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Advances in Experimental Medicine and... 2020The pancreatic ductal adenocarcinoma (PDAC) microenvironment is a diverse and complex milieu of immune, stromal, and tumor cells and is characterized by a dense stroma,...
The pancreatic ductal adenocarcinoma (PDAC) microenvironment is a diverse and complex milieu of immune, stromal, and tumor cells and is characterized by a dense stroma, which mediates the interaction between the tumor and the immune system within the tumor microenvironment (TME). The interaction between stromal and tumor cells signals and shapes the immune infiltration of TME. The desmoplastic compartment contains infiltrated immune cells including tumor-associated macrophages (TAMs) and large numbers of fibroblasts/myofibroblasts dominated by pancreatic stellate cells (PSCs) which contribute to fibrosis. The highly fibrotic stroma with its extensive infiltration of immunosuppressive cells forms the major component of the pro-tumorigenic microenvironment (Laklai et al. Nat Med 22:497-505, 2016, Zhu et al. Cancer Res 74:5057-5069, 2014) provides a barrier to the delivery of cytotoxic agents and limits T-cell access to tumor cells (Feig et al. Proc Natl Acad Sci USA 110:20212-20217, 2013, Provenzano et al Cancer Cell 21:418-429, 2012). Activated PSCs reduced infiltration of cytotoxic T cells to the juxtatumoral stroma (immediately adjacent to the tumor epithelial cells) of PDAC (Ene-Obong et al. Gastroenterology 145:1121-1132, 2013). M1 macrophages activate an immune response against tumor, but M2 macrophages are involved in immunosuppression promoting tumor progression (Noy and Pollard Immunity 41:49-61, 2014, Ruffell et al. Trends Immunol 33:119-126, 2012). The desmoplastic stroma is reported to protect tumor cells against chemotherapies, promoting their proliferation and migration. However, experimental depletion of the desmoplastic stroma has led to more aggressive cancers in animal studies (Nielsen et al. World J Gastroenterol 22:2678-2700, 2016). Hence reprogramming rather than simple depletion of the PDAC stroma has the potential for developing new therapeutic strategies for PC treatment. Modulation of PSCs/fibrosis and immune infiltration/inflammation composes the major aspects of TME reprogramming.
Topics: Animals; Carcinoma, Pancreatic Ductal; Pancreas; Pancreatic Neoplasms; Pancreatic Stellate Cells; Tumor Microenvironment
PubMed: 34185297
DOI: 10.1007/978-3-030-59038-3_15 -
Gastroenterology Feb 2022Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to...
BACKGROUND & AIMS
Acinar to ductal metaplasia (ADM) occurs in the pancreas in response to tissue injury and is a potential precursor for adenocarcinoma. The goal of these studies was to define the populations arising from ADM, the associated transcriptional changes, and markers of disease progression.
METHODS
Acinar cells were lineage-traced with enhanced yellow fluorescent protein (EYFP) to follow their fate post-injury. Transcripts of more than 13,000 EYFP+ cells were determined using single-cell RNA sequencing (scRNA-seq). Developmental trajectories were generated. Data were compared with gastric metaplasia, Kras-induced neoplasia, and human pancreatitis. Results were confirmed by immunostaining and electron microscopy. Kras was expressed in injury-induced ADM using several inducible Cre drivers. Surgical specimens of chronic pancreatitis from 15 patients were evaluated by immunostaining.
RESULTS
scRNA-seq of ADM revealed emergence of a mucin/ductal population resembling gastric pyloric metaplasia. Lineage trajectories suggest that some pyloric metaplasia cells can generate tuft and enteroendocrine cells (EECs). Comparison with Kras-induced ADM identifies populations associated with disease progression. Activation of Kras expression in HNF1B+ or POU2F3+ ADM populations leads to neoplastic transformation and formation of MUC5AC+ gastric-pit-like cells. Human pancreatitis samples also harbor pyloric metaplasia with a similar transcriptional phenotype.
CONCLUSIONS
Under conditions of chronic injury, acinar cells undergo a pyloric-type metaplasia to mucinous progenitor-like populations, which seed disparate tuft cell and EEC lineages. ADM-derived EEC subtypes are diverse. Kras expression is sufficient to drive neoplasia when targeted to injury-induced ADM populations and offers an alternative origin for tumorigenesis. This program is conserved in human pancreatitis, providing insight into early events in pancreas diseases.
Topics: Acinar Cells; Carcinoma, Pancreatic Ductal; Cell Plasticity; Enteroendocrine Cells; Gene Expression Profiling; Humans; Metaplasia; Mucin 5AC; Pancreas; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatitis; Proto-Oncogene Proteins p21(ras); Single-Cell Analysis
PubMed: 34695382
DOI: 10.1053/j.gastro.2021.10.027 -
Current Diabetes Reports Apr 2020Fibrocalculous pancreatic diabetes (FCPD) is an uncommon form of diabetes occurring in underprivileged developing countries of the world. We attempt to review the latest... (Review)
Review
PURPOSE OF REVIEW
Fibrocalculous pancreatic diabetes (FCPD) is an uncommon form of diabetes occurring in underprivileged developing countries of the world. We attempt to review the latest evidence on epidemiology, secular trends, etiopathogenic mechanisms, and treatment modalities of FCPD with particular reference to studies from the past decade.
RECENT FINDINGS
There has been little new data on FCPD over the past decade even from countries where it was considered to be prevalent. There appears to be a decline in prevalence of the condition of late. There is also some evidence to show that the condition develops due to as yet unknown environmental influences acting on a background of genetic susceptibility. FCPD is a severe form of diabetes and may be a premalignant condition. FCPD deserves more attention than it currently receives, because of its unique clinical features and management strategies, and its propensity to develop pancreatic adenocarcinoma.
Topics: Adenocarcinoma; Calcinosis; Developing Countries; Diabetes Mellitus; Fibrosis; Gene-Environment Interaction; Genetic Predisposition to Disease; Humans; Pancreatic Neoplasms; Pancreatitis, Chronic; Precancerous Conditions; Prevalence; Tropical Climate
PubMed: 32277298
DOI: 10.1007/s11892-020-01303-1 -
Radiology Jul 2023Pancreatic cystic lesions (PCLs) are widely prevalent and commonly encountered in abdominal radiology. Some PCLs can be definitively identified at imaging as benign... (Review)
Review
Pancreatic cystic lesions (PCLs) are widely prevalent and commonly encountered in abdominal radiology. Some PCLs can be definitively identified at imaging as benign subtypes or those with malignant potential, while others remain indeterminate. Notably, the degree of malignant potential and natural history of the most common subtype, branch-duct intraductal papillary mucinous neoplasms, are not clearly established. In the work-up of PCLs, patients may further be identified as high-risk individuals who are at elevated risk of pancreatic ductal adenocarcinoma due to familial and genetic factors. This review describes current PCL surveillance and management guidelines and highlights ongoing controversies and future directions to aid radiologists in their daily practice.
Topics: Humans; Pancreatic Cyst; Pancreas; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Radiologists
PubMed: 37489987
DOI: 10.1148/radiol.222778 -
The Surgical Clinics of North America Jun 2020Solid tumors of the pancreas encompass a variety of diagnoses with treatments ranging from observation to major abdominal surgery. Pancreatic ductal adenocarcinoma... (Review)
Review
Solid tumors of the pancreas encompass a variety of diagnoses with treatments ranging from observation to major abdominal surgery. Pancreatic ductal adenocarcinoma remains one of the most common and most lethal of these differential of diagnoses and requires a multimodality approach through a multidisciplinary team of specialists. This article reviews the classification, clinical presentation, and workup in differentiating solid tumors of the pancreas and serves as an additional tool for general surgeons faced with such a clinical finding, from a surgical oncology perspective.
Topics: Carcinoma, Pancreatic Ductal; Cholangiopancreatography, Endoscopic Retrograde; Diagnosis, Differential; Early Detection of Cancer; Endosonography; Humans; Lymphoma; Magnetic Resonance Imaging; Neoplasm Staging; Neuroendocrine Tumors; Pancreatectomy; Pancreatic Neoplasms; Pancreatitis; Positron Emission Tomography Computed Tomography; Prognosis; Survival Rate; Tomography, X-Ray Computed
PubMed: 32402301
DOI: 10.1016/j.suc.2020.02.008 -
Der Pathologe Sep 2021Beyond pancreatic ductal adenocarcinoma, which is by far the most frequent pancreatic neoplasm, a great variety of tumors occur in the pancreas. They include solid and... (Review)
Review
Beyond pancreatic ductal adenocarcinoma, which is by far the most frequent pancreatic neoplasm, a great variety of tumors occur in the pancreas. They include solid and cystic masses and epithelial and nonepithelial neoplasms, and they show a great diversity in their biological behavior, ranging from benign tumors to highly aggressive neoplasms. As examples of rare pancreatic tumors, clinical, morphological, and molecular aspects of acinar cell carcinoma, pancreatoblastoma, solid pseudopapillary neoplasm, and serous cystic neoplasms are presented and discussed.
Topics: Carcinoma, Acinar Cell; Carcinoma, Pancreatic Ductal; Humans; Pancreas; Pancreatic Neoplasms
PubMed: 34402979
DOI: 10.1007/s00292-021-00967-0 -
Abdominal Radiology (New York) May 2020Pancreatic ductal adenocarcinoma can be a difficult imaging diagnosis early in its course given its subtle imaging findings such as focal pancreatic duct dilatation,... (Review)
Review
Pancreatic ductal adenocarcinoma can be a difficult imaging diagnosis early in its course given its subtle imaging findings such as focal pancreatic duct dilatation, abrupt duct cut-off, and encasement of vasculature. A variety of pancreatitidies have imaging findings that mimic pancreatic ductal adenocarcinoma and lead to mass formation making diagnosis even more difficult on imaging alone. These conditions include acute focal pancreatitis, chronic pancreatitis, autoimmune pancreatitis, and paraduodenal ("groove") pancreatitis. This review will focus on imaging findings that can help differentiate these inflammatory processes from pancreatic ductal adenocarcinoma.
Topics: Adenocarcinoma; Carcinoma, Pancreatic Ductal; Diagnosis, Differential; Humans; Pancreatic Neoplasms; Pancreatitis
PubMed: 31559473
DOI: 10.1007/s00261-019-02233-7 -
Advances in Cancer Research 2023The Notch signaling pathway is an evolutionary conserved signal transduction cascade that is critical to embryonic and postnatal development, but aberrant Notch... (Review)
Review
The Notch signaling pathway is an evolutionary conserved signal transduction cascade that is critical to embryonic and postnatal development, but aberrant Notch signaling is also implicated in tumorigenesis of many organs including the pancreas. Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy in the pancreas, with a dismally low survival rate due to the late-stage diagnosis and peculiar therapeutic resistance. Upregulation of the Notch signaling pathway has been found in preneoplastic lesions as well as PDACs in genetically engineered mouse models and human patients, and inhibition of the Notch signaling suppresses tumor development and progression in mice as well as patient-derived xenograft tumor growth, suggesting a critical role for Notch in PDAC. However, the role of Notch signaling pathway remains contentious, exemplified by differential functions of Notch receptors and contrasting outcomes of abolishing Notch signaling in murine PDAC models with distinct cell-of-origin or at different stages. Glycosylation of Notch receptors represents a powerful regulatory mechanism of Notch signaling, and its functional significance in PDAC has begun to emerge. Beyond its impact on tumor cells, Notch signaling is an important regulator of the components of pancreatic tumor microenvironment, including blood vasculature, stellate cells, fibroblasts, and immune cells. Finally, Notch may act as a tumor suppressor in pancreatic neuroendocrine tumor, the second most common pancreatic neoplasm with the incidence on rise. This review summarizes the research on the complex roles of Notch signaling in pancreatic tumorigenesis and the development of potential Notch-targeting therapies for pancreatic cancer.
Topics: Humans; Mice; Animals; Pancreatic Neoplasms; Cell Transformation, Neoplastic; Carcinogenesis; Signal Transduction; Carcinoma, Pancreatic Ductal; Pancreas; Receptors, Notch; Tumor Microenvironment
PubMed: 37268393
DOI: 10.1016/bs.acr.2023.02.001 -
Pathologica Sep 2020Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is... (Review)
Review
Pancreatic malignant exocrine tumors represent the most important cause of cancer-related death for pancreatic neoplasms. The most common tumor type in this category is represented by pancreatic ductal adenocarcinoma (PDAC), an ill defined, stroma-rich, scirrhous neoplasm with glandular differentiation. Here we present the relevant characteristics of the most important PDAC variants, namely adenosquamous carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, signet ring carcinoma, medullary carcinoma and hepatoid carcinoma. The other categories of malignant exocrine tumors, characterized by fleshy, stroma-poor, circumscribed neoplasms, include acinar cell carcinoma (pure and mixed), pancreatoblastoma, and solid pseudopapillary neoplasms. The most important macroscopic, histologic, immunohistochemical and molecular hallmarks of all these tumors, highlighting their key diagnostic/pathological features are presented. Lastly, standardized indications regarding gross sampling and how to compile a formal pathology report for pancreatic malignant exocrine tumors will be provided.
Topics: Adenocarcinoma; Carcinoma, Pancreatic Ductal; Humans; Pancreas; Pancreas, Exocrine; Pancreatic Neoplasms
PubMed: 33179623
DOI: 10.32074/1591-951X-167 -
World Journal of Gastroenterology Dec 2021Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with a dismal 5-year survival rate. PDAC has a complex tumour microenvironment; characterised by... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with a dismal 5-year survival rate. PDAC has a complex tumour microenvironment; characterised by a robust desmoplastic stroma, extensive infiltration of immunesuppressive cells such as immature myeloid cells, tumour-associated macrophages, neutrophils and regulatory T cells, and the presence of exhausted and senescent T cells. The cross-talk between cells in this fibrotic tumour establishes an immune-privileged microenvironment that supports tumour cell escape from immune-surveillance, disease progression and spread to distant organs. PDAC tumours, considered to be non-immunogenic or cold, express low mutation burden, low infiltration of CD8 cytotoxic lymphocytes that are localised along the invasive margin of the tumour border in the surrounding fibrotic tissue, and often display an exhausted phenotype. Here, we review the role of T cells in pancreatic cancer, examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of T cells as therapy.
Topics: Carcinoma, Pancreatic Ductal; Humans; Lymphocyte Count; Pancreas; Pancreatic Neoplasms; Tumor Microenvironment
PubMed: 35046623
DOI: 10.3748/wjg.v27.i46.7956