FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2048488963> ?p ?o ?g. }

• W2048488963 endingPage "850" @default.
• W2048488963 startingPage "849" @default.
• W2048488963 abstract "Sherman MH, Yu RT, Engle DD, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell 2014;159:80–93. In pancreatic cancer, the activation of pancreatic stellate cells (PSCs) is a critical event resulting in the characteristic dense desmoplastic stroma that is important in pancreatic cancer development, progression, and therapy resistance (Gastroenterology 2013;144:1210–1219). In recent years, several studies have investigated novel therapeutic approaches targeting the tumor stroma with promising results in vitro and in vivo, but to date ensuing clinical trials have been disappointing. In this study, the authors demonstrate that reprogramming of the tumor stroma, by rendering activated PSCs physiologically quiescent, results in tumor regression and increases drug delivery in a genetically engineered mouse model of pancreatic cancer, resulting in a significant increase in median survival. First, changes in PSC gene expression by the trans-differentiation occurring in culture were studied by comparing the transcriptome of healthy mouse PSCs that were 3 days (n = 3) versus 7 days (n = 3) in culture using RNAseq, resulting in an “activation signature” of gene expression. In addition, a “cancer signature” was defined by alterations in the transcriptome of human PSCs isolated from pancreatic cancer patients (n = 5) compared with those isolated from benign tissue (n = 4). In keeping with phenotypic changes and previous reports (Clin Cancer Res 2011;17:5793–5800), both signatures demonstrated down-regulation of lipid storage genes and altered expression of multiple tumor-supporting genes, including various stromal components, inflammatory modulators, angiogenic regulators, cell adhesion molecules, paracrine growth factors, and signaling molecules. Interestingly, both quiescent and activated PSCs were also found to express high levels of the vitamin D receptor (VDR), an observation similar to the closely related hepatic stellate cells. Activation of VDR signaling by treatment with the vitamin D analog calcipotriol could trans-differentiate activated PSCs back into a quiescent phenotype, as demonstrated in vitro by reaccumulation of lipid droplets, decreased ACTA2 expression, and reduced expression of PSC activation and pancreatic cancer signature genes. The role of VDR in PSC activation, and its modulation with calcipotriol treatment, was further supported in wild-type and VDR-null C57BL6/J mice with cerulein-induced pancreatitis. Pancreata from mice treated with cerulein and calcipotriol demonstrated reduced fibrosis and isolated PSCs showed a reduced expression of activation and cancer signature genes such as COL1A1, IL6, CCL2, CXCL13, WNT2b, WNT9a, ACTA2, and MMP2. Subsequent paracrine effects on pancreatic cancer cells were studied by exposing pancreatic cancer cells, which demonstrated low levels of VDR expression, to conditioned medium from PSCs treated with calcipotriol. Cancer-associated changes in gene expression upon exposure to conditioned medium from untreated PSCs could be inhibited by conditioned medium from PSCs treated with calcipotriol with an associated decrease in phospho-STAT3 expression and reduced resistance to gemcitabine chemotherapy in vitro. To study the effects of combination treatment with gemcitabine and calcipotriol in vivo, mice with conditional expression of the oncogenic KRASG12D and mutant TP53R172H allele (KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx-1-Cre [KPC] mice) (Cancer Cell 2005;7:469–483), were treated with either single agent calcipotriol, gemcitabine, or a combination of those. Combination therapy, but not single agent treatment with calcipotriol, resulted in a reduction in collagen fibers with an associated reduction in tumor volume, increased intratumoral concentration of gemcitabine, and a striking 57% increase in median survival compared with treatment with chemotherapy alone. Thus, VDR activation with the vitamin D analog calcipotriol rendered PSCs quiescent, resulting in reduced fibrosis, tumor suppression, and improved drug delivery. Using detailed methods, transcriptome analyses, and orthotopic and genetically engineered mouse models, Sherman et al elegantly show that modulation, rather than ablation, of the desmoplastic stroma, in which PSC regain a more physiologic secretome, offers an attractive therapeutic strategy in pancreatic cancer. The imbalance of desmoplastic stroma driving aggressive tumor behavior has been demonstrated recently (J Pathol 2013;230:107–117). This approach, of reprogramming the pancreatic tumor stroma using physiologic, pleiotropic agents was first demonstrated by our group where PSCs were rendered quiescent with all-trans retinoic acid (ATRA), a vitamin A analog PSCs are known to store but lose rapidly during activation (Gastroenterology 2011;141:1486–1497). ATRA-induced PSC quiescence resulted in reduced cancer cell proliferation, increased apoptosis, and reduced invasion, in part, via restoration of secreted frizzled-related protein 4 expression by quiescent PSCs resulting in decreased Wnt–β-catenin signaling in pancreatic cancer cells (Gastroenterology 2011;141:1486–1497). Multiple other signaling cascades were also modulated, demonstrating a more widespread effect on cancer and immune cells. For example, quiescent PSCs also were shown to increase infiltration of CD8+ T cells into the juxtatumoral stromal compartments in vivo, a characteristic associated with better survival rates in patient samples, and ATRA exposure reduced CXCL12 expression and T-cell chemotaxis in vitro (Gastroenterology 2013;145:1121–1132). Thus, the cancer immune microenvironment could be modulated by restoring the homeostatic features of the desmoplastic microenvironment of the tumor. A characteristic feature of the activation of PSCs is the loss of their retinol-containing lipid droplets (Gut 1998;43:128–133; Gastroenterology 1998;115:421–432). In addition, patients with pancreatic cancer have a relative deficiency of fat-soluble vitamins (such as vitamins A and D) owing to the absence of biliary/pancreatic secretions, which may perpetuate a vicious cycle of PSC activation. In contrast with the underlying rationale for restoration of the vitamin A stores by treatment with retinoic acid, there was no difference in VDR expression in nonmalignant versus cancer-associated PSCs. Based on the authors’ previous work in hepatic stellate cells, in which they demonstrated an interaction of VDR with the transforming growth factor (TGF)β/SMAD pathway and proposed calcipotriol induced inhibition of SMAD3-mediated gene transcription (Cell 2013;153:601–613), they assessed the crosstalk between VDR and TGFβ/SMAD pathway in PSCs. Whereas calcipotriol decreased SMAD3 binding in the promoter regions of fibrogenic genes, this was only shown for 2 genes (the extracellular matrix components HAS2 [encoding hyaluronan synthase 2] and COL1A1 [encoding the major component of type I collagen]). However, the role of VDR in fibrosis is supported by the observation that VDR-null mice demonstrate spontaneous periacinar and periductal fibrosis. Using an orthotopic allograft model, the authors showed reduced fibrosis upon treatment with single agent calcipotriol in vivo; however, this effect was not demonstrated in the KPC model, which is widely considered as a representative model of human pancreatic cancer (Cancer Cell 2005;7:469–483). More KPC mice were treated with the combination of gemcitabine and calcipotriol compared with gemcitabine (n = 7 versus n = 4), and it would have been interesting to see whether there was any effect on metastatic potential. Nevertheless, the effects of co-targeting stroma are striking and support the notion of combining tumor-directed therapies with agents that reprogram, rather than deplete, the stroma and thus influence multiple signaling cascades. Recent studies have focused largely on targeting specific stromal components in pancreatic cancer, such as hedgehog inhibitors (Science 2009;324:1457–1461), enzymatic targeting of hyaluronan with a clinically formulated pegylated human recombinant PH20 hyaluronidase (Cancer Cell 2012;21:418–429; Gut 2013;62:112–120), CXCL12 inhibition (Proc Natl Acad Sci U S A 2013;110:20212–20217), inhibition of the matricellular signaling protein connective tissue growth factor (CTGF/CCN2; Proc Natl Acad Sci U S A 2013;110:12325–12330), or targeting of the characteristic hypovascular microenvironment with, for example gamma, secretase inhibitors (Gastroenterology 2009;136:1741–1749) or a low dose of cilengitide and verapamil as a vascular promotion therapy (Cancer Cell 2015;27:123–137). However, 2 recent studies highlighted the complexity of stroma-directed therapies. Stromal depletion, either by conditional deletion or targeting of the sonic hedgehog pathway (Cancer Cell 2014;25:735–747) or by depletion of activated myofibroblasts (Cancer Cell 2014;25:719–734), resulted in more aggressive tumors. These studies suggest that some elements or aspects in the tumor stroma spatiotemporal evolution may have an important role in restraining tumor cells. Reprogramming stellate cells into their quiescent phenotype by agents such as calcipotriol or ATRA reestablishes a more physiologic secretome affecting multiple signaling cascades in the tumor–stroma or stroma–stroma cross-talk. Therefore, homeostatic restoration of stroma is a tantalizingly more appealing therapeutic approach. In summary, this detailed work by Sherman et al reinforces the role of homeostatic restoration of the desmoplastic stroma in combination with anti-tumor cytotoxic or targeted therapy as a therapeutic approach in pancreatic cancer. Further clinical studies translating these findings into clinical practice are eagerly awaited." @default.
• W2048488963 created "2016-06-24" @default.
• W2048488963 creator A5024033591 @default.
• W2048488963 creator A5066104383 @default.
• W2048488963 date "2015-04-01" @default.
• W2048488963 modified "2023-10-18" @default.
• W2048488963 title "Homeostatic Restoration of Desmoplastic Stroma Rather Than Its Ablation Slows Pancreatic Cancer Progression" @default.
• W2048488963 doi "https://doi.org/10.1053/j.gastro.2015.02.043" @default.
• W2048488963 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25724458" @default.
• W2048488963 hasPublicationYear "2015" @default.
• W2048488963 type Work @default.
• W2048488963 sameAs 2048488963 @default.
• W2048488963 citedByCount "31" @default.
• W2048488963 countsByYear W20484889632016 @default.
• W2048488963 countsByYear W20484889632018 @default.
• W2048488963 countsByYear W20484889632019 @default.
• W2048488963 countsByYear W20484889632020 @default.
• W2048488963 countsByYear W20484889632021 @default.
• W2048488963 countsByYear W20484889632022 @default.
• W2048488963 countsByYear W20484889632023 @default.
• W2048488963 crossrefType "journal-article" @default.
• W2048488963 hasAuthorship W2048488963A5024033591 @default.
• W2048488963 hasAuthorship W2048488963A5066104383 @default.
• W2048488963 hasBestOaLocation W20484889631 @default.
• W2048488963 hasConcept C121608353 @default.
• W2048488963 hasConcept C126322002 @default.
• W2048488963 hasConcept C142724271 @default.
• W2048488963 hasConcept C204232928 @default.
• W2048488963 hasConcept C2778902805 @default.
• W2048488963 hasConcept C2779256057 @default.
• W2048488963 hasConcept C2780210213 @default.
• W2048488963 hasConcept C502942594 @default.
• W2048488963 hasConcept C52124034 @default.
• W2048488963 hasConcept C63645605 @default.
• W2048488963 hasConcept C71924100 @default.
• W2048488963 hasConceptScore W2048488963C121608353 @default.
• W2048488963 hasConceptScore W2048488963C126322002 @default.
• W2048488963 hasConceptScore W2048488963C142724271 @default.
• W2048488963 hasConceptScore W2048488963C204232928 @default.
• W2048488963 hasConceptScore W2048488963C2778902805 @default.
• W2048488963 hasConceptScore W2048488963C2779256057 @default.
• W2048488963 hasConceptScore W2048488963C2780210213 @default.
• W2048488963 hasConceptScore W2048488963C502942594 @default.
• W2048488963 hasConceptScore W2048488963C52124034 @default.
• W2048488963 hasConceptScore W2048488963C63645605 @default.
• W2048488963 hasConceptScore W2048488963C71924100 @default.
• W2048488963 hasIssue "4" @default.
• W2048488963 hasLocation W20484889631 @default.
• W2048488963 hasLocation W20484889632 @default.
• W2048488963 hasOpenAccess W2048488963 @default.
• W2048488963 hasPrimaryLocation W20484889631 @default.
• W2048488963 hasRelatedWork W2032175417 @default.
• W2048488963 hasRelatedWork W2050605814 @default.
• W2048488963 hasRelatedWork W2055554175 @default.
• W2048488963 hasRelatedWork W2068809410 @default.
• W2048488963 hasRelatedWork W2129563426 @default.
• W2048488963 hasRelatedWork W2198389860 @default.
• W2048488963 hasRelatedWork W2416582102 @default.
• W2048488963 hasRelatedWork W2417404793 @default.
• W2048488963 hasRelatedWork W2561933446 @default.
• W2048488963 hasRelatedWork W4379374925 @default.
• W2048488963 hasVolume "148" @default.
• W2048488963 isParatext "false" @default.
• W2048488963 isRetracted "false" @default.
• W2048488963 magId "2048488963" @default.
• W2048488963 workType "article" @default.