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Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 78030

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Special Issue Editor

Prof. Dr. Christian Pilarsky

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Guest Editor

Department of Surgery, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
Interests: pancreatic cancer; CRISPR/Cas; diagnosis; therapy; Kras; apoptosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pancreatic cancer is, worldwide, the 6th most frequent cause of cancer death. The incidence of this disease is rising worldwide, especially in Asian countries. Of all cancers it has the most abysmal five-year survival rate. This is due to a lack of sufficiently early detection methods and the fact that, if detected, the cancer has already spread, even if it is locally resectable using current imaging standards. While chemotherapy has improved in recent years, medical treatment serves only to prolong the life expectancy of patients, but rarely cures. Analyzing the common genetic changes demonstrate a rather monotone set of mutations, typically in KRAS, SMAD4, TP53 and CDKN2A. This has resulted in a resurrection of the importance of an understanding of epigenetic changes and has led to the introduction of pancreatic cancer subtypes, which might need different treatment approaches. With the advent of organoid culture methods, pre-testing for chemo resistance might be feasible to adjust therapeutic regimens and can be used to establish new genetic signatures for resistance. Together with improved immunooncology approaches like genetically-engineered CAR-T cells, this knowledge of molecular changes in pancreatic cancer might considerably improve survival rates. Looking forward, the area of improvement is vast and, within this Special Issue, we would like to show novel concepts for the diagnosis and treatment of pancreatic cancer based on new molecular biology insights.

Prof. Dr. Christian Pilarsky
Guest Editor

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Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

sequencing
organoids
CRISPR/Cas
early detection
prognosis
imaging
surgery
chemoresistance

Published Papers (13 papers)

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Research

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11 pages, 1037 KiB

Open AccessArticle

Upregulation of CD20 Positive B-Cells and B-Cell Aggregates in the Tumor Infiltration Zone is Associated with Better Survival of Patients with Pancreatic Ductal Adenocarcinoma

by Maximilian Brunner, Katharina Maier, Petra Rümmele, Anne Jacobsen, Susanne Merkel, Alan Benard, Christian Krautz, Stephan Kersting, Robert Grützmann and Georg F. Weber

Int. J. Mol. Sci. 2020, 21(5), 1779; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21051779 - 05 Mar 2020

Cited by 18 | Viewed by 2611

Abstract

Patients with pancreatic ductal adenocarcinoma (PDAC) normally have a poor long-term prognosis. However, some rare cases of long-term survivors have been reported. The tumor microenvironment, consisting of cellular and stromal components, possibly plays an important role and might influence prognosis. In this context, the role of tumor-infiltrating B-cells and its impact on the survival in patients with PDAC remains controversial. We therefore aimed to assess the prognostic value of CD20-positive B-cells and CD20-positive B-cell aggregates as well as CD138, IgM, Pax5, and Ki67 on the survival of patients with PDAC using immunohistochemistry of FFPE pancreatectomy tissue sections from patients that underwent primary surgery for pT3- and R0-pancreatic adenocarcinoma between 1995 and 2016. Patients with PDAC were matched and grouped in 16 long-term-survivors (LTS, median overall survival (OS): 96 months [range: 61–177 months]) and 16 short-term-survivors (STS, median OS: 16 months [range: 7–32 months]). CD20-positive B-cells and B-cell aggregates in the tumor infiltration zone were significantly upregulated in the LTS-group compared to the STS-group (p = 0.0499 respectively p = 0.0432). Regarding the entire patient cohort (n = 32) CD20 positive B-cell aggregates in the tumor infiltration zone were an independent prognostic marker for overall survival in multivariate analysis (HR 9.2, CI 1.6–51.4, p = 0.012). These results underline the importance of tumor-associated B-cells for prognosis of patients with PDAC. The detailed role of B cells in the pathomechanism of PDAC should be further investigated for predicting outcome, identifying appropriate treatment regimens, and developing novel therapeutic options. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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24 pages, 2111 KiB

Open AccessArticle

Establishment and Characterisation by Expression Microarray of Patient-Derived Xenograft Panel of Human Pancreatic Adenocarcinoma Patients

by Sandra Roche, Fiona O’Neill, Jean Murphy, Niall Swan, Justine Meiller, Neil T. Conlon, Justin Geoghegan, Kevin Conlon, Ray McDermott, Rozana Rahman, Sinead Toomey, Ninfa L. Straubinger, Robert M. Straubinger, Robert O’Connor, Gerard McVey, Michael Moriarty and Martin Clynes

Int. J. Mol. Sci. 2020, 21(3), 962; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21030962 - 31 Jan 2020

Cited by 11 | Viewed by 4204

Abstract

Pancreatic cancer remains among the most lethal cancers worldwide, with poor early detection rates and poor survival rates. Patient-derived xenograft (PDX) models have increasingly been used in preclinical and clinical research of solid cancers to fulfil unmet need. Fresh tumour samples from human pancreatic adenocarcinoma patients were implanted in severe combined immunodeficiency (SCID) mice. Samples from 78% of treatment-naïve pancreatic ductal adenocarcinoma patients grew as PDX tumours and were confirmed by histopathology. Frozen samples from F1 PDX tumours could be later successfully passaged in SCID mice to F2 PDX tumours. The human origin of the PDX was confirmed using human-specific antibodies; however, the stromal component was replaced by murine cells. Cell lines were successfully developed from three PDX tumours. RNA was extracted from eight PDX tumours and where possible, corresponding primary tumour (T) and adjacent normal tissues (N). mRNA profiles of tumour vs. F1 PDX and normal vs. tumour were compared by Affymetrix microarray analysis. Differential gene expression showed over 5000 genes changed across the N vs. T and T vs. PDX samples. Gene ontology analysis of a subset of genes demonstrated genes upregulated in normal vs. tumour vs. PDX were linked with cell cycle, cycles cell process and mitotic cell cycle. Amongst the mRNA candidates elevated in the PDX and tumour vs. normal were SERPINB5, FERMT1, AGR2, SLC6A14 and TOP2A. These genes have been associated with growth, proliferation, invasion and metastasis in pancreatic cancer previously. Cumulatively, this demonstrates the applicability of PDX models and transcriptomic array to identify genes associated with growth and proliferation of pancreatic cancer. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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11 pages, 1362 KiB

Open AccessArticle

CRISPR/Cas9-Mediated Knock-Out of Kras^G12D Mutated Pancreatic Cancer Cell Lines

by Eva Lentsch, Lifei Li, Susanne Pfeffer, Arif B. Ekici, Leila Taher, Christian Pilarsky and Robert Grützmann

Int. J. Mol. Sci. 2019, 20(22), 5706; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20225706 - 14 Nov 2019

Cited by 26 | Viewed by 8357

Abstract

In 90% of pancreatic ductal adenocarcinoma cases, genetic alteration of the proto-oncogene Kras has occurred, leading to uncontrolled proliferation of cancerous cells. Targeting Kras has proven to be difficult and the battle against pancreatic cancer is ongoing. A promising approach to combat cancer was the discovery of the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system, which can be used to genetically modify cells. To assess the potential of a CRISPR/CRISPR-associated protein 9 (Cas9) method to eliminate Kras mutations in cells, we aimed to knock-out the c.35G>A (p.G12D) Kras mutation. Therefore, three cell lines with a heterozygous Kras mutation (the human cell lines SUIT-2 and Panc-1 and the cell line TB32047 from a KPC mouse model) were used. After transfection, puromycin selection and single-cell cloning, proteins from two negative controls and five to seven clones were isolated to verify the knock-out and to analyze changes in key signal transduction proteins. Western blots showed a specific knock-out in the Kras^G12D protein, but wildtype Kras was expressed by all of the cells. Signal transduction analysis (for Erk, Akt, Stat3, AMPKα, and c-myc) revealed expression levels similar to the wildtype. The results described herein indicate that knocking-out the Kras^G12D mutation by CRISPR/Cas9 is possible. Additionally, under regular growth conditions, the knock-out clones resembled wildtype cells. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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12 pages, 2035 KiB

Open AccessArticle

Silenced ZNF154 Is Associated with Longer Survival in Resectable Pancreatic Cancer

by Felix Wiesmueller, Josephin Kopke, Daniela Aust, Janine Roy, Andreas Dahl, Christian Pilarsky and Robert Grützmann

Int. J. Mol. Sci. 2019, 20(21), 5437; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20215437 - 31 Oct 2019

Cited by 7 | Viewed by 3114

Abstract

Pancreatic cancer has become the third leading cause of cancer-related death in the Western world despite advances in therapy of other cancerous lesions. Late diagnosis due to a lack of symptoms during early disease allows metastatic spread of the tumor. Most patients are considered incurable because of metastasized disease. On a cellular level, pancreatic cancer proves to be rather resistant to chemotherapy. Hence, early detection and new therapeutic targets might improve outcomes. The detection of DNA promoter hypermethylation has been described as a method to identify putative genes of interest in cancer entities. These genes might serve as either biomarkers or might lead to a better understanding of the molecular mechanisms involved. We checked tumor specimens from 80 patients who had undergone pancreatic resection for promoter hypermethylation of the zinc finger protein ZNF154. Then, we further characterized the effects of ZNF154 on cell viability and gene expression by in vitro experiments. We found a significant association between ZNF154 hypermethylation and better survival in patients with resectable pancreatic cancer. Moreover, we suspect that the cell growth suppressor SLFN5 might be linked to a silenced ZNF154 in pancreatic cancer. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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15 pages, 3708 KiB

Open AccessArticle

Interstitial Flow Recapitulates Gemcitabine Chemoresistance in A 3D Microfluidic Pancreatic Ductal Adenocarcinoma Model by Induction of Multidrug Resistance Proteins

by Bart Kramer, Luuk de Haan, Marjolein Vermeer, Thomas Olivier, Thomas Hankemeier, Paul Vulto, Jos Joore and Henriëtte L. Lanz

Int. J. Mol. Sci. 2019, 20(18), 4647; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184647 - 19 Sep 2019

Cited by 29 | Viewed by 6317

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the most lethal cancers due to a high chemoresistance and poor vascularization, which results in an ineffective systemic therapy. PDAC is characterized by a high intratumoral pressure, which is not captured by current 2D and 3D in vitro models. Here, we demonstrated a 3D microfluidic interstitial flow model to mimic the intratumoral pressure in PDAC. We found that subjecting the S2-028 PDAC cell line to interstitial flow inhibits the proliferation, while maintaining a high viability. We observed increased gemcitabine chemoresistance, with an almost nine-fold higher EC50 as compared to a monolayer culture (31 nM versus 277 nM), and an alleviated expression and function of the multidrug resistance protein (MRP) family. In conclusion, we developed a 3D cell culture modality for studying intratissue pressure and flow that exhibits more predictive capabilities than conventional 2D cell culture and is less time-consuming, and more scalable and accessible than animal models. This increase in microphysiological relevance might support improved efficiency in the drug development pipeline. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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12 pages, 2475 KiB

Open AccessArticle

c-Met and PD-L1 on Circulating Exosomes as Diagnostic and Prognostic Markers for Pancreatic Cancer

by Alexander Lux, Christoph Kahlert, Robert Grützmann and Christian Pilarsky

Int. J. Mol. Sci. 2019, 20(13), 3305; https://doi.org/10.3390/ijms20133305 - 05 Jul 2019

Cited by 111 | Viewed by 4634

Abstract

Exosomes are membrane vesicles which offer potential as blood derived biomarkers for malign tumors in clinical practice. Pancreatic cancer is counted among cancer diseases with the highest mortality. The present work seeks to assess whether pancreatic carcinomas release exosomes which express c-Met (proto-oncogene mesenchymal-epithelial transition factor) and PD-L1 (programmed cell death 1 ligand 1), and whether the detection of such expression in serum has diagnostic or prognostic meaning for the affected patients. Exosome isolation was performed on culture media of one benign pancreatic cell line and ten pancreatic carcinoma cell lines as well as on serum samples from 55 patients with pancreatic ductal adenocarcinoma (PDAC), 26 patients with chronic pancreatitis and 10 patients with benign serous cyst adenoma of the pancreas. Exosomes were bound to latex beads and stained with antibodies against c-Met or PD-L1. Analysis of fluorescence intensity was performed by flow cytometry. In terms of c-Met, the mean fluorescence intensity of PDAC-patients was significantly higher than the fluorescence intensity of the comparative patients with benign disease (p < 0.001). A diagnostic test based on c-Met resulted in a sensitivity of 70%, a specificity of 85% and a diagnostic odds ratio of 13:2. The specificity of the test can be further improved by combining it with the established tumor marker carbohydrate antigen 19-9 (CA 19-9). In addition, c-Met-positive patients showed a significantly shorter postoperative survival time (9.5 vs. 21.7 months, p < 0.001). In terms of PD-L1, no significant difference between fluorescence intensity of PDAC-patients and comparative patients was detectable. However, PD-L1-positive PDAC-patients also showed a significantly shorter postoperative survival time (7.8 vs. 17.2 months, p = 0.043). Thus, both markers can be considered as negative prognostic factors. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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Review

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32 pages, 2020 KiB

Open AccessReview

CD36 and CD97 in Pancreatic Cancer versus Other Malignancies

by Cristiana Tanase, Ancuta-Augustina Gheorghisan-Galateanu, Ionela Daniela Popescu, Simona Mihai, Elena Codrici, Radu Albulescu and Mihail Eugen Hinescu

Int. J. Mol. Sci. 2020, 21(16), 5656; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165656 - 06 Aug 2020

Cited by 22 | Viewed by 5412

Abstract

Starting from the recent identification of CD36 and CD97 as a novel marker combination of fibroblast quiescence in lung during fibrosis, we aimed to survey the literature in search for facts about the separate (or concomitant) expression of clusters of differentiation CD36 and CD97 in either tumor- or pancreatic-cancer-associated cells. Here, we provide an account of the current knowledge on the diversity of the cellular functions of CD36 and CD97 and explore their potential (common) contributions to key cellular events in oncogenesis or metastasis development. Emphasis is placed on quiescence as an underexplored mechanism and/or potential target in therapy. Furthermore, we discuss intricate signaling mechanisms and networks involving CD36 and CD97 that may regulate different subpopulations of tumor-associated cells, such as cancer-associated fibroblasts, adipocyte-associated fibroblasts, tumor-associated macrophages, or neutrophils, during aggressive pancreatic cancer. The coexistence of quiescence and activated states in cancer-associated cell subtypes during pancreatic cancer should be better documented, in different histological forms. Remodeling of the local microenvironment may also change the balance between growth and dormant state. Taking advantage of the reported data in different other tissue types, we explore the possibility to induce quiescence (similar to that observed in normal cells), as a therapeutic option to delay the currently observed clinical outcome. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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26 pages, 453 KiB

Open AccessReview

Pancreatic Cancer and Its Microenvironment—Recent Advances and Current Controversies

by Kinga B. Stopa, Agnieszka A. Kusiak, Mateusz D. Szopa, Pawel E. Ferdek and Monika A. Jakubowska

Int. J. Mol. Sci. 2020, 21(9), 3218; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21093218 - 01 May 2020

Cited by 33 | Viewed by 5552

Abstract

Pancreatic ductal adenocarcinoma (PDAC) causes annually well over 400,000 deaths world-wide and remains one of the major unresolved health problems. This exocrine pancreatic cancer originates from the mutated epithelial cells: acinar and ductal cells. However, the epithelia-derived cancer component forms only a relatively small fraction of the tumor mass. The majority of the tumor consists of acellular fibrous stroma and diverse populations of the non-neoplastic cancer-associated cells. Importantly, the tumor microenvironment is maintained by dynamic cell-cell and cell-matrix interactions. In this article, we aim to review the most common drivers of PDAC. Then we summarize the current knowledge on PDAC microenvironment, particularly in relation to pancreatic cancer therapy. The focus is placed on the acellular stroma as well as cell populations that inhabit the matrix. We also describe the altered metabolism of PDAC and characterize cellular signaling in this cancer. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

28 pages, 1344 KiB

Open AccessReview

Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions

by Maximilian Brunner, Zhiyuan Wu, Christian Krautz, Christian Pilarsky, Robert Grützmann and Georg F. Weber

Int. J. Mol. Sci. 2019, 20(18), 4543; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184543 - 13 Sep 2019

Cited by 63 | Viewed by 6308

Abstract

Pancreatic cancer is one of the most lethal malignancies and is associated with a poor prognosis. Surgery is considered the only potential curative treatment for pancreatic cancer, followed by adjuvant chemotherapy, but surgery is reserved for the minority of patients with non-metastatic resectable tumors. In the future, neoadjuvant treatment strategies based on molecular testing of tumor biopsies may increase the amount of patients becoming eligible for surgery. In the context of non-metastatic disease, patients with resectable or borderline resectable pancreatic carcinoma might benefit from neoadjuvant chemo- or chemoradiotherapy followed by surgeryPatients with locally advanced or (oligo-/poly-)metastatic tumors presenting significant response to (neoadjuvant) chemotherapy should undergo surgery if R0 resection seems to be achievable. New immunotherapeutic strategies to induce potent immune response to the tumors and investigation in molecular mechanisms driving tumorigenesis of pancreatic cancer may provide novel therapeutic opportunities in patients with pancreatic carcinoma and help patient selection for optimal treatment. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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19 pages, 716 KiB

Open AccessReview

Chemoresistance in Pancreatic Cancer

by Siyuan Zeng, Marina Pöttler, Bin Lan, Robert Grützmann, Christian Pilarsky and Hai Yang

Int. J. Mol. Sci. 2019, 20(18), 4504; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184504 - 11 Sep 2019

Cited by 340 | Viewed by 13910

Abstract

Pancreatic ductal adenocarcinoma (PDAC), generally known as pancreatic cancer (PC), ranks the fourth leading cause of cancer-related deaths in the western world. While the incidence of pancreatic cancer is displaying a rising tendency every year, the mortality rate has not decreased significantly because of late diagnosis, early metastasis, and limited reaction to chemotherapy or radiotherapy. Adjuvant chemotherapy after surgical resection is typically the preferred option to treat early pancreatic cancer. Although 5-fluorouracil/leucovorin with irinotecan and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel can profoundly improve the prognosis of advanced pancreatic cancer, the development of chemoresistance still leads to poor clinical outcomes. Chemoresistance is multifactorial as a result of the interaction among pancreatic cancer cells, cancer stem cells, and the tumor microenvironment. Nevertheless, more pancreatic cancer patients will benefit from precision treatment and targeted drugs. Therefore, we outline new perspectives for enhancing the efficacy of gemcitabine after reviewing the related factors of gemcitabine metabolism, mechanism of action, and chemoresistance. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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14 pages, 736 KiB

Open AccessReview

The Role of Exosomes in Pancreatic Cancer

by Bin Lan, Siyuan Zeng, Robert Grützmann and Christian Pilarsky

Int. J. Mol. Sci. 2019, 20(18), 4332; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20184332 - 04 Sep 2019

Cited by 55 | Viewed by 5958

Abstract

Pancreatic cancer remains one of the deadliest cancers in the world, as a consequence of late diagnosis, early metastasis and limited response to chemotherapy, under which conditions the potential mechanism of pancreatic cancer progression requires further study. Exosomes are membrane vesicles which are important in the progression, metastasis and chemoresistance in pancreatic cancer. Additionally, they have been verified to be potential as biomarkers, targets and drug carriers for pancreatic cancer treatment. Thus, studying the role of exosomes in pancreatic cancer is significant. This paper focuses on the role of exosomes in the proliferation, metastasis and chemoresistance, as well as their potential applications for pancreatic cancer. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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17 pages, 968 KiB

Open AccessReview

The Clinical Potential of Oligonucleotide Therapeutics against Pancreatic Cancer

by Kazuki Takakura, Atsushi Kawamura, Yuichi Torisu, Shigeo Koido, Naohisa Yahagi and Masayuki Saruta

Int. J. Mol. Sci. 2019, 20(13), 3331; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20133331 - 06 Jul 2019

Cited by 37 | Viewed by 6695

Abstract

Although many diagnostic and therapeutic modalities for pancreatic cancer have been proposed, an urgent need for improved therapeutic strategies remains. Oligonucleotide therapeutics, such as those based on antisense RNAs, small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are promising agents against pancreatic cancer, because they can identify a specific mRNA fragment of a given sequence or protein, and interfere with gene expression as molecular-targeted agents. Within the past 25 years, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Several clinical and preclinical studies of oligonucleotides have been conducted for patients with pancreatic cancer. To support the discovery of effective diagnostic or therapeutic options using oligonucleotide-based strategies, in the absence of satisfactory therapies for long-term survival and the increasing trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients, with underlying preclinical and scientific data, and focus on the possibility of oligonucleotides for targeting pancreatic cancer in clinical implications. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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13 pages, 704 KiB

Open AccessReview

Preclinical Modelling of PDA: Is Organoid the New Black?

by Sabrina D’Agosto, Silvia Andreani, Aldo Scarpa and Vincenzo Corbo

Int. J. Mol. Sci. 2019, 20(11), 2766; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20112766 - 05 Jun 2019

Cited by 13 | Viewed by 4266

Abstract

Pancreatic ductal adenocarcinoma (PDA) is a malignancy of the exocrine pancreas with the worst prognosis among all solid tumours, and soon to become the second leading cause of cancer-related deaths. A more comprehensive understanding of the molecular mechanisms underlying this disease is crucial to the development of diagnostic tools as well as to the identification of more effective therapies. High-frequency mutations in PDA occur in “undruggable” genes, and molecular subtyping based on bulk transcriptome analysis does not yet nominate valid therapeutic intervention strategies. Genome-wide sequencing studies have also demonstrated a considerable intra- and inter-patient’s genetic heterogeneity, which further complicate this dire scenario. More than in other malignancies, functionalization of the PDA genome and preclinical modelling at the individual patient level appear necessary to substantially improve survival rates for pancreatic cancer patients. Traditional human PDA models, including monolayer cell cultures and patient-derived xenografts, have certainly led to valuable biological insights in the past years. However, those model systems suffer from several limitations that have contributed to the lack of concordance between preclinical and clinical studies for PDA. Pancreatic ductal organoids have recently emerged as a reliable culture system to establish models from both normal and neoplastic pancreatic tissues. Pancreatic organoid cultures can be efficiently generated from small tissue biopsies, which opens up the possibility of longitudinal studies in individual patients. A proof-of-concept study has demonstrated that patient-derived PDA organoids are able to predict responses to conventional chemotherapy. The use of this three-dimensional culture system has already improved our understanding of PDA biology and promises to implement precision oncology by enabling the alignment of preclinical and clinical platforms to guide therapeutic intervention in PDA. Full article

(This article belongs to the Special Issue Unraveling Pancreatic Cancer: Pathogenesis, Development, Diagnostic and Treatment)

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