Amelioration of Pancreatic Fibrosis in Mice With Defective TGF-?? Signaling

Yoo, Byung Moo; Yeo, Myoung-Souk; Oh, Tae Young; Choi, Jae Young; Kim, Wook Whan; Kim, Jin Hong; Cho, Sung Won; Kim, Seong‐Jin; Hahm, Ki‐Baik

doi:10.1097/01.mpa.0000157388.54016.0a

Cited by 66 publications

(50 citation statements)

References 38 publications

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“…Because type I collagen is the predominant matrix in the desmoplastic reaction (4,5), and because genetic studies have shown that MT1-MMP is a primary regulator of interstitial collagenolysis (16), our data suggest that inhibition of TGF-h1 signaling would also help to block tumor progression in vivo. Importantly, TGF-h1 has also been shown to promote a desmoplastic reaction in vivo following orthotopic transplantation of TGF-h1-transfected pancreatic cancer cells in an experimental model of human pancreatic carcinoma (46), whereas conditional loss of TGF-h1 signaling within the pancreas significantly ameliorated chemical-induced pancreatic fibrosis (47,48). Based on our data and on recent reports showing that the desmoplastic reaction is detrimental to the host (7,35), modulation of TGF-h1 signaling using small-molecule inhibitors, a number of which are currently under development (49), could be a potential approach for the treatment of this highly lethal cancer.…”

Section: Discussionmentioning

confidence: 99%

Extracellular Matrix–Mediated Membrane-Type 1 Matrix Metalloproteinase Expression in Pancreatic Ductal Cells Is Regulated by Transforming Growth Factor-β1

et al. 2006

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Pancreatic ductal adenocarcinoma (PDAC) is associated with an intense fibrotic reaction around the tumor known as desmoplastic reaction. This tissue is composed of interstitial matrix, predominantly type I collagen, together with proliferating fibroblastic cells. Despite the recognized importance of tumor-stromal interactions, very little is known about the interactions among pancreatic cells, myofibroblasts, and the interstitial matrix. The current study was undertaken to test the hypothesis that the desmoplastic reaction alters PDAC gene expression and cellular behavior. Evaluation of human pancreatic specimens showed increased fibrosis and enhanced membrane type 1-matrix metalloproteinase (MT1-MMP) expression in tumor specimens compared with normal pancreas. Using an in vitro model of tumor cell-stromal interactions, type I collagen and the extracellular matrix deposited by pancreatic fibroblasts and PDAC cells regulated motility of human papillomavirus-immortalized human pancreatic ductal epithelial (HPDE) cells. These ''stromal'' matrices also regulated MT1-MMP expression by HPDE cells, without affecting the expression of tissue inhibitor of metalloproteinase 2. Treatment with transforming growth factor-B1 (TGF-B1) type I receptor kinase inhibitors and functionblocking anti-TGF-B1 antibody abrogated matrix-mediated MT1-MMP induction. TGF-B1 also promoted MT1-MMPdependent migration by HPDE cells. Moreover, compared with normal tissue, there was increased TGF-B1 signaling in grade 3 tumor specimens as shown by increased phosphoSmad2 staining. These data show that the crosstalk between cancer cells and stromal elements mediated by TGF-B1 influences cell surface-and pericellular matrix-degrading potential in vitro and may contribute to pancreatic cancer progression in vivo.

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Section: Discussionmentioning

confidence: 99%

Extracellular Matrix–Mediated Membrane-Type 1 Matrix Metalloproteinase Expression in Pancreatic Ductal Cells Is Regulated by Transforming Growth Factor-β1

et al. 2006

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“…It was reported that TGF is the key regulating factor of fibrosis. Modulation of TGF-β signaling may be the therapeutic target for the prevention of chronic pancreatitis [18] . It was reported that emodin could inhibit the expression of TGF-β1 in liver fibrosis model of rats [6] .…”

Section: Discussionmentioning

confidence: 99%

Effect of emodin on pancreatic fibrosis in rats

Wang

Gao²,

Yu³

et al. 2007

WJG

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AIM:To establish the rats model of chronic fibrosing pancreatitis and to prove the anti-fibrotic effect of emodin in chronic pancreatitis with fibrosis. METHODS:Fifty rats were randomly divided into five groups, 10 rats in each group. Trinitrobenzene sulfonic acid (TNBS) was infused into the pancreatic duct to induce chronic pancreatitis in rats (except for normal group). Emodin-treated rats were fed with different doses of emodin (20, 40 and 80 mg/kg body weight) for 28 d, while normal group and control group received 0.9% sodium chloride solution. Serum levels of hyaluronic acid (HA) and laminin (LN) were determined by radioimmunoassay. Histopathological alterations were studied by optical microscopy. Expression of collagen was also examined while transforming growth factorbeta-1 (TGF-β1) was localized by immunochemistry. RESULTS:In emodin-treated rats, the serum levels of HA and LN were decreased significantly (HA, 62.2 ± 19.3 µg/L vs 112.7 ± 26.5 µg/L, P < 0.05; LN 44.3 ± 10.4 µg/L vs 86.2 ± 16.5 µg/L, P < 0.05); the degree of fibrosis was ameliorated observably; the expression of collagen in pancreatic tissue was reduced especially in high-dose emodin-treated group (36% ± 5% vs 42% ± 6%, P < 0.05); with the increased doses of emodin, the expression of TGF-β1 was declined, compared with those in control group. CONCLUSION:Emodin has an anti-fibrotic effect on pancreatic fibrosis in rats. Because of its anti-fibrotic effect, it could be a potential herb for the treatment of chronic pancreatitis.

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“…Agents showing benefit in experimental chronic pancreatitis include inhibitors of angiotensin II-converting enzyme and antagonists of the angiotensin II receptor (50,108); vitamin E (118) and DA-9601 (119), which function as antioxidants; troglitazone and thiazolidinedione, which are PPARγ ligands (120,121); camostat, which is a serine protease inhibitor (62,122); the herbal preparation Saiko-keishito, which has antioxidant and antiinflammatory properties (123); and COX-2 inhibitors (124). In addition, strategies aimed at blocking TGF-β signaling pathways (113,125) have proved effective in reducing experimental pancreatic fibrosis in rodents. Considering the importance of PaSC pathobiology in both chronic pancreatitis and pancreatic cancer, there should be increased effort devoted to addressing PaSC functions in these disorders and the development of therapeutic strategies that include targeting the PaSC.…”

Section: Potential Treatments For Pasc Disordersmentioning

confidence: 99%