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      Translational molecular imaging in exocrine pancreatic cancer

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          Abstract

          Effective treatment for pancreatic cancer remains challenging, particularly the treatment of pancreatic ductal adenocarcinoma (PDAC), which makes up more than 95% of all pancreatic cancers. Late diagnosis and failure of chemotherapy and radiotherapy are all too common, and many patients die soon after diagnosis. Here, we make the case for the increased use of molecular imaging in PDAC preclinical research and in patient management.

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          Most cited references80

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          Beyond the endoplasmic reticulum: atypical GRP78 in cell viability, signalling and therapeutic targeting.

          GRP78 (glucose-regulated protein of 78 kDa) is traditionally regarded as a major ER (endoplasmic reticulum) chaperone facilitating protein folding and assembly, protein quality control, Ca(2+) binding and regulating ER stress signalling. It is a potent anti-apoptotic protein and plays a critical role in tumour cell survival, tumour progression and angiogenesis, metastasis and resistance to therapy. Recent evidence shows that GRP78 can also exist outside the ER. The finding that GRP78 is present on the surface of cancer but not normal cells in vivo represents a paradigm shift on how GRP78 controls cell homoeostasis and provides an opportunity for cancer-specific targeting. Cell-surface GRP78 has emerged as an important regulator of tumour cell signalling and viability as it forms complexes with a rapidly expanding repertoire of cell-surface protein partners, regulating proliferation, PI3K (phosphoinositide 3-kinase)/Akt signalling and cell viability. Evidence is also emerging that GRP78 serves as a receptor for viral entry into host cells. Additionally, a novel cytosolic form of GRP78 has been discovered prominently in leukaemia cells. These, coupled with reports of nucleus- and mitochondria-localized forms of GRP78, point to the previously unanticipated role of GRP78 beyond the ER that may be critical for cell viability and therapeutic targeting. © The Authors Journal compilation © 2011 Biochemical Society
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            Oncogenic KRAS signalling in pancreatic cancer

            Pancreatic ductal adenocarcinoma (PDAC) is almost universally fatal. The annual number of deaths equals the number of newly diagnosed cases, despite maximal treatment. The overall 5-year survival rate of <5% has remained stubbornly unchanged over the last 30 years, despite tremendous efforts in preclinical and clinical science. There is unquestionably an urgent need to further improve our understanding of pancreatic cancer biology, treatment response and relapse, and to identify novel therapeutic targets. Rigorous research in the field has uncovered genetic aberrations that occur during PDAC development and progression. In most cases, PDAC is initiated by oncogenic mutant KRAS, which has been shown to drive pancreatic neoplasia. However, all attempts to target KRAS directly have failed in the clinic and KRAS is widely assumed to be undruggable. This has led to intense efforts to identify druggable critical downstream targets and nodes orchestrated by mutationally activated KRAS. This includes context-specific KRAS effector pathways, synthetic lethal interaction partners and KRAS-driven metabolic changes. Here, we review recent advances in oncogenic KRAS signalling and discuss how these might benefit PDAC treatment in the future.
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              Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE).

              Effective new markers of pancreatic carcinoma are urgently needed. In a previous analysis of gene expression in pancreatic adenocarcinoma using serial analysis of gene expression (SAGE), we found that the tag for the mesothelin mRNA transcript was present in seven of eight SAGE libraries derived from pancreatic carcinomas but not in the two SAGE libraries derived from normal pancreatic duct epithelial cells. In this study, we evaluate the potential utility of mesothelin as a tumor marker for pancreatic adenocarcinoma. Mesothelin mRNA expression was evaluated in pancreatic adenocarcinomas using reverse-transcription PCR (RT-PCR) and in situ hybridization, whereas mesothelin protein expression was evaluated by immunohistochemistry. Using an online SAGE database (http://www.ncbi.nlm.gov/SAGE), we found the tag for mesothelin to be consistently present in the mesothelioma, ovarian cancer, and pancreatic cancer libraries but not in normal pancreas libraries. Mesothelin mRNA expression was confirmed by in situ hybridization in 4 of 4 resected primary pancreatic adenocarcinomas and by RT-PCR in 18 of 20 pancreatic cancer cell lines, whereas mesothelin protein expression was confirmed by immunohistochemistry in all 60 resected primary pancreatic adenocarcinomas studied. The adjacent normal pancreas in these 60 cases did not label, or at most only rare benign pancreatic ducts showed weak labeling for mesothelin. Mesothelin is a new marker for pancreatic adenocarcinoma identified by gene expression analysis. Mesothelin overexpression in pancreatic adenocarcinoma has potential diagnostic, imaging, and therapeutic implications.
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                Author and article information

                Contributors
                bart.cornelissen@oncology.ox.ac.uk
                Journal
                Eur J Nucl Med Mol Imaging
                Eur. J. Nucl. Med. Mol. Imaging
                European Journal of Nuclear Medicine and Molecular Imaging
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                1619-7070
                1619-7089
                17 September 2018
                17 September 2018
                2018
                : 45
                : 13
                : 2442-2455
                Affiliations
                [1 ]ISNI 0000 0004 1936 8948, GRID grid.4991.5, CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, , Oxford University, ; Oxford, UK
                [2 ]ISNI 0000 0004 1808 1697, GRID grid.419546.b, Istituto Oncologico Veneto I.R.C.C.S., ; Padova, Italy
                [3 ]ISNI 0000 0001 2290 8069, GRID grid.8767.e, Vrije Universiteit Brussel, ; Brussels, Belgium
                [4 ]GRID grid.410567.1, Department of Radiology, , Universitätsspital Basel, ; Basel, Switzerland
                [5 ]ISNI 0000 0001 0790 385X, GRID grid.4691.a, Universita’ degli Studi di Napoli “Federico II”, ; Naples, Italy
                [6 ]GRID grid.4817.a, CRCINA, INSERM, CNRS, Université d’Angers, Université de Nantes, ; Nantes, France
                [7 ]ISNI 000000040459992X, GRID grid.5645.2, Department of Radiology & Nuclear Medicine, , Erasmus MC, ; Rotterdam, The Netherlands
                [8 ]ISNI 0000000089452978, GRID grid.10419.3d, Interventional Molecular Imaging Laboratory, Department of Radiology, , Leiden University Medical Center, ; Leiden, The Netherlands
                Article
                4146
                10.1007/s00259-018-4146-5
                6208802
                30225616
                9016ef8b-335d-4022-8651-8dade8a4f3e4
                © The Author(s) 2018

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 11 April 2018
                : 22 August 2018
                Funding
                Funded by: University of Oxford
                Categories
                Review Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                Radiology & Imaging
                pancreatic ductal adenocarcinoma,molecular imaging,pet,spect,preclinical developments

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