Differential and Synergistic Effects of Platelet-derived Growth Factor-BB and Transforming Growth Factor-??1 on Activated Pancreatic Stellate Cells

Kordes, Claus; Brookmann, Stefanie; Häussinger, Dieter; Klonowski-Stumpe, Hanne

doi:10.1097/01.mpa.0000168222.05591.a0

Cited by 43 publications

(30 citation statements)

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“…A direct fibrogenic effect of CCK could be an important mediator of pancreatic fibrosis, suggesting that CCK receptors could be an interesting therapeutic target in patients with chronic pancreatitis. To date, the cytokine TGF-␤ had been the most potent stimulator of collagen synthesis in PSC (35). As shown in Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Similar to TGF-␤, and in contrast to other cytokines like PDGF (35), both CCK and gastrin inhibited proliferation. As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Because numerous studies have found that rat acinar cells express only CCK1R, expression of both CCK1R and CCK2R in rat PSC was unexpected. Previous studies using CCK1R antibodies in rat, pig, and human pancreas (33) or CCK1R and CCK2R autoradiography in human pancreas (35) did not describe expression of CCK1R on fibroblast-like cells. Because PSC represent only a minority of cells in the normal pancreas, single positive PSCs on thin sections might be missed.…”

Section: Discussionmentioning

confidence: 99%

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CCK1 and CCK2 Receptors Are Expressed on Pancreatic Stellate Cells and Induce Collagen Production

Berna¹,

Seiz²,

Nast

et al. 2010

Journal of Biological Chemistry

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The gastrointestinal hormone cholecystokinin (CCK) can induce acute pancreatitis in rodents through its action on acinar cells. Treatment with CCK, in combination with other agents, represents the most commonly used model to induce experimental chronic pancreatitis. Pancreatic stellate cells (PSC) are responsible for pancreatic fibrosis and therefore play a predominant role in the genesis of chronic pancreatitis. However, it is not known whether PSC express CCK receptors. Using real time PCR techniques, we demonstrate that CCK1 and CCK2 receptors are expressed on rat PSC. Interestingly both CCK and gastrin significantly induced type I collagen synthesis. Moreover, both inhibit proliferation. These effects are comparable with TGF-␤-stimulated PSC. Furthermore, the natural agonists CCK and gastrin induce activation of pro-fibrogenic pathways Akt, ERK, and Src. Using specific CCK1 and CCK2 receptor (CCK2R) inhibitors, we found that Akt activation is mainly mediated by CCK2R. Akt activation by CCK and gastrin could be inhibited by the PI3K inhibitor wortmannin. Activation of ERK and the downstream target Elk-1 could be inhibited by the MEK inhibitor U0126. These data suggest that CCK and gastrin have direct activating effects on PSC, are able to induce collagen synthesis in these cells, and therefore appear to be important regulators of pancreatic fibrogenesis. Furthermore, similar to TGF-␤, both CCK and gastrin inhibit proliferation in PSC.

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Section: Discussionmentioning

confidence: 98%

“…Similar to TGF-␤, and in contrast to other cytokines like PDGF (35), both CCK and gastrin inhibited proliferation. As shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

CCK1 and CCK2 Receptors Are Expressed on Pancreatic Stellate Cells and Induce Collagen Production

Berna¹,

Seiz²,

Nast

et al. 2010

Journal of Biological Chemistry

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“…An interesting finding presented here is the strong positive correlation between serum PDGF-BB and TGF-β1 concentrations in patients with CP. In vitro studies showed that PDGF-BB causes upregulation of TGF-β1 synthesis in pancreatic stellate cells [6]. Therefore, it cannot be ruled out that PDGF-BB stimulates TGF-β1 synthesis in CP patients.…”

Section: Discussionmentioning

confidence: 99%

“…Several in vitro studies postulated that myofibroblasts (transformed pancreatic stellate cells) and profibrotic cytokines such as platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-β1 (TGF-β1) play an important role in pancreatic fibrosis [1,2,3,4,5,6,7,8,9,10,11]. …”

Section: Introductionmentioning

confidence: 99%

Coordinated Increase in Serum Platelet-Derived Growth Factor-BB and Transforming Growth Factor-β1 in Patients with Chronic Pancreatitis

et al. 2011

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Stromal biology of pancreatic cancer

Chu

Kimmelman

Hezel

et al. 2007

J of Cellular Biochemistry

297

232

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The genetic paradigm of cancer, focused largely on sequential molecular aberrations and associated biological impact in the neoplastic cell compartment of malignant tumors, has dominated our view of cancer pathogenesis. For the most part, this conceptualization has overlooked the dynamic and complex contributions of the surrounding microenvironment comprised of non-tumor cells (stroma) that may resist, react to, and/or foster tumor development. Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease in which a prominent tumor stroma compartment is a defining characteristic. Indeed, the bulk of PDAC tumor volume consists of non-neoplastic fibroblastic, vascular, and inflammatory cells surrounded by immense quantities of extracellular matrix, far exceeding that found in most other tumor types. Remarkably, little is known about the composition and physiology of the PDAC tumor microenvironment, in particular, the role of stroma in tumor initiation and progression. This review attempts to define key challenges, opportunities and state-of-knowledge relating to the PDAC microenvironment research with an emphasis on how inflammatory processes and key cancer pathways may shape the ontogeny of the tumor stroma. Such knowledge may be used to understand the evolution and biology of this lethal cancer and may convert these insights into new points of therapeutic intervention.

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Differential and Synergistic Effects of Platelet-derived Growth Factor-BB and Transforming Growth Factor-??1 on Activated Pancreatic Stellate Cells

Cited by 43 publications

References 43 publications

CCK1 and CCK2 Receptors Are Expressed on Pancreatic Stellate Cells and Induce Collagen Production

CCK1 and CCK2 Receptors Are Expressed on Pancreatic Stellate Cells and Induce Collagen Production

Coordinated Increase in Serum Platelet-Derived Growth Factor-BB and Transforming Growth Factor-β1 in Patients with Chronic Pancreatitis

Stromal biology of pancreatic cancer

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