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Pancreatic stellate cell

Verena M Throm, David Männle, Thomas Giese, Andrea S Bauer, Matthias M Gaida, Juergen Kopitz, Thomas Bruckner, Konstanze Plaschke, Svetlana P Grekova, Klaus Felix, Thilo Hackert, Nathalia A Giese, Oliver Strobel
Smoking is associated with increased risk and poorer prognosis of pancreatic ductal adenocarcinoma (PDAC). Nicotine acts through cholinergic nicotinic receptors, preferentially α7 (CHRNA7) that also binds the endogenous ligand SLURP1 (Secreted Ly-6/uPAR-Related Protein 1). The clinical significance of SLURP1 and its interaction with nicotine in PDAC are unclear. We detected similar levels of SLURP1 in sera from healthy donors and patients with chronic pancreatitis or PDAC; higher preoperative values were associated with significantly better survival in patients with resected tumors...
February 20, 2018: Oncotarget
Irene Sangrador, Xavier Molero, Fiona Campbell, Sebastià Franch-Expósito, Maria Rovira-Rigau, Esther Samper, Manuel Domínguez Fraile, Cristina Fillat, Antoni Castells, Eva C Vaquero
The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/-)...
February 28, 2018: Cancer Research
Marc Diedisheim, Masaya Oshima, Olivier Albagli, Charlotte Wennberg Huldt, Ingela Ahlstedt, Maryam Clausen, Suraj Menon, Alexander Aivazidis, Anne-Christine Andreasson, William G Haynes, Piero Marchetti, Lorella Marselli, Mathieu Armanet, Fabrice Chimienti, Raphael Scharfmann
OBJECTIVE: Dedifferentiation could explain reduced functional pancreatic β-cell mass in type 2 diabetes (T2D). METHODS: Here we model human β-cell dedifferentiation using growth factor stimulation in the human β-cell line, EndoC-βH1, and human pancreatic islets. RESULTS: Fibroblast growth factor 2 (FGF2) treatment reduced expression of β-cell markers, (INS, MAFB, SLC2A2, SLC30A8, and GCK) and activated ectopic expression of MYC, HES1, SOX9, and NEUROG3...
February 8, 2018: Molecular Metabolism
Yaojie Fu, Shanshan Liu, Shan Zeng, Hong Shen
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant diseases worldwide. It is refractory to conventional treatments, and consequently has a documented 5-year survival rate as low as 7%. Increasing evidence indicates that activated pancreatic stellate cells (PSCs), one of the stromal components in tumor microenvironment (TME), play a crucial part in the desmoplasia, carcinogenesis, aggressiveness, metastasis associated with PDAC. Despite the current understanding of PSCs as a "partner in crime" to PDAC, detailed regulatory roles of PSCs and related microenvironment remain obscure...
February 19, 2018: Molecular Cancer
Rei Suzuki, Hiroyuki Asama, Yuichi Waragai, Tadayuki Takagi, Takuto Hikichi, Mitsuru Sugimoto, Naoki Konno, Ko Watanabe, Jun Nakamura, Hitomi Kikuchi, Yuki Sato, Shigeru Marubashi, Atsushi Masamune, Hiromasa Ohira
We investigated whether serum microRNAs (miRNAs) could be diagnostic or prognostic markers in pancreatic ductal adenocarcinoma (PDAC). We first identified miRNAs showing altered expression in human pancreatic stellate cells (hPSCs) co-cultured with PDAC cells (Panc-1 and BxPC-3) as compared to hPSCs cultured alone. Among the miRNAs with altered expression, let-7d exhibited reduced expression in an in silico analysis of The Cancer Genome Atlas data. Inhibition of let-7d resulted in enhanced expression of fibrosis-related genes...
January 12, 2018: Oncotarget
Oleksiy Gryshchenko, Julia V Gerasimenko, Shuang Peng, Oleg V Gerasimenko, Ole H Petersen
Physiological Ca 2+ signals in pancreatic acinar cells control fluid and enzyme secretion, whereas excessive Ca 2+ signals induced by pathological agents induce destructive processes leading to acute pancreatitis. Ca 2+ signals in the peri-acinar stellate cells may also play a role in the development of acute pancreatitis. In this study, we have explored Ca 2+ signalling in the different cell types to be found in the acinar environment of the pancreatic tissue. We have, for the first time, recorded depolarization-evoked Ca 2+ signals in pancreatic nerves and shown that whereas acinar cells receive a functional cholinergic innervation, there is no evidence for functional innervation of the stellate cells...
February 9, 2018: Journal of Physiology
Li Sun, Ming Xiu, Shuhua Wang, David R Brigstock, Hongyan Li, Limei Qu, Runping Gao
Pancreatic stellate cells (PSCs) play a critical role in fibrogenesis during alcoholic chronic pancreatitis (ACP). Transforming growth factor-beta1 (TGF-β1) is a key regulator of extracellular matrix production and PSC activation. Endotoxin lipopolysaccharide (LPS) has been recognized as a trigger factor in the pathogenesis of ACP. This study aimed to investigate the mechanisms by which LPS modulates TGF-β1 signalling and pancreatic fibrosis. Sprague-Dawley rats fed with a Lieber-DeCarli alcohol (ALC) liquid diet for 10 weeks with or without LPS challenge during the last 3 weeks...
February 9, 2018: Journal of Cellular and Molecular Medicine
Divya Chakravarthy, Amanda R Muñoz, Angel Su, Rosa F Hwang, Brian R Keppler, Daniel E Chan, Glenn Halff, Rita Ghosh, Addanki P Kumar
Reciprocal interaction between pancreatic stellate cells (PSCs) and cancer cells (PCCs) in the tumor microenvironment (TME) promotes tumor cell survival and progression to lethal, therapeutically resistant pancreatic cancer. The goal of this study was to test the ability of Palmatine (PMT) to disrupt this reciprocal interaction in vitro and examine the underlying mechanism of interaction. We show that PSCs secrete glutamine into the extracellular environment under nutrient deprivation. PMT suppresses glutamine-mediated changes in GLI signaling in PCCs resulting in the inhibition of growth and migration while inducing apoptosis by inhibition of survivin...
January 31, 2018: Cancer Letters
Jonas Schnittert, Marcel A Heinrich, Praneeth R Kuninty, Gert Storm, Jai Prakash
Pancreatic stellate cells (PSCs) are the precursors of cancer-associated fibroblasts (CAFs), which potentiate pancreatic tumor growth and progression. In this study, we investigated whether Lipoxin A4 (LXA4), an endogenous bioactive lipid, can inhibit the differentiation of human PSCs (hPSCs) into CAF-like myofibroblasts and thereby hPSC-induced pro-tumorigenic effects. LXA4 significantly inhibited TGF-β-mediated differentiation of hPSCs by inhibiting pSmad2/3 signalling. Furthermore, treatment with LXA4 abolished the paracrine effects (proliferation and migration of Panc-1 tumor cells) of hPSCs in vitro...
February 2, 2018: Cancer Letters
Zi-Sheng Kang, Cong Wang, Xiao-Lin Han, Jun-Jie Du, Yan-Yi Li, Can Zhang
Chronic pancreatitis (CP) is a serious disease that characterized by the progressive replacement of functional pancreas tissue by fibrotic tissue. Vitamin D receptor (VDR) plays a critical role in the development of CP, since it inhibits excessive deposition of extracellular matrix (ECM) in activated pancreatic stellate cells (PSCs). Herein, a novel series of non-secosteriodal VDR ligands were designed and synthesized, and their VDR affinity and anti-fibrosis activity were evaluated. The identification of the potent compound 9c was found over structural optimization, which inhibited ECM deposition and fibrotic gene expression in the western blot and qPCR assays, respectively...
January 31, 2018: European Journal of Medicinal Chemistry
Amanda R Muñoz, Divya Chakravarthy, Jingjing Gong, Glenn A Halff, Rita Ghosh, Addanki P Kumar
Purpose of the review: The 5-year survival rate of patients with pancreatic cancer (PanCA) has remained stagnant. Unfortunately, the incidence is almost equal to mortality rates. These facts underscore the importance of concerted efforts to understand the pathology of this disease. Deregulation of multiple signaling pathways involved in a wide variety of cellular processes including proliferation, apoptosis, invasion, and metastasis contribute not only to cancer development but also to therapeutic resistance...
December 2017: Current Pharmacology Reports
Peter Wallbaum, Sarah Rohde, Luise Ehlers, Falko Lange, Alexander Hohn, Carina Bergner, Sarah Marie Schwarzenböck, Bernd Joachim Krause, Robert Jaster
AIM: To study the molecular effects of three different D-vitamins, vitamin D2, vitamin D3 and calcipotriol, in pancreatic stellate cells (PSCs). METHODS: Quiescent PSCs were isolated from mouse pancreas and activated in vitro by seeding on plastic surfaces. The cells were exposed to D-vitamins as primary cultures (early-activated PSCs) and upon re-culturing (fully-activated cells). Exhibition of vitamin A-containing lipid droplets was visualized by oil-red staining...
January 14, 2018: World Journal of Gastroenterology: WJG
Y K Stella Man, James A Davies, Lynda Coughlan, Constantia Pantelidou, Alfonso Blázquez-Moreno, John F Marshall, Alan L Parker, Gunnel Halldén
Metastatic pancreatic ductal adenocarcinomas (PDAC) are incurable due to the rapid development of resistance to all current therapeutics. Oncolytic adenoviral mutants have emerged as a promising new strategy that negates such resistance. In contrast to normal tissue, the majority of PDACs express the αvβ6 integrin receptor. To exploit this feature, we modified our previously reported oncolytic adenovirus, AdΔΔ, to selectively target αvβ6 integrins to facilitate systemic delivery. Structural modifications to AdΔΔ include the expression of the small but potent αvβ6-binding peptide, A20FMDV2, and ablation of binding to the native coxsackie and adenovirus receptor (CAR) within the fiber knob region...
February 2018: Molecular Cancer Therapeutics
Pavana G Rotti, Weiliang Xie, Ananta Poudel, Yaling Yi, Xingshen Sun, Scott R Tyler, Aliye Uc, Andrew W Norris, Manami Hara, John F Engelhardt, Katherine N Gibson-Corley
In cystic fibrosis (CF), there is early destruction of the exocrine pancreas, and this results in a unique form of diabetes that affects approximately half of adult CF individuals. An animal model of cystic fibrosis-related diabetes has been developed in the ferret, which progresses through phases of glycemic abnormalities because of islet remodeling during and after exocrine destruction. Herein, we quantified the pancreatic histopathological changes that occur during these phases. There was an increase in percentage ductal, fat, and islet area in CF ferrets over time compared with age-matched wild-type controls...
January 31, 2018: American Journal of Pathology
Ji-Hyun Lee, Seul-Ki Kim, Iftikhar Ali Khawar, Su-Yeong Jeong, Seok Chung, Hyo-Jeong Kuh
BACKGROUND: Pancreatic stellate cells (PSCs), a major component of the tumor microenvironment in pancreatic cancer, play roles in cancer progression as well as drug resistance. Culturing various cells in microfluidic (microchannel) devices has proven to be a useful in studying cellular interactions and drug sensitivity. Here we present a microchannel plate-based co-culture model that integrates tumor spheroids with PSCs in a three-dimensional (3D) collagen matrix to mimic the tumor microenvironment in vivo by recapitulating epithelial-mesenchymal transition and chemoresistance...
January 12, 2018: Journal of Experimental & Clinical Cancer Research: CR
Dong Tang, Qi Wu, Jingqiu Zhang, Hongpeng Zhang, Zhongxu Yuan, Jiaming Xu, Yang Chong, Yuqin Huang, Qingquan Xiong, Sen Wang, Ying Tian, Yongdie Lu, Xiao Ge, Wenjing Shen, Daorong Wang
Chronic pancreatitis/pancreatic cancer (CP/PC) is characterized by fibrous connective tissue proliferation induced by activated pancreatic stellate cells (PSCs). Galectin-1 is upregulated in activated PSCs and is important for the continuing activation of PSCs. The aim of this study was to evaluate the effect of galectin-1 derived from activated PSCs on the progression of fibrosis in CP/PC. To this end, the expression of desmin, α-SMA, galectin-1, fibronectin and collagen type I in normal pancreatic, CP and PC tissues, as well as quiescent/activated PSCs, was investigated...
January 9, 2018: Oncology Reports
Haiyan Song, Yuxiang Zhang
BACKGROUND: Activated pancreatic stellate cells (PaSCs) are the key cellular source of cancer-associated fibroblasts in the pancreatic stroma of patients with pancreatic ductal adenocarcinoma (PDAC), however, the activation mechanism of PaSCs is not yet known. The Notch signaling pathway, components of which are expressed in stromal cells, is involved in the fibrosis of several organs, including the lung and liver. In the current study, we investigated whether Notch signal transduction is involved in PaSC activation in PDAC...
January 5, 2018: BMC Cancer
Peter Yu, Ka Liu, Xuxia Gao, Harry Karmouty-Quintana, Jennifer M Bailey, Yanna Cao, Tien C Ko
OBJECTIVES: To investigate regulation of microRNA (miR)-200 family (a, b, c, 141, and 429) in chronic pancreatitis (CP). This was accomplished by examining miR-200 family levels in a mouse model in vivo and their regulation in pancreatic cells in vitro. METHODS: Chronic pancreatitis was induced by cerulein for 4 weeks (50 μg/kg, 5 hourly intraperitoneal injections/day, and 3 days/week). Control mice received normal saline. The pancreata were harvested for fibrosis assessment by Sirius red staining and for miRNA, collagen, and fibronectin levels by quantitative PCR...
January 5, 2018: Pancreas
Yoshiaki Sunami, Artur Rebelo, Jörg Kleeff
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second deadliest cancer by 2030, and the overall 5-year survival rate is currently less than 7%. Cancer cells frequently exhibit reprogramming of their metabolic activity. It is increasingly recognized that aberrant de novo lipid synthesis and reprogrammed lipid metabolism are both associated with the development and progression of various cancers, including pancreatic cancer. In this review, the current knowledge about lipid metabolism and lipid droplets in pancreatic cancer is discussed...
December 23, 2017: Cancers
Philipp Mayer, Christine Dinkic, Ralf Jesenofsky, Miriam Klauss, Peter Schirmacher, Ulrike Dapunt, Thilo Hackert, Florian Uhle, G Maria Hänsch, Matthias M Gaida
In pancreatic cancer (PDAC) intratumor infiltration of polymorphonuclear neutrophils (PMN) is associated with histologically apparent alterations of the tumor growth pattern. The aim of this study was to examine possible associations between PMN infiltration, tumor microarchitecture, and water diffusivity in diffusion-weighted magnetic resonance imaging (DW-MRI), and to further asses the underlying mechanisms. Methods: DW-MRI was performed in 33 PDAC patients prior to surgery. In parallel, tissue specimen were examined histologically for growth pattern, azurocidin-positive PMN infiltrates, and the presence of alpha-smooth muscle actin (α-SMA) and metalloproteinase 9 (MMP9)-positive myofibroblastic cells...
2018: Theranostics
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