StellaTUM: current consensus and discussion on pancreatic stellate cell research

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

Recruitment and Activation of Pancreatic Stellate Cells from the Bone Marrow in Pancreatic Cancer: A Model of Tumor-Host Interaction

BACKGROUND AND AIMS: Chronic pancreatitis and pancreatic cancer are characterised by extensive stellate cell mediated fibrosis, and current therapeutic development includes targeting pancreatic cancer stroma and tumor-host interactions. Recent evidence has suggested that circulating bone marrow derived stem cells (BMDC) contribute to solid organs. We aimed to define the role of circulating haematopoietic cells in the normal and diseased pancreas. METHODS: Whole bone marrow was harvested from male β-actin-EGFP donor mice and transplanted into irradiated female recipient C57/BL6 mice. Chronic pancreatitis was induced with repeat injections of caerulein, while carcinogenesis was induced with an intrapancreatic injection of dimethylbenzanthracene (DMBA). Phenotype of engrafted donor-derived cells within the pancreas was assessed by immunohistochemistry, immunofluorescence and in situ hybridisation. RESULTS: GFP positive cells were visible in the exocrine pancreatic epithelia from 3 months post transplantation. These exhibited acinar morphology and were positive for amylase and peanut agglutinin. Mice administered caerulein developed chronic pancreatitis while DMBA mice exhibited precursor lesions and pancreatic cancer. No acinar cells were identified to be donor-derived upon cessation of cerulein treatment, however rare occurrences of bone marrow-derived acinar cells were observed during pancreatic regeneration. Increased recruitment of BMDC was observed within the desmoplastic stroma, contributing to the activated pancreatic stellate cell (PaSC) population in both diseases. Expression of stellate cell markers CELSR3, PBX1 and GFAP was observed in BMD cancer-associated PaSCs, however cancer-associated, but not pancreatitis-associated BMD PaSCs, expressed the cancer PaSC specific marker CELSR3. CONCLUSIONS: This study demonstrates that BMDC can incorporate into the pancreas and adopt the differentiated state of the exocrine compartment. BMDC that contribute to the activated PaSC population in chronic pancreatitis and pancreatic cancer have different phenotypes, and may play important roles in these diseases. Further, bone marrow transplantation may provide a useful model for the study of tumor-host interactions in cancer and pancreatitis

Retinoid Signaling in Pancreatic Cancer, Injury and Regeneration

Background: Activation of embryonic signaling pathways quiescent in the adult pancreas is a feature of pancreatic cancer (PC). These discoveries have led to the development of novel inhibitors of pathways such as Notch and Hedgehog signaling that are currently in early phase clinical trials in the treatment of several cancer types. Retinoid signaling is also essential for pancreatic development, and retinoid therapy is used successfully in other malignancies such as leukemia, but little is known concerning retinoid signaling in PC. Methodology/Principal Findings: We investigated the role of retinoid signaling in vitro and in vivo in normal pancreas, pancreatic injury, regeneration and cancer. Retinoid signaling is active in occasional cells in the adult pancreas but is markedly augmented throughout the parenchyma during injury and regeneration. Both chemically induced and genetically engineered mouse models of PC exhibit a lack of retinoid signaling activity compared to normal pancreas. As a consequence, we investigated Cellular Retinoid Binding Protein 1 (CRBP1), a key regulator of retinoid signaling known to play a role in breast cancer development, as a potential therapeutic target. Loss, or significant downregulation of CRBP1 was present in 70% of human PC, and was evident in the very earliest precursor lesions (PanIN-1A). However, in vitro gain and loss of function studies and CRBP1 knockout mice suggested that loss of CRBP1 expression alone was not sufficient to induce carcinogenesis or to alter PC sensitivity to retinoid based therapies. Conclusions/Significance: In conclusion, retinoid signalling appears to play a role in pancreatic regeneration and carcinogenesis, but unlike breast cancer, it is not mediated directly by CRBP1

Individual susceptibility to alcoholic pancreatitis

The observation that only a minority of heavy drinkers develop pancreatitis has prompted an intensive search for a trigger factor/cofactor/susceptibility factor that may precipitate a clinical attack. Putative susceptibility factors examined so far include diet, smoking, amount and type of alcohol consumed, the pattern of drinking and lipid intolerance. In addition, a range of inherited factors have been assessed including blood group antigens, human leukocyte antigen serotypes, alpha-1-antitrypsin phenotypes and several genotypes. The latter group comprises mutations/polymorphisms in genes related to alcohol-metabolizing enzymes, detoxifying enzymes, pancreatic digestive enzymes, pancreatic enzyme inhibitors, cystic fibrosis and cytokines. Disappointingly, despite this concerted research effort, no clear association has been established between the above factors and alcoholic pancreatitis. Experimentally, the secretagogue cholecystokinin (CCK) has been investigated as a candidate ‘trigger’ for alcoholic pancreatitis. However, the clinical relevance of CCK as a trigger factor has to be questioned, as it is difficult to envisage a situation in humans where abnormally high levels of CCK would be released into the circulation to trigger pancreatitis in alcoholics. In contrast, bacterial endotoxemia is a candidate cofactor that does have relevance to the clinical situation. Plasma lipopolysaccharide (LPS, an endotoxin) levels are significantly higher in drinkers (either after chronic alcohol intake or a single binge) compared to non-drinkers. We have recently shown that alcohol-fed animals challenged with otherwise innocuous doses of LPS exhibit significant pancreatic injury. Moreover, repeated LPS exposure in alcohol-fed rats leads to progressive injury to the gland characterized by significant pancreatic fibrosis. These studies support the concept that endotoxin may be an important factor in the initiation and progression of alcoholic pancreatitis. Scope remains for further studies examining proteins related to cellular anti-oxidant defenses, minor cystic fibrosis (CF) mutations and trans-heterozygosity involving a combination of mutations of different genes (such as CFTR alterations combined with SPINK1 or PRSS1 variants), as potential triggers of alcoholic pancreatitis. Apte, M. V., Pirola, R. C., & Wilson, J. S. (2008). Individual susceptibility to alcoholic pancreatitis. Journal of Gastroenterology and Hepatology, 23(S1), S63-S68. doi:10.1111/j.1440-1746.2007.05287.

Molecular mechanisms of alcoholic pancreatitis

Alcoholic pancreatitis is a major complication of alcohol abuse. Since only a minority of alcoholics develop pancreatitis, there has been a keen interest in identifying the factors that may confer individual susceptibility to the disease. Numerous possibilities have been evaluated including diet, drinking patterns and a range of inherited factors. However, at the present time, no susceptibility factor has been unequivocally identified. In contrast, considerable progress has been made with respect to the constant effects of alcohol on the pancreas. The molecular mechanisms of alcohol-induced pancreatic injury are being increasingly defined with an emphasis, in recent years, on the acinar cell itself as the principal site on ethanol-related damage. It has now been established that the acinar cell is capable of metabolizing alcohol and that the direct toxic effects of alcohol and/or its metabolites on acinar cells may predispose the gland to autodigestive injury in the presence of an appropriate triggering factor. A significant recent development relates to the characterization of pancreatic stellate cells, increasingly implicated in alcoholic pancreatic fibrosis. Here the current concepts regarding the mechanisms/pathways mediating alcohol-induced pancreatic injury are outlined

Etiopathogenesis And Epidemiology Of Alcohol-Induced Acute Pancreatitis

The most encyclopedic book on the pancreas - providing clear guidance for practicing clinicians & surgeons. In the past decade, extraordinary developments in diagnostic and therapeutic radiology and endoscopy have been coupled with major advances in surgical techniques and basic sciences. As a result the management of pancreatic disorders is now handled by a multidisciplinary team. This book shows you how to achieve superior patient management by taking the team approach to in-hospital care. [Excerpt from publisher\u27s website] ISBN: 978-1-4051-4664-

Where there’s smoke there’s not necessarily fire

Although alcohol abuse is a major association of chronic pancreatitis, it is well known that only a minority of heavy drinkers develop clinically evident pancreatitis.1,2 This observation has led to a sustained effort to identify factors that may increase the susceptibility of alcoholics to the development and progression of the disease. One of the candidate susceptibility factors is smoking. The interest in smoking as a risk factor for the development and accelerated progression of alcoholic pancreatitis is understandable given that a number of smoking/nicotine related effects on the pancreas have been described in the literature. High concentrations of nicotine have been shown to increase pancreatic protein synthesis in isolated acini.3 Nicotine has also been shown to induce vacuolisation and nuclear pyknosis in acinar cells.4 Serum levels of pancreatic enzymes are reported to be significantly increased in smokers after intravenous secretin.5–7 In addition, in vivo and in vitro studies have demonstrated that smoking significantly inhibits pancreatic secretion.8,9 The concept that smoking enhances the toxic effects of alcohol on the pancreas was examined in a recent experimental study where cigarette smoke was administered to anaesthetised rats receiving intravenous ethanol; the

Role of Pancreatic Tumour-Derived Exosomes and Their Cargo in Pancreatic Cancer-Related Diabetes

One of the most common and deadly types of pancreatic cancer (PC) is pancreatic ductal adenocarcinoma (PDAC), with most patients succumbing to the disease within one year of diagnosis. Current detection strategies do not address asymptomatic PC; therefore, patients are diagnosed at an advanced stage when curative treatment is often no longer possible. In order to detect PC in asymptomatic patients earlier, the risk factors that could serve as reliable markers need to be examined. Diabetic mellitus (DM) is a significant risk factor for this malignancy and can be both a cause and consequence of PC. Typically, DM caused by PC is known as new-onset, pancreatogenic, pancreoprivic, or pancreatic cancer-related diabetes (PCRD). Although PCRD is quite distinct from type 2 DM (T2DM), there are currently no biomarkers that differentiate PCRD from T2DM. To identify such biomarkers, a better understanding of the mechanisms mediating PCRD is essential. To this end, there has been a growing research interest in recent years to elucidate the role of tumour-derived exosomes and their cargo in the pathogenesis of PCRD. Exosomes derived from tumours can be recognized for their specificity because they reflect the characteristics of their parent cells and are important in intercellular communication. Their cargo consists of proteins, lipids, and nucleic acids, which can be transferred to and alter the behaviour of recipient cells. This review provides a concise overview of current knowledge regarding tumour-derived exosomes and their cargo in PCRD and discusses the potential areas worthy of further study