Treatment of pancreatic fibrosis with siRNA against a collagen-specific chaperone in vitamin A-coupled liposomes

Ishiwatari, Hirotoshi; Sato, Yasushi; Murase, Kazuyuki; Yoneda, Akihiro; Fujita, Ryosuke; Nishita, Hiroki; Birukawa, Naoko; Hayashi, Tsuyoshi; Sato, Tsutomu; Miyanishi, Koji; Takimoto, Rishu; Kobune, Masayoshi; Ota, Shigenori; Kimura, Yasutoshi; Hirata, Koichi; Kato, Junji; Niitsu, Yoshiro

doi:10.1136/gutjnl-2011-301746

Cited by 65 publications

(48 citation statements)

References 25 publications

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“…Recent studies have demonstrated that the therapeutic resistance of PDAC can be overcome by combining classical chemotherapy with matrix-degrading approaches, such as enzymatic degradation of hyaluronic acid (8,36), drug stabilization and stromal depletion by nab-paclitaxel (6,37) or the hedgehog signaling inhibitor IPI-926 (7,38), or siRNA-mediated targeting of a collagen type I-specific chaperone in PSCs (39). A phase II clinical trial has already demonstrated beneficial effects of combinatorial therapy with gemcitabine and nab-paclitaxel on the survival of patients with pancreatic cancer (37).…”

Section: Discussionmentioning

confidence: 99%

Prevailing Role of Contact Guidance in Intrastromal T-cell Trapping in Human Pancreatic Cancer

Hartmann

Giese

et al. 2014

Clinical Cancer Research

172

132

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Purpose: Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive collagen-rich stroma. T cells that infiltrate pancreatic cancers frequently become trapped in the stroma and do not contact tumor cells. Here, we aimed to analyze how chemokines and extracellular matrix (ECM) collagen interact in mediating T-cell infiltration in PDAC.Experimental Design: T-cell distribution and ECM structure within tumors were analyzed. Chemokine concentrations in human PDAC were compared with the levels of immune cell infiltration. We assessed the influences of selected chemokines and collagen on directed and random T-cell movement using in vitro migration systems.Results: PDAC overproduced several T-cell-active chemokines, but their levels were not correlated with intratumoral T-cell infiltration. In the absence of collagen, directed migration of activated T cells was induced by chemokines. Interestingly, collagen itself promoted high migratory activity of T cells, but completely abolished chemokine-guided movement. This effect was not altered by a b 1 -integrin blocking antibody. Activated T cells actively migrated in low-density collagen matrices, but migration was inhibited in dense collagen. Accordingly, T cells were heterogeneously distributed in the pancreatic cancer stroma, with the majority residing in areas of low-density collagen far from tumor clusters.Conclusion: The excessive desmoplasia in PDAC promotes T-cell migration by contact guidance, which abrogates tumor cell-directed movement. Furthermore, dense collagen networks represent a physical barrier, additionally rearranging T-cell distribution to favor tumor stroma. These mechanisms are mainly responsible for intrastromal T-cell trapping in pancreatic cancer and may hinder the development of T-cellbased immunotherapies. Clin Cancer Res; 20(13); 3422-33. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 99%

Prevailing Role of Contact Guidance in Intrastromal T-cell Trapping in Human Pancreatic Cancer

Hartmann

Giese

et al. 2014

Clinical Cancer Research

172

132

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“…This correlational expression of Hsp47 and collagens is important for the potential treatment of fibrotic disorders because down-regulation of Hsp47 expression by RNAi or antisense RNA methods markedly delays the progression of fibrosis and concomitantly reduces the level of collagen in the extracellular matrix (27)(28)(29)(30)(31). Recently, knockdown of Hsp47 in the HSCs of rat, which was achieved using a drug delivery system to target RNAi specifically to these cells, was shown to markedly prevent the progression of experimental liver fibrosis (28,30). In this report, apoptotic death of HSCs in rats treated with Hsp47-targeting RNAi was suggested to be a major reason underlying the dramatic therapeutic effects on liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the induction of the death of activated HSCs by suppression of Hsp47 expression may be an attractive therapeutic strategy for liver fibrosis. Actually, suppression of Hsp47 expression was reported to attenuate liver fibrosis via inducing the apoptosis of HSCs (28,30); however, the reason why apoptosis is induced upon suppression of Hsp47 expression remains unknown. We previously reported that ER stress causes apoptotic cell death with the induction of CHOP expression in Hsp47-disrupted mice and cells (18,20,22).…”

mentioning

confidence: 99%

“…A recent study showed that TGF-␤, a pro-fibrotic cytokine, regulates Hsp47 production in fibroblast cell lines (26). Fibrotic progression is attenuated by down-regulation of Hsp47 expression (27)(28)(29)(30)(31). Because of the pivotal role of collagen-producing cells in fibrosis, clearance of activated HSCs through cell death might be expected to alleviate and recover from liver fibrosis.…”

mentioning

confidence: 99%

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Deletion of the Collagen-specific Molecular Chaperone Hsp47 Causes Endoplasmic Reticulum Stress-mediated Apoptosis of Hepatic Stellate Cells

Kawasaki

Ushioda

Ito

et al. 2015

Journal of Biological Chemistry

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Background: Although knockdown of heat shock protein 47 (Hsp47) attenuates liver fibrosis, the underlying molecular mechanism is unknown. Results: Deletion of Hsp47 caused activated hepatic stellate cells (HSCs) to undergo ER stress-mediated apoptosis when autophagy was inhibited. Conclusion: ER stress-induced apoptosis may underlie the clearance of collagen-producing HSCs. Significance: Hsp47 could be an attractive therapeutic target for fibrosis treatment.

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“…26 The DBTC solution was administered into the left jugular vein with a syringe at 5 mg/kg body weight, according to a previous report. 27 In the control group, one volume of solvent …”

Section: Induction Of Chronic Pancreatitis and Human Amsc Transplantamentioning

confidence: 99%

Effect of Fetal Membrane-Derived Mesenchymal Stem Cell Transplantation in Rats With Acute and Chronic Pancreatitis

et al. 2016

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Treatment of pancreatic fibrosis with siRNA against a collagen-specific chaperone in vitamin A-coupled liposomes

Cited by 65 publications

References 25 publications

Prevailing Role of Contact Guidance in Intrastromal T-cell Trapping in Human Pancreatic Cancer

Prevailing Role of Contact Guidance in Intrastromal T-cell Trapping in Human Pancreatic Cancer

Deletion of the Collagen-specific Molecular Chaperone Hsp47 Causes Endoplasmic Reticulum Stress-mediated Apoptosis of Hepatic Stellate Cells

Effect of Fetal Membrane-Derived Mesenchymal Stem Cell Transplantation in Rats With Acute and Chronic Pancreatitis

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