Regulation of pancreatic stellate cell function in vitro: biological and molecular effects of all-trans retinoic acid

Jaster, Robert; Hilgendorf, Inken; Fitzner, Brit; Brock, Peter; Sparmann, Gisela; Emmrich, Jörg; Liebe, Stefan

doi:10.1016/s0006-2952(03)00390-3

Cited by 60 publications

(35 citation statements)

References 43 publications

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“…In addition, forced expression of cellular retinol binding protein (CRABP1), a mediator of RA signaling, in transgenic mice results in the development of poorly differentiated pancreatic cancer (43), further supporting a role of aberrant RA signaling in pancreatic cancer evolution. The transcript profile data presented here suggests the RA signaling pathway has a role in pancreatic cancer, specifically, a number of RA-responsive genes known to be important in pancreatic cancer and PanIN development were aberrantly expressed in this study: MUC4 mucin is overexpressed in a significant proportion of pancreatic cancer (44) and PanIN (32) and can be induced through RAR-a activation (45); similarly, MMP9 is expressed in pancreatic cancer (33) and is up-regulated by RA treatment (12) as is uPAR, HB-EGF, and p21 WAF1/CIP1 (46). Id-1, which antagonizes basic helix loop helix proteins, inhibits differentiation and can enhance cell proliferation is overexpressed in PanIN lesions (34) and is also RA responsive (47).…”

Section: Discussionmentioning

confidence: 66%

“…Such a shift from an exocrine to a predominantly ductal phenotype is characteristic of mouse models of pancreatic cancer development. In addition, pancreatic stellate cells, which are essential for the development of fibrosis associated with chronic pancreatitis and pancreatic cancer, store retinoids in fat droplets, and in turn can have their function altered with RA analogue treatment in vitro (12). The retinoid signal is transduced by two families of nuclear transcription factors: RA receptors (RAR) and retinoid X receptors, that are members of the nuclear receptor superfamily, which in the presence of ligand heterodimerize to activate the transcription of target genes through RA response elements (13).…”

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confidence: 99%

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Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia

Segara

Biankin

Kench

et al. 2005

Clinical Cancer Research

150

118

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Purpose: Despite significant progress in understanding the molecular pathology of pancreatic cancer and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility as prognostic or therapeutic markers. Here, we used oligonucleotide microarrays to interrogate mRNA expression of pancreatic cancer tissue and normal pancreas to identify novel molecular pathways dysregulated in the development and progression of pancreatic cancer. Experimental Design: RNA was hybridized to Affymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created to identify candidate genes potentially relevant to pancreatic cancer. The protein expression of one candidate, homeobox B2 (HOXB2), in PanIN and pancreatic cancer was assessed using immunohistochemistry. Results: We identified aberrant expression of several components of the retinoic acid (RA) signaling pathway (RARa, MUC4, Id-1, MMP9, uPAR, HB-EGF, HOXB6, and HOXB2), many of which are known to be aberrantly expressed in pancreatic cancer and PanIN. HOXB2, a downstream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pancreas. Immunohistochemistry revealed ectopic expression of HOXB2 in15% of early PanIN lesions and 48 of 128 (38%) pancreatic cancer specimens. Expression of HOXB2 was associated with nonresectable tumors and was an independent predictor of poor survival in resected tumors. Conclusions: We identified aberrant expression of RA signaling components in pancreatic cancer, including HOXB2, which was expressed in a proportion of PanIN lesions. Ectopic expression of HOXB2 was associated with a poor prognosis for all patients with pancreatic cancer and was an independent predictor of survival in patients who underwent resection.Pancreatic cancer is the fifth leading cause of cancer death in Western societies with a 5-year survival rate of <10% (1). Pancreatic cancer presents at an advanced stage; thus, only 10% to 20% of patients are suitable for surgical treatment at the time of presentation (1). Clinical management of these patients is complicated by inconsistencies in the influence of conventional clinicopathologic variables on outcome suggesting that some of these variables lack accuracy. In addition, preoperative assessment of some variables such as lymph node metastases is difficult. Whereas in other cancers assessment of aberrations in gene expression that cosegregate with therapeutic response and outcome are being adopted routinely to increase predictive power (e.g., ER and HER-2/neu in breast cancer), there remain no molecular markers of clinical utility in pancreatic cancer. This highlights the need for the identification of novel regulatory pathways important in pancreatic cancer that may also have diagnostic, therapeutic and prognostic utility.There is now compelling histopathologic and molecular evidence to support the evolution of pancreatic cancer through a series of noninvasive duct...

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia

Segara

Biankin

Kench

et al. 2005

Clinical Cancer Research

150

118

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“…During this Matrigel cultivation, the PSC lost their myofibroblastic morphology and regained the ability to store vitamin A in lipid vesicles, a feature of nonactivated native PSC. 8,9 This vitamin A storage may not only be a mere feature of quiescent PSC but functionally contribute to the maintenance of this state, as Jaster et al 53 have shown, that retinoic acids through the binding to their nuclear receptors are able to partially block the activation of PSC. In the immortalized PSC expression of Col I, TGFb1 and CTGF were downregulated by culture on Matrigel compared to cultivation on plain tissue culture plates, reminiscent of the expression pattern in not-activated PSC.…”

Section: Deactivation Of Pancreatic Stellate Cells R Jesnowski Et Almentioning

confidence: 99%

Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine

Jesnowski

Fürst

Ringel

et al. 2005

Laboratory Investigation

132

134

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Tissue fibrosis is one of the characteristics of chronic pancreatitis and pancreatic adenocarcinoma. Activated pancreatic stellate cells (PSC) play a central role in this process. However, analysis of the molecular mechanisms leading to PSC activation is hampered by the lack of an established human PSC line. To overcome this problem, we immortalized and characterized primary human PSC. The cells were isolated by the outgrowth method and were immortalized by transfection with SV40 large T antigen and human telomerase (hTERT). Primary human PSC served as controls. An immortalized line, RLT-PSC, was analyzed for the expression of stellate cell markers. Moreover, the effects of transforming growth factor b 1(TGFb1) or platelet-derived growth factor stimulation and of cultivation on basement membrane components or N-acetylcysteine (NAC) treatment on gene and protein expression and proliferation were analyzed. Immortal RLT-PSC cells retained the phenotype of activated PSC proven by the expression of a-smooth muscle actin (aSMA), vimentin, desmin and glial fibrillary acidic protein (GFAP). TGFb1 treatment upregulated the expression of aSMA, collagen type I (Col I), fibronectin and TGFb1. Incubation of RLT-PSC cells and primary human activated PSC on Matrigel plus NAC treatment resulted in a deactivated phenotype as evidenced by a decrease of aSMA, connective tissue growth factor and Col I expression and by a decreased proliferation of the cells. Moreover, this treatment restored the ability of the cells to store vitamin A in cytoplasmic vesicles. In conclusion, we have established an immortal pancreatic stellate cell line, without changing the characteristic phenotype. Importantly, we were able to demonstrate that besides soluble factors, the matrix surrounding PSC plays a pivotal role in the maintenance of the activation process of PSC. Cultivation of activated PSC on a reconstituted basement membrane plus treatment with NAC was able to deactivate the cells, thus pointing to the possibility of an antifibrosis therapy in chronic pancreatitis.

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“…Afterwards, they were cultured for 24h in complete culture medium supplemented with 2.5µCi/ml [ 3 H]-proline (48Ci/mmol), 50µg/ml ascorbate, 50µg/ml β-aminoproprionitrile and tet as indicated. All further steps, including normalisation of raw data, were performed as described before [21].…”

Section: Measurement Of Collagen Synthesismentioning

confidence: 99%

Peroxisome proliferator - activated receptor ? overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells

et al. 2005

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Pancreatic stellate cells (PSCs) play a key role in the development of pancreatic fibrosis, a constant feature of chronic pancreatitis and pancreatic cancer. In response to pro‐fibrogenic mediators, PSCs undergo an activation process that involves proliferation, enhanced production of extracellular matrix proteins and a phenotypic transition towards myofibroblasts. Ligands of the peroxisome proliferator‐activated receptor gamma (PPARγ), such as thiazolidinediones, are potent inhibitors of stellate cell activation and fibrogenesis in pancreas and liver. The effects of PPARγ ligands, however, however, are at least in part mediated through PPARγ‐independent pathways. Here, we have chosen a different approach to study regulatory functions of PPARγ in PSCs. Using immortalised rat PSCs, we have established a model of tetracycline (tet)‐regulated PPARγ over‐expression. Induction of PPARγ expression strongly inhibited proliferation and enhanced the rate of apoptotic cell death. Furthermore, PPARγ‐overexpressing cells synthesised less collagen than controls. To monitor effects of PPARγ on PSC gene expression, we employed Affymetrix microarray technology. Using stringent selection criteria, we identified 21 up‐ and 19 down‐regualated genes in PPARγ‐overexpressing cells. Most of the corresponding gene products are either involved in lipid metabolism, play a role in signal transduction, or are secreted molecules that regulate cell growth and differentition. In conclusion, our data suggest an active role of PPARγ in the induction of a quiescent PSC phenotype. PPARγ‐regulated genes in PSCs may serve as novel targets for the development of antifibrotic therapies.

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Regulation of pancreatic stellate cell function in vitro: biological and molecular effects of all-trans retinoic acid

Cited by 60 publications

References 43 publications

Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia

Expression of HOXB2, a Retinoic Acid Signaling Target in Pancreatic Cancer and Pancreatic Intraepithelial Neoplasia

Immortalization of pancreatic stellate cells as an in vitro model of pancreatic fibrosis: deactivation is induced by matrigel and N-acetylcysteine

Peroxisome proliferator - activated receptor ? overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells

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