The Experts below are selected from a list of 3666 Experts worldwide ranked by ideXlab platform
Minoti V Apte - One of the best experts on this subject based on the ideXlab platform.
-
Pancreatic Stellate Cells: Aiding and abetting Pancreatic cancer progression
Pancreatology, 2020Co-Authors: Srinivasa P. Pothula, Jeremy S. Wilson, Romano C. Pirola, Minoti V ApteAbstract:Abstract Tumour-stromal interactions have now been acknowledged to play a major role in Pancreatic cancer (PC) progression. The abundant collagenous stroma is produced by a specific Cell type in the pancreas-the Pancreatic Stellate Cell (PSC). Pancreatic Stellate Cells (PSCs) are a unique resident Cell type of pancreas and with a critical role in both healthy and diseased pancreas. Accumulating evidence indicates that PSCs interact closely with cancer Cells as well as with other Cell types of the stroma such as immune Cells, endothelial Cells and neuronal Cells, to set up a growth permissive microenvironment for Pancreatic tumours, which facilitates local tumour growth as well as distant metastasis. Consequently, recent work in the field has focused on the development of novel therapeutic approaches targeting the stroma to inhibit PC progression. Such a multi-pronged approach targeting both tumour and stromal elements of PC has been successfully applied in pre-clinical settings. The challenge now is to translate the pre-clinical findings into the clinical setting to achieve better outcomes for Pancreatic cancer patients.
-
Pancreatic Stellate Cells
Stellate Cells in Health and Disease, 2015Co-Authors: Minoti V Apte, Romano C. Pirola, Jeremy S. WilsonAbstract:Of all the different Cell types in the Pancreatic parenchyma, the most recently discovered Cell is the Pancreatic Stellate Cell (PSC). PSCs were first described more than 30 years ago, in 1982. Sixteen years later, in 1998, methods were developed to isolate and culture PSCs from the pancreas, which provided a much-needed impetus to studies on PSC biology. In the relatively short period of the past decade and a half, rapid advances have been made in our understanding of the role of PSCs in healthy and diseased pancreas. Recent studies have provided evidence for a role for PSCs in health via their capacity to act as progenitor Cells, immune Cells, and intermediary Cells in human Pancreatic exocrine secretion. With regard to Pancreatic disease, the Cells play a central role in the fibrosis of chronic pancreatitis, and are also critical to the repair processes of the gland after acute pancreatitis. PSCs are also responsible for producing the collagenous stroma (desmoplasia) of Pancreatic cancer, but more notably, they interact closely with cancer Cells as well as other stromal Cells such as endothelial Cells and immune Cells, to facilitate tumor progression. Improved understanding of PSC functions in chronic pancreatitis and Pancreatic cancer has led to the development of novel therapeutic approaches that have often been effective in the pre-clinical setting. Needless to say, successful translation of such pre-clinical strategies to the clinical situation is the next important step for improving the outcome of patients with these diseases.
-
the role of the hepatocyte growth factor c met pathway in Pancreatic Stellate Cell endothelial Cell interactions antiangiogenic implications in Pancreatic cancer
Carcinogenesis, 2014Co-Authors: Mishaal Patel, Minoti V Apte, Romano C. Pirola, David Goldstein, Srinivasa Pothula, Alexandra Lee, Jeremy S. WilsonAbstract:Activated cancer-associated human Pancreatic Stellate Cells (CAhPSCs, which produce the collagenous stroma of Pancreatic cancer [PC]) are known to play a major role in PC progression. Apart from inducing cancer Cell proliferation and migration, CAhPSCs have also been implicated in neoangiogenesis in PC. However, the mechanisms mediating the observed angiogenic effects of CAhPSCs are unknown. A candidate pathway that may be involved in this process is the hepatocyte growth factor (HGF)/cMET pathway and its helper molecule, urokinase-type plasminogen activator (uPA). This study investigated the effects of CAhPSC secretions on endothelial Cell function in the presence and absence of HGF, c-MET and uPA inhibitors. HGF levels in CAhPSC secretions were quantified using ELISA. CAhPSC secretions were then incubated with human microvascular endothelial Cells (HMEC-1) and angiogenesis assessed by quantifying HMEC-1 tube formation and proliferation. CAhPSC-secreted HGF significantly increased HMEC-1 tube formation and proliferation; notably, these effects were downregulated by inhibition of HGF, its receptor c-MET and uPA. Phosphorylation of p38 mitogen-activated protein kinase was downregulated during inhibition of the HGF/c-MET pathway, whereas phosphatidylinositol-3 kinase and ERK1/2 remained unaffected. Our studies have shown for the first time that CAhPSCs induce proliferation and tube formation of HMEC1 and that the HGF/c-MET pathway plays a major role in this induction. Given that standard antiangiogenic treatment targeting vascular endothelial growth factor has had limited success in the clinical setting, the findings of the current study provide strong support for a novel, alternative antiangiogenic approach targeting the HGF/c-MET and uPA pathways in PC.
-
extraCellular matrix composition significantly influences Pancreatic Stellate Cell gene expression pattern role of transgelin in psc function
American Journal of Physiology-gastrointestinal and Liver Physiology, 2013Co-Authors: Minoti V Apte, Romano C. Pirola, Phoebe A Phillips, Lu Yang, Warren Kaplan, Mark J Cowley, Jeremy S. WilsonAbstract:Activated Pancreatic Stellate Cells (PSCs) are responsible for the fibrotic matrix of chronic pancreatitis and Pancreatic cancer. In vitro protocols examining PSC biology have usually involved PSCs...
-
stellatum current consensus and discussion on Pancreatic Stellate Cell research
Gut, 2012Co-Authors: Mert Erkan, Helmut Friess, Guido Adler, Minoti V Apte, Max G Bachem, Malte Buchholz, Sonke Detlefsen, Irene Esposito, Thomas M Gress, Hans Joerg HabischAbstract:The field of Pancreatic Stellate Cell (PSC) biology is very young, as the essential in-vitro tools to study these Cells (ie, methods to isolate and culture PSC) were only developed as recently as in 1998. Nonetheless, there has been an exponential increase in research output in this field over the past decade, with numerous research groups around the world focusing their energies into elucidating the biology and function of these Cells. It is now well established that PSC are responsible for producing the stromal reaction (fibrosis) of two major diseases of the pancreas—chronic pancreatitis and Pancreatic cancer. Despite exponentially increasing data, the methods for studying PSC remain variable. Although within individual laboratories methods are consistent, different methodologies used by various research groups make it difficult to compare results and conclusions. This article is not a review article on the functions of PSC. Instead, members of the Pancreatic Star Alliance (http://www.Pancreaticstaralliance.com) discuss here and consolidate current knowledge, to outline and delineate areas of consensus or otherwise (eg, with regard to methodological approaches) and, more importantly, to identify essential directions for future research. Hepatic Stellate Cells (HSC) were first described by Karl von Kupffer in 1876; however, similar Cells in the pancreas were first observed in the 1980s.1–3 In 1998, Apte et al 4 and Bachem et al 5 isolated and cultured PSC.4 5 In the normal pancreas, PSC are located in close proximity to the basal aspect of Pancreatic acinar Cells. In sections immunostained for the marker desmin (a cytoskeletal protein), quiescent PSC can be seen as Cells with a central Cell body and long cytoplasmic projections extending along the base of adjacent acinar Cells similar to that of pericytes in the mammary gland. …
Jeremy S. Wilson - One of the best experts on this subject based on the ideXlab platform.
-
Pancreatic Stellate Cells: Aiding and abetting Pancreatic cancer progression
Pancreatology, 2020Co-Authors: Srinivasa P. Pothula, Jeremy S. Wilson, Romano C. Pirola, Minoti V ApteAbstract:Abstract Tumour-stromal interactions have now been acknowledged to play a major role in Pancreatic cancer (PC) progression. The abundant collagenous stroma is produced by a specific Cell type in the pancreas-the Pancreatic Stellate Cell (PSC). Pancreatic Stellate Cells (PSCs) are a unique resident Cell type of pancreas and with a critical role in both healthy and diseased pancreas. Accumulating evidence indicates that PSCs interact closely with cancer Cells as well as with other Cell types of the stroma such as immune Cells, endothelial Cells and neuronal Cells, to set up a growth permissive microenvironment for Pancreatic tumours, which facilitates local tumour growth as well as distant metastasis. Consequently, recent work in the field has focused on the development of novel therapeutic approaches targeting the stroma to inhibit PC progression. Such a multi-pronged approach targeting both tumour and stromal elements of PC has been successfully applied in pre-clinical settings. The challenge now is to translate the pre-clinical findings into the clinical setting to achieve better outcomes for Pancreatic cancer patients.
-
Pancreatic Stellate Cell physiologic role role in fibrosis and cancer
Current Opinion in Gastroenterology, 2015Co-Authors: Minote Apte, Romano C. Pirola, Jeremy S. WilsonAbstract:Purpose of reviewEver since the first descriptions of methods to isolate Pancreatic Stellate Cells (PSCs) from rodent and human pancreas 17 years ago, rapid advances have been made in our understanding of the biology of these Cells and their functions in health and disease. This review updates recen
-
Pancreatic Stellate Cells
Stellate Cells in Health and Disease, 2015Co-Authors: Minoti V Apte, Romano C. Pirola, Jeremy S. WilsonAbstract:Of all the different Cell types in the Pancreatic parenchyma, the most recently discovered Cell is the Pancreatic Stellate Cell (PSC). PSCs were first described more than 30 years ago, in 1982. Sixteen years later, in 1998, methods were developed to isolate and culture PSCs from the pancreas, which provided a much-needed impetus to studies on PSC biology. In the relatively short period of the past decade and a half, rapid advances have been made in our understanding of the role of PSCs in healthy and diseased pancreas. Recent studies have provided evidence for a role for PSCs in health via their capacity to act as progenitor Cells, immune Cells, and intermediary Cells in human Pancreatic exocrine secretion. With regard to Pancreatic disease, the Cells play a central role in the fibrosis of chronic pancreatitis, and are also critical to the repair processes of the gland after acute pancreatitis. PSCs are also responsible for producing the collagenous stroma (desmoplasia) of Pancreatic cancer, but more notably, they interact closely with cancer Cells as well as other stromal Cells such as endothelial Cells and immune Cells, to facilitate tumor progression. Improved understanding of PSC functions in chronic pancreatitis and Pancreatic cancer has led to the development of novel therapeutic approaches that have often been effective in the pre-clinical setting. Needless to say, successful translation of such pre-clinical strategies to the clinical situation is the next important step for improving the outcome of patients with these diseases.
-
the role of the hepatocyte growth factor c met pathway in Pancreatic Stellate Cell endothelial Cell interactions antiangiogenic implications in Pancreatic cancer
Carcinogenesis, 2014Co-Authors: Mishaal Patel, Minoti V Apte, Romano C. Pirola, David Goldstein, Srinivasa Pothula, Alexandra Lee, Jeremy S. WilsonAbstract:Activated cancer-associated human Pancreatic Stellate Cells (CAhPSCs, which produce the collagenous stroma of Pancreatic cancer [PC]) are known to play a major role in PC progression. Apart from inducing cancer Cell proliferation and migration, CAhPSCs have also been implicated in neoangiogenesis in PC. However, the mechanisms mediating the observed angiogenic effects of CAhPSCs are unknown. A candidate pathway that may be involved in this process is the hepatocyte growth factor (HGF)/cMET pathway and its helper molecule, urokinase-type plasminogen activator (uPA). This study investigated the effects of CAhPSC secretions on endothelial Cell function in the presence and absence of HGF, c-MET and uPA inhibitors. HGF levels in CAhPSC secretions were quantified using ELISA. CAhPSC secretions were then incubated with human microvascular endothelial Cells (HMEC-1) and angiogenesis assessed by quantifying HMEC-1 tube formation and proliferation. CAhPSC-secreted HGF significantly increased HMEC-1 tube formation and proliferation; notably, these effects were downregulated by inhibition of HGF, its receptor c-MET and uPA. Phosphorylation of p38 mitogen-activated protein kinase was downregulated during inhibition of the HGF/c-MET pathway, whereas phosphatidylinositol-3 kinase and ERK1/2 remained unaffected. Our studies have shown for the first time that CAhPSCs induce proliferation and tube formation of HMEC1 and that the HGF/c-MET pathway plays a major role in this induction. Given that standard antiangiogenic treatment targeting vascular endothelial growth factor has had limited success in the clinical setting, the findings of the current study provide strong support for a novel, alternative antiangiogenic approach targeting the HGF/c-MET and uPA pathways in PC.
-
extraCellular matrix composition significantly influences Pancreatic Stellate Cell gene expression pattern role of transgelin in psc function
American Journal of Physiology-gastrointestinal and Liver Physiology, 2013Co-Authors: Minoti V Apte, Romano C. Pirola, Phoebe A Phillips, Lu Yang, Warren Kaplan, Mark J Cowley, Jeremy S. WilsonAbstract:Activated Pancreatic Stellate Cells (PSCs) are responsible for the fibrotic matrix of chronic pancreatitis and Pancreatic cancer. In vitro protocols examining PSC biology have usually involved PSCs...
Robert Jaster - One of the best experts on this subject based on the ideXlab platform.
-
cdkn1a is a key mediator of rat Pancreatic Stellate Cell senescence
Pancreatology, 2013Co-Authors: Brit Fitzner, Andreas Lange, Sarah Muller, Robert JasterAbstract:Abstract Background/objectives Completion of Pancreatic wound healing requires termination of Pancreatic Stellate Cell (PSC) activation to prevent fibrosis. Besides induction of apoptosis and return to a quiescent phenotype, senescence of PSC followed by immune Cell-mediated cytolysis represents a potential mechanism. Here, we have studied if the Cell cycle inhibitor cyclin-dependent kinase inhibitor 1A (Cdkn1a, p21/Waf1), expression of which is increased in senescent rat PSC, plays a causative role in the senescence process. Methods Senescence was induced by doxorubicin treatment. The functions of Cdkn1a were analyzed using two approaches, treatment of primary rat PSC with siRNA and tetracycline-regulated overexpression of Cdkn1a in immortalized rat Cells. Expression of senescence-associated β-galactosidase (SA β-Gal) was used as a surrogate marker of senescence. Results The knockdown of Cdkn1a significantly attenuated the growth-inhibitory effect of doxorubicin and strongly diminished the portion of SA β-Gal-positive Cells. Overexpression of Cdkn1a enhanced both the antiproliferative effect of doxorubicin and induction of senescence. In primary PSC, doxorubicin treatment was associated with increased expression of interleukin-6 (IL-6) and matrix metalloproteinase (MMP)-9, while expression of the activation marker α-smooth muscle actin (α-SMA), p53, Cdk1 and Rad54 was diminished. The application of Cdkn1a siRNA specifically antagonized the effects of doxorubicin on the expression of p53, Cdk1 and Rad54 but not IL-6 and α-SMA, while MMP-9 expression and also activity were even enhanced. Conclusions Cdkn1a plays a direct role in the process of rat PSC senescence. Additional Cdkn1a-independent pathways may contribute to the partial maintenance of a gene expression profile typical of senescent PSC.
-
inhibitory effects of interferons on Pancreatic Stellate Cell activation
World Journal of Gastroenterology, 2006Co-Authors: Jantido Baumert, Gisela Sparmann, J Emmrich, Stefan Liebe, Robert JasterAbstract:AIM: To analyze and to compare the effects of interferon (IFN)-α, IFN-β, and IFN-γ on Pancreatic Stellate Cell (PSC) activation in vitro and to elucidate the molecular basis of IFN action. METHODS: PSCs were isolated from rat’s Pancreatic tissue, cultured and stimulated with recombinant rat IFNs. Cell proliferation and collagen synthesis were assessed by measuring the incorporation of 5-bromo-2’-deoxyuridine (BrdU) into DNA and [3H]-proline into acetic acid-soluble proteins, respectively. Apoptotic Cells were determined by FACS analysis (sub-G1 peak method). Exhibition of the myofibroblastic PSC phenotype was monitored by immunoblot analysis of α-smooth muscle actin (α-SMA) expression. To assess the activation of signal transducer and activator of transcription (STAT), Western blots using phospho-STAT-specific antibodies were performed. In studies on STAT1 function, expression of the protein was inhibited by siRNA. RESULTS: IFN-β and IFN-γ, but not IFN-α significantly diminished PSC proliferation and collagen synthesis. IFN-γ was the only IFN that clearly inhibited α-SMA expression. Under the experimental conditions used, no enhanced rate of apoptotic Cell death was observed in response to any IFN treatment. IFN-β and IFN-γ induced a strong increase of STAT1 and STAT3 tyrosine phosphorylation, while the effect of IFN-α was much weaker. Inhibition of STAT1 expression with siRNA was associated with a significantly reduced growth-inhibitory effect of IFN-γ. CONCLUSION: IFN-β and particularly IFN-γ display inhibitory effects on PSC activation in vitro and should be tested regarding their in vitro efficiency. Growth inhibition by IFN-γ action requires STAT1.
-
Galectin-1 is an inductor of Pancreatic Stellate Cell activation.
Cellular Signalling, 2005Co-Authors: Brit Fitzner, Gisela Sparmann, J Emmrich, Stefan Liebe, Hermann Walzel, Robert JasterAbstract:Abstract Pancreatic Stellate Cells (PSCs) play a key role in the development of Pancreatic fibrosis, a pathological feature of chronic pancreatitis and Pancreatic cancer. Here, we show that activation of rat PSCs in vitro is associated with increased expression of galectin-1 (gal-1) and that gal -1 modulates PSC function. Expression of the lectin was stimulated by fetal calf serum and platelet-derived growth factor. PSCs exposed to exogenous gal -1 proliferated at a higher rate and synthesised more collagen than controls. Gal -1-dependent collagen synthesis was blocked by lactose but not by Cellobiose, suggesting that gal -1 acts on PSCs through targeting β-galactoside-containing glycoconjugates. Analysis of gal -1 signalling in PSCs revealed an activation of the extraCellular signal-regulated kinases 1 and 2 and enhanced DNA binding of AP-1 transcription factors. Together, our data implicate gal -1 in PSC activation and suggest further studies to analyse the role of endogenous lectins in the development of Pancreatic fibrosis in vivo.
-
Involvement of AP-1 proteins in Pancreatic Stellate Cell activation in vitro
International Journal of Colorectal Disease, 2004Co-Authors: Brit Fitzner, Gisela Sparmann, J Emmrich, Stefan Liebe, Robert JasterAbstract:Background and aims Pancreatic Stellate Cells (PSCs) play a key role in the development of Pancreatic fibrosis. The molecular mechanisms underlying their activation in response to profibrogenic mediators, however, are largely unknown. Extending previous studies on the transcriptional regulation of PSC activation, we have now focused on the involvement of activator protein (AP)-1. Materials and methods Using cultured rat PSCs, phenotypic transition of PSCs towards activated myofibroblasts was monitored by an immunoblot analysis of α-smooth muscle actin (α-SMA) expression. Transcription factor activation profiles were studied by electrophoretic mobility shift assays. DNA synthesis in PSCs was assessed through the quantification of 5-bromo-2’-deoxyuridine incorporation. Results Activated AP-1 complexes were detectable already before high levels of α-SMA were expressed. Maximal DNA binding activity of AP-1, as well as of NF-κB, was observed early in the course of PSC culture, while the strongest activation of STAT3 was observed much later. A detailed analysis of AP-1 complex composition revealed that phenotypic transition of PSCs towards myofibroblasts was accompanied by an increase of the JunD content relative to the one of JunB. Studies on the role of JunB and JunD in PSC activation indicated an inhibition of platelet-derived growth factor-induced DNA synthesis by antisense oligonucleotides to JunB but not JunD. Conclusions The results of this study implicate AP-1 in PSC activation and suggest distinct roles of individual Jun proteins in the regulation of PSC function. In further studies, it should be analyzed whether signaling pathways involved in PSC activation might be suitable targets for antifibrotic therapies.
-
Involvement of AP-1 proteins in Pancreatic Stellate Cell activation in vitro
International Journal of Colorectal Disease, 2004Co-Authors: Brit Fitzner, Gisela Sparmann, J Emmrich, Stefan Liebe, Robert JasterAbstract:Background and aims Pancreatic Stellate Cells (PSCs) play a key role in the development of Pancreatic fibrosis. The molecular mechanisms underlying their activation in response to profibrogenic mediators, however, are largely unknown. Extending previous studies on the transcriptional regulation of PSC activation, we have now focused on the involvement of activator protein (AP)-1.
Stephen J Pandol - One of the best experts on this subject based on the ideXlab platform.
-
yes associated protein 1 plays major roles in Pancreatic Stellate Cell activation and fibroinflammatory responses
Frontiers in Physiology, 2019Co-Authors: Stephen J Pandol, Jiayue Yang, Richard T Waldron, Mengmeng Zhi, Qing Xia, Aurelia LugeaAbstract:Background: Yes-associated protein 1 (YAP), a transcriptional co-activator and major effector of the Hippo pathway, regulates Cell differentiation and morphology in many Cell types and supports aberrant tumor growth. Recent studies showed that YAP is expressed in pancreas tissues in Pancreatic ductal adenocarcinoma (PDAC) patients and experimental models of PDAC, with YAP largely found in cancer Cells and Pancreatic Stellate Cells (PaSC) in the stroma. Methods and Results: We studied here the role of YAP in the activated phenotype of PaSC. We found that YAP is expressed at low levels in normal mouse pancreas, but protein levels significantly increased after pancreas inflammatory damage induced by repeated cerulein administration in wild-type mice or upon initiation of neoplastic transformation of the pancreas parenchyma in Ptf1-Cre;LSL-KrasG12D/+ (KC) mice. In these animal models, YAP upregulation occurred in parallel with activation and proliferation of PaSC. Consistent with these findings, we found robust YAP expression in culture-activated mouse and human PaSC but not in quiescent, freshly isolated Cells. Fully activated PaSC isolated from KC mice or PDAC patient tissues exhibited robust nuclear YAP suggesting YAP transcriptional activity. Agents that induce quiescence such as the Bromodomain and Extra-Terminal (BET) inhibitor iBET151 and the p38 MAPK inhibitor SB203580 reduced YAP levels in PaSC. Stimulation of PaSC with the potent mitogen PDGF elicited marked YAP Ser127 phosphorylation. However, unexpectedly, this effect did not diminish YAP nuclear localization, suggesting that YAP phosphorylation at this site does not govern YAP Cellular localization in PaSC. siRNA-mediated knockdown of YAP reduced PDGF-induced PaSC expansion in culture and blunted the persistent activation of Akt and ERK elicited by PDGF stimulation, supporting a role for YAP in PDGF-induced Cell growth. YAP knockdown also blunted fibroinflammatory gene expression responses both in unstimulated and transforming growth factor beta 1 (TGFβ1)-stimulated PaSC. Conclusion: Our data suggest a central role for YAP in sustaining the activated phenotype and fibroinflammatory responses in PaSC. Moreover, our findings indicate that a complex crosstalk between YAP, TGFβ1, and PDGF pathways regulates PaSC activity and growth.
-
epidemiology risk factors and the promotion of Pancreatic cancer role of the Stellate Cell
Journal of Gastroenterology and Hepatology, 2012Co-Authors: Stephen J Pandol, Anna S Gukovskaya, Mouad Edderkoui, David W Dawson, Guido Eibl, Aurelia LugeaAbstract:There are approximately 277 000 new cases of Pancreatic cancer and 266 000 deaths from Pancreatic cancer annually, indicating a mortality rate of 96% of the cases diagnosed. Because of the ineffectiveness of therapies, a major emphasis needs to be placed on prevention. This paper reviews the epidemiology and risk factors for Pancreatic cancer, and uses this information to propose plausible research directions for determining the biological mechanisms mediating the effects of risk factors on the promotion of Pancreatic cancer, with a focus on the Pancreatic Stellate Cell.
-
the Pancreatic Stellate Cell a star on the rise in Pancreatic diseases
Journal of Clinical Investigation, 2007Co-Authors: Bishr M Omary, Aurelia Lugea, Anson W Lowe, Stephen J PandolAbstract:Pancreatic Stellate Cells (PaSCs) are myofibroblast-like Cells found in the areas of the pancreas that have exocrine function. PaSCs are regulated by autocrine and paracrine stimuli and share many features with their hepatic counterparts, studies of which have helped further our understanding of PaSC biology. Activation of PaSCs induces them to proliferate, to migrate to sites of tissue damage, to contract and possibly phagocytose, and to synthesize ECM components to promote tissue repair. Sustained activation of PaSCs has an increasingly appreciated role in the fibrosis that is associated with chronic pancreatitis and with Pancreatic cancer. Therefore, understanding the biology of PaSCs offers potential therapeutic targets for the treatment and prevention of these diseases.
Aurelia Lugea - One of the best experts on this subject based on the ideXlab platform.
-
yes associated protein 1 plays major roles in Pancreatic Stellate Cell activation and fibroinflammatory responses
Frontiers in Physiology, 2019Co-Authors: Stephen J Pandol, Jiayue Yang, Richard T Waldron, Mengmeng Zhi, Qing Xia, Aurelia LugeaAbstract:Background: Yes-associated protein 1 (YAP), a transcriptional co-activator and major effector of the Hippo pathway, regulates Cell differentiation and morphology in many Cell types and supports aberrant tumor growth. Recent studies showed that YAP is expressed in pancreas tissues in Pancreatic ductal adenocarcinoma (PDAC) patients and experimental models of PDAC, with YAP largely found in cancer Cells and Pancreatic Stellate Cells (PaSC) in the stroma. Methods and Results: We studied here the role of YAP in the activated phenotype of PaSC. We found that YAP is expressed at low levels in normal mouse pancreas, but protein levels significantly increased after pancreas inflammatory damage induced by repeated cerulein administration in wild-type mice or upon initiation of neoplastic transformation of the pancreas parenchyma in Ptf1-Cre;LSL-KrasG12D/+ (KC) mice. In these animal models, YAP upregulation occurred in parallel with activation and proliferation of PaSC. Consistent with these findings, we found robust YAP expression in culture-activated mouse and human PaSC but not in quiescent, freshly isolated Cells. Fully activated PaSC isolated from KC mice or PDAC patient tissues exhibited robust nuclear YAP suggesting YAP transcriptional activity. Agents that induce quiescence such as the Bromodomain and Extra-Terminal (BET) inhibitor iBET151 and the p38 MAPK inhibitor SB203580 reduced YAP levels in PaSC. Stimulation of PaSC with the potent mitogen PDGF elicited marked YAP Ser127 phosphorylation. However, unexpectedly, this effect did not diminish YAP nuclear localization, suggesting that YAP phosphorylation at this site does not govern YAP Cellular localization in PaSC. siRNA-mediated knockdown of YAP reduced PDGF-induced PaSC expansion in culture and blunted the persistent activation of Akt and ERK elicited by PDGF stimulation, supporting a role for YAP in PDGF-induced Cell growth. YAP knockdown also blunted fibroinflammatory gene expression responses both in unstimulated and transforming growth factor beta 1 (TGFβ1)-stimulated PaSC. Conclusion: Our data suggest a central role for YAP in sustaining the activated phenotype and fibroinflammatory responses in PaSC. Moreover, our findings indicate that a complex crosstalk between YAP, TGFβ1, and PDGF pathways regulates PaSC activity and growth.
-
epidemiology risk factors and the promotion of Pancreatic cancer role of the Stellate Cell
Journal of Gastroenterology and Hepatology, 2012Co-Authors: Stephen J Pandol, Anna S Gukovskaya, Mouad Edderkoui, David W Dawson, Guido Eibl, Aurelia LugeaAbstract:There are approximately 277 000 new cases of Pancreatic cancer and 266 000 deaths from Pancreatic cancer annually, indicating a mortality rate of 96% of the cases diagnosed. Because of the ineffectiveness of therapies, a major emphasis needs to be placed on prevention. This paper reviews the epidemiology and risk factors for Pancreatic cancer, and uses this information to propose plausible research directions for determining the biological mechanisms mediating the effects of risk factors on the promotion of Pancreatic cancer, with a focus on the Pancreatic Stellate Cell.
-
the Pancreatic Stellate Cell a star on the rise in Pancreatic diseases
Journal of Clinical Investigation, 2007Co-Authors: Bishr M Omary, Aurelia Lugea, Anson W Lowe, Stephen J PandolAbstract:Pancreatic Stellate Cells (PaSCs) are myofibroblast-like Cells found in the areas of the pancreas that have exocrine function. PaSCs are regulated by autocrine and paracrine stimuli and share many features with their hepatic counterparts, studies of which have helped further our understanding of PaSC biology. Activation of PaSCs induces them to proliferate, to migrate to sites of tissue damage, to contract and possibly phagocytose, and to synthesize ECM components to promote tissue repair. Sustained activation of PaSCs has an increasingly appreciated role in the fibrosis that is associated with chronic pancreatitis and with Pancreatic cancer. Therefore, understanding the biology of PaSCs offers potential therapeutic targets for the treatment and prevention of these diseases.
