Enhanced Expression of TGF-βs and Their Receptors in Human Acute Pancreatitis

Frieß, Helmut; Zhao, Lu; Riesle, Erick; Uhl, Waldemar; Bründler, Anne Marie; Horváth, L; Gold, Leslie I.; Korc, Murray; Büchler, Markus W.

doi:10.1097/00000658-199801000-00014

Cited by 71 publications

(53 citation statements)

References 39 publications

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“…In pulmonary arterial endothelial cells, BMP2 signaling has been shown to upregulate apelin expression (36), whereas BMP4, -7, and -9 were reported to downregulate apelin expression in pulmonary endothelial vascular cells (31). Our results showed that TGF-␤, a major signal behind the inflammation-fibrosis cascade in pancreatitis (10,23,39), upregulated PTHrP expression in acinar cells and PSCs. These findings were important since the present study showed that PTHrP upregulated pancreatic gremlin expression.…”

Section: Discussionmentioning

confidence: 60%

“…BMP2 was shown to signal through Smad1 to reduce TGF-␤-stimulated fibrosis in PSCs (11). Additionally, BMPR2/Smad1/5/8 signaling exerted a protective role against Cer-induced fibrosis by inhibition of Smad2 and p38 (MAPK) pathways (10). Based on these activities and the discovery of a pancreatic BMP2-apelin-PTHrP network, we propose that the BMP2-apelin-PTHrP network functions to regulate the inflammation-fibrosis cascade of CP.…”

Section: Discussionmentioning

confidence: 91%

“…Three weeks after start of Cer injections, relative BMP2 and BMPR2 expression levels declined significantly but remained elevated (P Ͻ 0.05) compared with corresponding control levels. Pancreatic BMP2 protein levels have been shown to increase in mice with Cer-induced CP (10). IHC analysis showed that immunoreactive BMP2 levels in pancreatic acinar cells increased in mice with repetitive Cer injections or PDL (Fig.…”

Section: Induction Of Cp By Either Pdl or Repetitive Cer Injections Ementioning

confidence: 89%

“…Examples are the fibroblast-growth factors -1 and -2 (FGF-1 and -2), IGF-1, connective tissue growth factor (CTGF), and EGF (7,8,10,14,23,25,39). Interestingly, the extent to which endogenous protective and injurious factors interact with each other has not been investigated.…”

Section: Discussionmentioning

confidence: 99%

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Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

Rastellini

Han

Bhatia

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 91%

Section: Induction Of Cp By Either Pdl or Repetitive Cer Injections Ementioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

Rastellini

Han

Bhatia

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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show abstract

“…Of particular relevance to the latter point is the recent work by Friess et al (35,36) showing that increased expression of TGFh and VEGF in stromal areas of pancreatic cancer is associated with poor patient outcome.…”

Section: Discussionmentioning

confidence: 97%

Pancreatic Stellate Cells: Partners in Crime with Pancreatic Cancer Cells

et al. 2008

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Pancreatic stellate cells (PSC) produce the stromal reaction in pancreatic cancer, but their role in cancer progression is not fully elucidated. We examined the influence of PSCs on pancreatic cancer growth using (a) an orthotopic model of pancreatic cancer and (b) cultured human PSCs (hPSC) and human pancreatic cancer cell lines MiaPaCa-2 and Panc-1. Athymic mice received an intrapancreatic injection of saline, hPSCs, MiaPaCa-2 cells, or hPSCs + MiaPaCa-2. After 7 weeks, tumor size, metastases, and tumor histology were assessed. In vitro studies assessed the effect of cancer cell secretions on PSC migration and the effect of hPSC secretions on cancer cell proliferation, apoptosis, and migration. Possible mediators of the effects of hPSC secretions on cancer cell proliferation were examined using neutralizing antibodies. Compared with mice receiving MiaPaCa-2 cells alone, mice injected with hPSCs + MiaPaCa-2 exhibited (a) increased tumor size and regional and distant metastasis, (b) fibrotic bands (desmoplasia) containing activated PSCs within tumors, and (c) increased tumor cell numbers. In vitro studies showed that, in the presence of pancreatic cancer cells, PSC migration was significantly increased. Furthermore, hPSC secretions induced the proliferation and migration, but inhibited the apoptosis, of MiaPaCa-2 and Panc-1 cells. The proliferative effect of hPSC secretions on pancreatic cancer cells was inhibited in the presence of neutralizing antibody to platelet-derived growth factor. Our studies indicate a significant interaction between pancreatic cancer cells and stromal cells (PSCs) and imply that pancreatic cancer cells recruit stromal cells to establish an environment that promotes cancer progression.

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Smad4/TGF-β Signaling Pathways in Pancreatic Cancer Pathogenesis

Norris¹,

Korc²

2010

Pancreatic Cancer

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Copyright: Grover et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Pancreatic Ductal Adenocarcinoma (PDA) has a mortality rate that nearly matches its incidence rate. Transforming Growth Factor Beta (TGF-β) is a cytokine with a dual role in tumor development switching from a tumor suppressor to a tumor promoter. There is limited knowledge of how TGF-β function switches during tumorigenesis. Mucin 1 (MUC1) is an aberrantly glycosylated, membrane-bound, glycoprotein that is overexpressed in >80% of PDA cases and is associated with poor prognosis. In PDA, MUC1 promotes tumor progression and metastasis via signaling through its cytoplasmic tail (MUC1-CT) and interacting with other oncogenic signaling molecules. We hypothesize that high levels of MUC1 in PDA may be partly responsible for the TGF-β functional switch during oncogenesis. We report that overexpression of MUC1 in BxPC3 human PDA cells (BxPC3.MUC1) enhances the induction of epithelial to mesenchymal transition leading to increased invasiveness in response to exogenous TGF-β1. Simultaneously, these cells resist TGF-β induced apoptosis by downregulating levels of cleaved caspases. We show that mutating the tyrosines in MUC1-CT to phenylalanine reverses the TGF-β induced invasiveness. This suggests that the tyrosine residues in MUC1-CT are required for TGF-β induced invasion. Some of these tyrosines are phosphorylated by the tyrosine kinase c-Src. Thus, treatment of BxPC3.MUC1 cells with a c-Src inhibitor (PP2) significantly reduces TGF-β induced invasiveness. Similar observations were confirmed in the Chinese hamster ovarian (CHO) cell line. Data strongly suggests that MUC1 may regulate TGF-β function in PDA cells and thus have potential clinical relevance in the use of TGF-β inhibitors in clinical trials.

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Enhanced Expression of TGF-βs and Their Receptors in Human Acute Pancreatitis

Cited by 71 publications

References 39 publications

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

Induction of chronic pancreatitis by pancreatic duct ligation activates BMP2, apelin, and PTHrP expression in mice

Pancreatic Stellate Cells: Partners in Crime with Pancreatic Cancer Cells

Smad4/TGF-β Signaling Pathways in Pancreatic Cancer Pathogenesis

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