Differential and synergistic effects of platelet-derived growth factor-BB and transforming growth factor-β1 on activated pancreatic stellate cells

Lim

J of Cellular Biochemistry

et al. 2008

Activated pancreatic stellate cells (PSCs) play a pivotal role in the pathogenesis of pancreatic fibrosis, but the detailed mechanism for dysregulated accumulation of extracellular matrix (ECM) remains unclear. Cultured rat PSCs become activated by profibrogenic mediators, but these mediators failed to alter the expression levels of matrix metalloproteinases (MMPs) to the endogenous tissue inhibitors of metalloproteinases (TIMPs). Here, we examined the expression of RECK, a novel membrane-anchored MMP inhibitor, in PSCs. Although RECK mRNA levels were largely unchanged, RECK protein expression was barely detected at 2, 5 days after plating PSCs, but appeared following continued in vitro culture and cell passage which result in PSC activation. When PSCs at 5 days after plating (PSCs-5d) were treated with pepstatin A, an aspartic protease inhibitor, or TGF-beta1, a profibrogenic mediator, RECK protein was detected in whole cell lysates. Conversely, Smad7 overexpression or suppression of Smad3 expression in PSCs after passage 2 (PSCs-P2) led to the loss of RECK protein expression. These findings suggest that RECK is post-translationally processed in pre-activated PSCs but protected from proteolytic degradation by TGF-beta signaling. Furthermore, collagenolytic activity of PSCs-5d was greatly reduced by TGF-beta1, whereas that of PSCs-P2 was increased by anti-RECK antibody. Increased RECK levels were also observed in cerulein-induced acute pancreatitis. Therefore, our results suggest for the first time proteolytic processing of RECK as a mechanism regulating RECK activity, and demonstrate that TGF-beta signaling in activated PSCs may promote ECM accumulation via a mechanism that preserves the protease inhibitory activity of RECK.

Section: Resultsmentioning

confidence: 99%

TGF‐β signaling preserves RECK expression in activated pancreatic stellate cells

Lim

J of Cellular Biochemistry

et al. 2008

J Cellular Molecular Medi

“…Albeit much effort has been made to study the effects of PDGF-BB and TGF-β on HSC, their interaction is still unclear, but it is most likely that both cytokines have differential and synergistic effects in the course of fibrogenesis. A recent study investigating the potential crosstalk between PDGF-BB and TGF-β1 in activated pancreatic stellate cells, which are similar to HSC, found that PDGF-BB augments the effects of TGF-β1 presumably because of an elevated expression of TGF-β1 and a common use of signalling pathways and probably because of up-regulation of TGF-β1 synthesis and subsequent enhanced auto-stimulation of pancreatic stellate cells [65]. Although the linkage of PDGF signalling and TGF-β-triggered cascades are not understood in HSC, there is emerging evidence indicating that both cytokines activate HSC by transmitting their signals through the c-Jun N-terminal kinase-dependent Smad2/3 phosphorylation, both in vivo and in vitro [66].…”

Section: Figmentioning

confidence: 99%

Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF‐β as major players and therapeutic targets

Gressner

Weiskirchen

2006

671

582

Hepatic fibrosis is a scarring process that is associated with an increased and altered deposition of extracellular matrix in liver. At the cellular and molecular level, this progressive process is mainly characterized by cellular activation of hepatic stellate cells and aberrant activity of transforming growth factor-β1 and its downstream cellular mediators. Although the cellular responses to this cytokine are complex, the signalling pathways of this pivotal cytokine during the fibrogenic response and its connection to other signal cascades are now understood in some detail. Based on the current advances in understanding the pleiotropic reactions during fibrogenesis, various inhibitors of transforming growth factor-β were developed and are now being investigated as potential drug candidates in experimental models of hepatic injury. Although it is too early to favour one of these antagonists for the treatment of hepatic fibrogenesis in human, the experimental results obtained yet provide stimulatory impulses for the development of an effective treatment of choice in the not too distant future. The present review summarises the actual knowledge on the pathogenesis of hepatic fibrogenesis, the role of transforming growth factor-β and its signalling pathways in promoting the fibrogenic response, and the therapeutic modalities that are presently in the spotlight of many investigations and are already on the way to take the plunge into clinical studies.

J of Cellular Biochemistry

“…MMPs are expressed by PDAC cancer cells as well as fibroblasts, activated PSCs, and immunocytes. MMP-1, -2, -3, -7, -9, -11, -13, MT1-MMP, and tissue inhibitors TIMP-1 and -2 have been described in at least one PDAC cellular compartment [Yamamoto et al, 2001;Shek et al, 2002;Phillips et al, 2003;Kordes et al, 2005]. Additional MMPs have been reported yet require more extensive validation.…”

Section: Matrix Metalloproteinasesmentioning

confidence: 99%

Stromal biology of pancreatic cancer

Chu

Kimmelman

Hezel

et al. 2007

293

232

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.