The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) is attributed to intrinsic chemoresistance and a growth-permissive tumor microenvironment. Conversion of quiescent to activated ...pancreatic stellate cells (PSCs) drives the severe stromal reaction that characterizes PDA. Here, we reveal that the vitamin D receptor (VDR) is expressed in stroma from human pancreatic tumors and that treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumor stroma. We show that VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state, resulting in induced stromal remodeling, increased intratumoral gemcitabine, reduced tumor volume, and a 57% increase in survival compared to chemotherapy alone. This work describes a molecular strategy through which transcriptional reprogramming of tumor stroma enables chemotherapeutic response and suggests vitamin D priming as an adjunct in PDA therapy.
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•VDR is a master transcriptional regulator in pancreatic stellate cells•VDR ligands suppress pancreatitis•Stromal VDR activation overcomes chemotherapeutic drug resistance•VDR ligand plus gemcitabine enhances survival in a PDA mouse model
The vitamin D receptor transcriptionally reprograms activated pancreatic stellate cells to a quiescent state to suppress pancreatitis as well as sensitize the stroma to conventional chemotherapy.
ABSTRACT
The impact of increasing vertebrate predator numbers on bird populations is widely debated among the general public, game managers and conservationists across Europe. However, there are few ...systematic reviews of whether predation limits the population sizes of European bird species. Views on the impacts of predation are particularly polarised in the UK, probably because the UK has a globally exceptional culture of intensive, high‐yield gamebird management where predator removal is the norm. In addition, most apex predators have been exterminated or much depleted in numbers, contributing to a widely held perception that the UK has high numbers of mesopredators. This has resulted in many high‐quality studies of mesopredator impacts over several decades. Here we present results from a systematic review of predator trends and abundance, and assess whether predation limits the population sizes of 90 bird species in the UK. Our results confirm that the generalist predators Red Fox (Vulpes vulpes) and Crows (Corvus corone and C. cornix) occur at high densities in the UK compared with other European countries. In addition, some avian and mammalian predators have increased numerically in the UK during recent decades. Despite these high and increasing densities of predators, we found little evidence that predation limits populations of pigeons, woodpeckers and passerines, whereas evidence suggests that ground‐nesting seabirds, waders and gamebirds can be limited by predation. Using life‐history characteristics of prey species, we found that mainly long‐lived species with high adult survival and late onset of breeding were limited by predation. Single‐brooded species were also more likely to be limited by predation than multi‐brooded species. Predators that depredate prey species during all life stages (i.e. from nest to adult stages) limited prey numbers more than predators that depredated only specific life stages (e.g. solely during the nest phase). The Red Fox and non‐native mammals (e.g. the American Mink Neovison vison) were frequently identified as numerically limiting their prey species. Our review has identified predator–prey interactions that are particularly likely to result in population declines of prey species. In the short term, traditional predator‐management techniques (e.g. lethal control or fencing to reduce predation by a small number of predator species) could be used to protect these vulnerable species. However, as these techniques are costly and time‐consuming, we advocate that future research should identify land‐use practices and landscape configurations that would reduce predator numbers and predation rates.
Pancreatic ductal adenocarcinoma is a devastating disease, and patient outcomes have not improved in decades. Treatments that target tumor cells have largely failed. This could be because research ...has focused on cancer cells and the influence of the stroma on tumor progression has been largely ignored. The focus of pancreatic cancer research began to change with the identification of pancreatic stellate cells, which produce the pancreatic tumor stroma. There is compelling in vitro and in vivo evidence for the influence of pancreatic stellate cells on pancreatic cancer development; several recent preclinical studies have reported encouraging results with approaches designed to target pancreatic stellate cells and the stroma. We review the background and recent advances in these areas, along with important areas of future research that could improve therapy.
One of the characteristic features of the majority of pancreatic ductal adenocarcinomas is an abundant desmoplastic/stromal reaction. Until recently, this stroma had received little attention from ...researchers studying the pathogenesis of pancreatic cancer, with most of the research focus resting on the biology of tumor cells themselves. However, evidence is now accumulating that the stroma plays a critical role in pancreatic cancer progression. The cells responsible for producing the stromal reaction in pancreatic cancer are activated pancreatic stellate cells (PSCs, the key effector cells in pancreatic fibrogenesis). In vitro and in vivo studies have convincingly demonstrated a close bi‐directional interaction between PSCs and pancreatic cancer cells, which facilitates local tumor growth as well as distant metastasis. PSCs also interact closely with endothelial cells to stimulate angiogenesis and are possibly involved in the known resistance of pancreatic cancer to chemotherapy and radiation. Most interestingly, it has recently been shown that PSCs from the primary tumor can travel to distant metastatic sites where they likely facilitate the seeding, survival, and proliferation of cancer cells. Thus, it is now recognized that the stroma is an important alternative therapeutic target in this disease and concerted pre‐clinical research is underway to develop strategies to modulate/deplete the stromal reaction to inhibit cancer progression. The challenge is to translate these developments into clinically applicable treatments for patients.
Chronic pancreatitis (CP) is characterized by progressive pancreatic damage that eventually results in significant impairment of exocrine as well as endocrine functions of the gland. In Western ...societies, the commonest association of chronic pancreatitis is alcohol abuse. Our understanding of the pathogenesis of CP has improved in recent years, though important advances that have been made with respect to delineating the mechanisms responsible for the development of pancreatic fibrosis (a constant feature of CP) following repeated acute attacks of pancreatic necroinflammation (the necrosis-fibrosis concept). The pancreatic stellate cells (PSCs) are now established as key cells in fibrogenesis, particularly when activated either directly by toxic factors associated with pancreatitis (such as ethanol, its metabolites or oxidant stress) or by cytokines released during pancreatic necroinflammation. In recent years, research effort has also focused on the genetic abnormalities that may predispose to CP. Genes regulating trypsinogen activation/inactivation and cystic fibrosis transmembrane conductance regulator (CFTR) function have received particular attention. Mutations in these genes are now increasingly recognized for their potential ‘disease modifier’ role in distinct forms of CP including alcoholic, tropical, and idiopathic pancreatitis. Treatment of uncomplicated CP is usally conservative with the major aim being to effectively alleviate pain, maldigestion and diabetes, and consequently, to improve the patient’s quality of life. Surgical and endoscopic interventions are reserved for complications such as pseudocysts, abscess, and malignancy.
Ever 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 recent literature in the field, which indicates an increasingly complex role for the cells in normal pancreas, pancreatitis and pancreatic cancer.
Work reported over the past 12 months includes improved methods of PSC immortalization, a role for PSCs in islet fibrosis, novel factors causing PSC activation as well as those inducing quiescence, and translational research aimed at inhibiting the facilitatory effects of PSCs on disease progression in chronic pancreatitis as well as pancreatic cancer.
Improved understanding of the role of PSCs in pancreatic pathophysiology has prompted a focus on translational studies aimed at developing novel approaches to modulate PSC function in a bid to improve clinical outcomes of two major fibrotic diseases of the pancreas: chronic pancreatitis and pancreatic cancer.
1. Recreational hunting is widespread and can benefit nature conservation when well-practised, monitored, and regulated. Management for recreational red grouse Lagopus lagopus scotica shooting on ...upland heathland in the UK causes conservation conflict because the intensive habitat, predator, and disease management needed to maintain high-grouse densities for "driven" shooting has detrimental environmental impacts, notably for raptor populations. 2. Sustainable management of mountain hares Lepus timidus scoticus, a game species in the same landscapes, poses a challenge. Control of transmission to grouse of a viral disease, louping-ill, for which mountain hares are a host, has become an additional motivation to kill mountain hares since research during 1993-2001 suggested that culls might reduce infection rates in grouse. 3. We analysed population trends of mountain hares from spring counts on moorland managed for grouse shooting and on contiguous alpine land. On moorland sites, a long-term decline (4.6% per annum) from 1954 to 1999 increased to 30.7% per annum from then until 2017, with a density index falling to <1% of initial levels after 2008. Before 1999, declines were associated with conifer planting and were least severe where heather burning characteristic of grouse management was present. Grouse moors had the highest rate of decline after 1999. 4. On alpine sites, the density index increased by 2.0% per annum from 1954 to 2007, then declined by 12.3% per annum but remained within the previous range of variation. 5. Despite lack of evidence that it increases grouse numbers, reduction of louping-ill transmission to grouse became a more frequent justification for mountain hare culls at a time consistent with it causing these recent, rapid mountain hare declines on grouse moors. 6. Synthesis and applications. Long-term field counts suggest that intensification of game bird management has resulted in severe, recent declines in mountain hare numbers, exacerbating longer term declines associated with land-use change. Management practices founded on misinterpretation of earlier research are the probable cause. Regulation of hare culling would provide a framework for formal tests of whether culls affect grouse surpluses. It would also provide an opportunity to examine mountain hare populations' resilience to culls of varying size and seasonal timing.
Pancreatic cancer is characterised by a prominent desmoplastic/stromal reaction that has received little attention until recent times. Given that treatments focusing on pancreatic cancer cells alone ...have failed to significantly improve patient outcome over many decades, research efforts have now moved to understanding the pathophysiology of the stromal reaction and its role in cancer progression. In this regard, our Group was the first to identify the cells(pancreatic stellate cells, PSCs) that produced the collagenous stroma of pancreatic cancer and to demonstrate that these cells interacted closely with cancer cells to facilitate local tumour growth and distant metastasis. Evidence is accumulating to indicate that stromal PSCs may also mediate angiogenesis, immune evasion and the well known resistance of pancreatic cancer to chemotherapy and radiotherapy. This review will summarise current knowledge regarding the critical role of pancreatic stellate cells and the stroma in pancreatic cancer biologyand the therapeutic approaches being developed to target the stroma in a bid to improve the outcome of this devastating disease.
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