The ECM proteoglycan decorin links desmoplasia and inflammation in chronic pancreatitis

Köninger, Jörg; Giese, N.; Bartel, Michael J.; Mola, Fabio F. di; Berberat, Pascal O.; Sebastiano, Pierluigi di; Giese, Thomas; Büchler, Markus W.; Friess, H

doi:10.1136/jcp.2004.023135

Cited by 36 publications

(36 citation statements)

References 41 publications

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“…Simulations of the model indicated that TNF-α, TGF-β, IL-6, and PDGF are likely to increase in the pancreatic microenvironment during chronic pancreatitis. These results are consistent with those observed from prior clinical data (46)(47)(48)(49). The model can be used to explore, in silico, the efficacy of treatments that target some of the overexpressed cytokines.…”

Section: Discussionsupporting

confidence: 83%

Mathematical model of chronic pancreatitis

Hao

Komar

Hart

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Chronic pancreatitis (CP) is a progressive inflammatory disease of the pancreas, leading to its fibrotic destruction. There are currently no drugs that can stop or slow the progression of the disease. The etiology of the disease is multifactorial, whereas recurrent attacks of acute pancreatitis are thought to precede the development of CP. A better understanding of the pathology of CP is needed to facilitate improved diagnosis and treatment strategies for this disease. The present paper develops a mathematical model of CP based on a dynamic network that includes macrophages, pancreatic stellate cells, and prominent cytokines that are present at high levels in the CP microenvironment. The model is represented by a system of partial differential equations. The model is used to explore in silico potential drugs that could slow the progression of the disease, for example infliximab (anti-TNF-α) and tocilizumab or siltuximab (anti-IL-6/IL-6R).mathematical model | chronic pancreatitis | drug studies

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Section: Discussionsupporting

confidence: 83%

Mathematical model of chronic pancreatitis

Hao

Komar

Hart

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…[33][34][35][36] It is therefore noteworthy that decorin has been shown to act as a proinflammatory factor and is produced at sites of inflammation. 18,[37][38][39][40][41] In contrast, Decorin, obesity and type 2 diabetes K Bolton et al decorin has also been reported to bind and inhibit the proinflammatory activity of the complement protein C1q 42 and has been hypothesized to antagonize C1q-induced insulin resistance in adipose tissue that is associated with obesity. 16 These observations indicate that decorin may play a role in inflammation associated with obesity in adipose tissue; however, this is likely to be a complex interaction between pro-and anti-inflammatory activities.…”

Section: Discussionmentioning

confidence: 99%

Decorin is a secreted protein associated with obesity and type 2 diabetes

et al. 2008

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Objective: To characterize the expression of the small leucine-rich glycoprotein decorin in adipose tissue. Design: Real-time PCR was used to measure decorin gene expression in adipose tissue from normal glucose tolerant (NGT), impaired glucose tolerant and type 2 diabetic (T2D) Psammomys obesus. Adipose tissue was fractionated to determine which cells were responsible for decorin expression. The location of decorin protein expression in adipose tissue was determined using immunohistochemistry. Real-time PCR was used to measure decorin mRNA levels in human adipose tissue from 16 insulinsensitive, 16 insulin-resistant and 6 T2D human subjects. Circulating plasma decorin concentrations were measured by enzymelinked immunosorbent assay in 145 NGT and 141 T2D human individuals from a large-scale epidemiological study in Mauritius. Results: Decorin mRNA was found to be highly expressed in adipose tissue, and decorin gene expression was significantly higher in visceral than that in subcutaneous adipose tissue depots in both P. obesus and human subjects (P ¼ 0.002 and P ¼ 0.001, respectively). Decorin mRNA was predominantly expressed by stromal/vascular cells of adipose tissue, and decorin protein in adipose tissue was primarily detected adjacent to blood vessels. Circulating plasma decorin levels in humans were elevated by 12% in T2D (P ¼ 0.049) compared to NGT subjects. There was a significant independent correlation between plasma decorin levels and waist-to-hip ratio (WHR, P ¼ 0.024). In male subjects, plasma decorin levels were significantly correlated with WHR (P ¼ 0.006), and fasting and 2-h glucose levels in an oral glucose tolerance test (P ¼ 0.027 and P ¼ 0.001, respectively). Conclusions: Decorin expression in adipose tissue was markedly upregulated in the obese state and may therefore play a role in adipose tissue homeostasis or in pathophysiology associated with obesity.

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“…Standard markers which stain CP and PDAC stroma include the intracellular marker a-SMA and the ECM components such as collagen I, collagen III, decorin, tenascin, and fibronectin. A series of expression profiling studies of PDAC have collectively identified a lengthy list of genes upregulated not only in PDAC stroma but also in CP stroma as well [Crnogorac-Jurcevic et al, 2001;Binkley et al, 2004;Sato et al, 2004;Shen et al, 2004;Fukushima et al, 2005;Esposito et al, 2006;Koninger et al, 2006]. Indeed, serum biomarker studies for tumor routinely use CP for controls [Koopmann et al, 2006].…”

Section: Formation Of Pdac Stroma (I): Fibroblasts and Other Mesenchymentioning

confidence: 96%

Stromal biology of pancreatic cancer

Chu

Kimmelman

Hezel

et al. 2007

J of Cellular Biochemistry

294

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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The ECM proteoglycan decorin links desmoplasia and inflammation in chronic pancreatitis

Cited by 36 publications

References 41 publications

Mathematical model of chronic pancreatitis

Mathematical model of chronic pancreatitis

Decorin is a secreted protein associated with obesity and type 2 diabetes

Stromal biology of pancreatic cancer

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