 3T3 fibroblasts were transfected with the full-length cDNA for mD52. Expression of mD52 was confirmed by reverse transcription-PCR (RT-PCR), real-time PCR, and Western blot analysis compared with 3T3 and vector-transfected 3T3 (3T3.V), and the resultant cell line was designated 3T3.mD52. At 4 weeks, 3T3.mD52 gained a 2-fold increase in growth rate, lost contact inhibition, and exhibited a marked phenotype change. Further characterization revealed an acquired ability for anchorage-independent cell growth. To determine whether 3T3.mD52 had become tumorigenic, naïve, healthy, immunocompetent syngeneic mice were inoculated subcutaneously with varying cell doses. Tumors measuring >1 cm 2 were detected 60 days postinoculation with 3T3.mD52, and a 50% subcutaneous tumor incidence was obtained with as few as 5 Â 10 5 3T3.mD52 cells. Remarkably, when lungs from 3T3.mD52 tumor-bearing mice were analyzed, numerous tumor nodules were observed, ranging from nodules less than 10 to nodules too numerous to count (inoculation with 1 Â 10 5 and 5 Â 10 6 cells, respectively). Further support for the metastatic capacity of 3T3.mD52 was the demonstration that transforming growth factor (TGF)-BR1 (receptor) expression decreased and TGF-B1 secretion increased in 3T3.mD52 compared with 3T3 controls. cDNA microarray analysis showed a gene expression pattern that further supported mD52-induced transformation and metastasis. Together, these data suggest that mD52 expression in 3T3 cells initiated cellular transformation, tumorigenesis, and progression to metastasis. (Mol Cancer Res 2007;5(2):133 -44)

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“…We speculate that this may be a fairly common mechanism whereby tumor cells specifically become resistant to TGF-b-induced growth arrest, while remaining responsive to TGF-b's pro-oncogenic activities, since in many different tumor cells expression of either TbRII or TbRI/ALK5 is downregulated. This has been shown to result from altered levels of Ets transcription factors required for the expression of TbRII, hypermethylation of CpG islands in TbRI/ALK5 or TbRII gene promoters or from mutations in the promoter of TbRII that impair transcription factor binding Derynck et al, 2001;Jonson et al, 2001). Our current results indicate that an important determinant of the biological response to TGF-b is the time that the active Smad complexes remain nuclear after TGF-b stimulation, and we propose that the levels of TGF-b receptors could dictate this.…”

Section: The Time That the Active Smad Complexes Remain Nuclear Influmentioning

confidence: 99%

“…This would be expected to inhibit all TGF-b signaling and would not account for specific loss of TGF-b-induced growth arrest. A more frequent observation is that levels of the TGF-b receptors are decreased in advanced human tumors (Baldwin et al, 1996;Wagner et al, 1998;Kim et al, 2000;Derynck et al, 2001;Jonson et al, 2001). …”

Section: Introductionmentioning

confidence: 99%

Attenuation of the TGF-β-Smad signaling pathway in pancreatic tumor cells confers resistance to TGF-β-induced growth arrest

2003

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We have investigated the mechanism whereby tumor cells become resistant to the antiproliferative effects of transforming growth factor (TGF)-b, while maintaining other responses that can lead to increased malignancy and invasiveness. TGF-b signaling results in nuclear accumulation of active Smad complexes which regulate transcription of target genes. Here we show that in two pancreatic carcinoma cell lines, PT45 and Panc-1, that are resistant to TGF-b-induced growth arrest, the TGF-b-Smad signaling pathway is attenuated compared with epithelial cells that are sensitive to the antiproliferative effects of TGF-b (HaCaT and Colo-357). In PT45 and Panc-1 cells, active Smad complexes remain nuclear for only 1-2 h compared with more than 6 h in HaCaT and Colo-357 cells. The attenuated pathway in PT45 and Panc-1 cells correlates with low levels of TGF-b type I receptor and results in an altered expression profile of TGF-b-inducible genes required for cell cycle arrest. Most significantly, expression of the CDK inhibitor, p21 Cip1/WAF1 , which is required for TGF-b-induced growth arrest in these cells, is not maintained. Moreover, we show that artificially attenuating the TGF-b-Smad signaling pathway in HaCaT cells is sufficient to prevent TGF-b-induced growth arrest. Our results demonstrate that the duration of TGF-b-Smad signaling is a critical determinant of the specificity of the TGF-b response.

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Altered expression of TGFB receptors and mitogenic effects of TGFB in pancreatic carcinomas

Cited by 37 publications

References 0 publications

Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

Tgfbr1 Haploinsufficiency Inhibits the Development of Murine Mutant Kras-Induced Pancreatic Precancer

Induction of Tumorigenesis and Metastasis by the Murine Orthologue of Tumor Protein D52

Attenuation of the TGF-β-Smad signaling pathway in pancreatic tumor cells confers resistance to TGF-β-induced growth arrest

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