Special Issue "Recent Advances in Pancreatic Ductal Adenocarcinoma"

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: 30 June 2021.

Special Issue Editors

Dr. Sumit Sahni
Website
Guest Editor
The University of Sydney, Sydney, Australia
Interests: pancreatic ductal adenocarcinoma; biomarkers; tumour microenvironment
Dr. Anubhav Mittal
Website
Guest Editor
Northern Clinical School, The University of Sydney, Sydney, Australia
Interests: pancreatic ductal adenocarcinoma, surgery, post-surgical complications, prognostic biomarkers
Prof. Dr. Jaswinder Samra
Website
Guest Editor
Northern Clinical School, The University of Sydney, Sydney, Australia
Interests: pancreatic ductal adenocarcinoma, surgery, neoadjuvant chemotherapy

Special Issue Information

Dear Colleagues,

We would like to invite you to submit either original research or review articles for this Special Issue on “Recent Advances in Pancreatic Ductal Adenocarcinoma (PDAC)”. The journal has an impact factor of 6.1, and you are receiving this letter as a personal invitation on behalf of one of the editors.
This Special Issue will focus on the recent advances in the field of PDAC research. The topics will include but are not limited to advances in (1) pancreatic cancer surgery, especially around the equipoise of laparoscopic/robotic vs. open resections, arterial resections, and surgical management of stage 4 PDAC; (2) diagnostic and prognostic biomarkers in blood, urine, and/or tissues; (3) the pancreatic tumor microenvironment; (4) chemotherapy in neoadjuvant, adjuvant, and palliative settings; (5) radiotherapy or radio/chemotherapy; (6) postsurgical complications; (7) novel targeted therapies; (8) immunotherapy; and (9) pancreatic tumor microbiome.

Thank you for your consideration.

Kind regards,

Dr Sumit Sahni
Dr Anubhav Mittal
Prof Dr. Jaswinder Samra
Guest Editors

Manuscript Submission Information

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 papers will be 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2200 CHF (Swiss Francs). 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

  • pancreatic ductal adenocarcinoma
  • pancreatoduodenectomy
  • distal pancreatectomy
  • neoadjuvant chemotherapy
  • biomarkers
  • postsurgical complications
  • targeted therapies
  • tumor microenvironment

Published Papers (16 papers)

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Research

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Open AccessArticle
Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer
Cancers 2021, 13(2), 249; https://doi.org/10.3390/cancers13020249 - 11 Jan 2021
Abstract
Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet [...] Read more.
Background: Pancreatic cancer‐associated diabetes mellitus (PC‐DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. Methods: Langerhans islet invasion was systematically analyzed in 68 patients with pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to islet cells. Results: Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri‐insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo‐insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV) adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. Conclusions: We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, more research on this prevailing feature of pancreatic cancer is needed to better understand underlying principles. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessArticle
Comparative Proton and Photon Irradiation Combined with Pharmacological Inhibitors in 3D Pancreatic Cancer Cultures
Cancers 2020, 12(11), 3216; https://doi.org/10.3390/cancers12113216 - 31 Oct 2020
Cited by 1
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly therapy-resistant tumor entity of unmet needs. Over the last decades, radiotherapy has been considered as an additional treatment modality to surgery and chemotherapy. Owing to radiosensitive abdominal organs, high-precision proton beam radiotherapy has been regarded as [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a highly therapy-resistant tumor entity of unmet needs. Over the last decades, radiotherapy has been considered as an additional treatment modality to surgery and chemotherapy. Owing to radiosensitive abdominal organs, high-precision proton beam radiotherapy has been regarded as superior to photon radiotherapy. To further elucidate the potential of combination therapies, we employed a more physiological 3D, matrix-based cell culture model to assess tumoroid formation capacity after photon and proton irradiation. Additionally, we investigated proton- and photon-irradiation-induced phosphoproteomic changes for identifying clinically exploitable targets. Here, we show that proton irradiation elicits a higher efficacy to reduce 3D PDAC tumoroid formation and a greater extent of phosphoproteome alterations compared with photon irradiation. The targeting of proteins identified in the phosphoproteome that were uniquely altered by protons or photons failed to cause radiation-type-specific radiosensitization. Targeting DNA repair proteins associated with non-homologous endjoining, however, revealed a strong radiosensitizing potential independent of the radiation type. In conclusion, our findings suggest proton irradiation to be potentially more effective in PDAC than photons without additional efficacy when combined with DNA repair inhibitors. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessArticle
Primary Granulocyte Colony-Stimulating Factor Prophylaxis in Metastatic Pancreatic Cancer Patients Treated with FOLFIRINOX as the First-Line Treatment
Cancers 2020, 12(11), 3137; https://doi.org/10.3390/cancers12113137 - 27 Oct 2020
Cited by 1
Abstract
Although FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) has been proven efficacious in metastatic pancreatic cancer (MPC), physicians hesitate to administer it due to its hematologic toxicities. We investigated the usefulness of primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. We reviewed electronic medical records of [...] Read more.
Although FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) has been proven efficacious in metastatic pancreatic cancer (MPC), physicians hesitate to administer it due to its hematologic toxicities. We investigated the usefulness of primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. We reviewed electronic medical records of MPC patients with good performance status who were administered FOLFIRINOX as the first-line treatment from 2011 to 2017. The patients were divided into primary G-CSF prophylaxis users (group A) and non-users or therapeutic/secondary users (group B). Cumulative relative dose (cRDI), adverse effects (AEs), and overall survival (OS) were compared. A total of 165 patients (group A (57) vs. group B (108)) were investigated. Intergroup differences in baseline characteristics were not significant, although the cRDI and the number of treatment cycles were both higher in group A than in group B (cRDI: 80.6% vs. 73.9%, p = 0.007; 9 vs. 6 cycles, p = 0.004). Primary G-CSF prophylaxis reduced the risk of neutropenia (55.6% to 31.6%, p = 0.003) and febrile neutropenia (18.5% to 1.8%, p = 0.002) and improved OS (8.8 to 14.7 months; hazard ratio [HR]: 1.766, 95% CI: 1.257–2.481, p = 0.001). When administering FOLFIRINOX for MPC, primary G-CSF prophylaxis could be rationalized to reduced AEs and improve survival; more prospective studies are needed. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessArticle
FGFR4 Inhibitor BLU9931 Attenuates Pancreatic Cancer Cell Proliferation and Invasion While Inducing Senescence: Evidence for Senolytic Therapy Potential in Pancreatic Cancer
Cancers 2020, 12(10), 2976; https://doi.org/10.3390/cancers12102976 - 14 Oct 2020
Abstract
Fibroblast growth factor receptor 4 (FGFR4), one of four tyrosine kinase receptors for FGFs, is involved in diverse cellular processes. Activation of FGF19/FGFR4 signaling is closely associated with cancer development and progression. In this study, we examined the expression and roles of FGF19/FGFR4 [...] Read more.
Fibroblast growth factor receptor 4 (FGFR4), one of four tyrosine kinase receptors for FGFs, is involved in diverse cellular processes. Activation of FGF19/FGFR4 signaling is closely associated with cancer development and progression. In this study, we examined the expression and roles of FGF19/FGFR4 signaling in human pancreatic ductal adenocarcinoma (PDAC). In human PDAC cases, FGFR4 expression positively correlated with larger primary tumors and more advanced stages. Among eight PDAC cell lines, FGFR4 was expressed at the highest levels in PK-1 cells, in which single-nucleotide polymorphism G388R in FGFR4 was detected. For inhibition of autocrine/paracrine FGF19/FGFR4 signaling, we used BLU9931, a highly selective FGFR4 inhibitor. Inhibition of signal transduction through ERK, AKT, and STAT3 pathways by BLU9931 reduced proliferation in FGF19/FGFR4 signaling-activated PDAC cells. By contrast, BLU9931 did not alter stemness features, including stemness marker expression, anticancer drug resistance, and sphere-forming ability. However, BLU9931 inhibited cell invasion, in part, by downregulating membrane-type matrix metalloproteinase-1 in FGF19/FGFR4 signaling-activated PDAC cells. Furthermore, downregulation of SIRT1 and SIRT6 by BLU9931 contributed to senescence induction, priming these cells for quercetin-induced death, a process termed senolysis. Thus, we propose that BLU9931 is a promising therapeutic agent in FGFR4-positive PDAC, especially when combined with senolysis (195/200). Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessArticle
Molecular Pathogenesis of Pancreatic Ductal Adenocarcinoma: Impact of miR-30c-5p and miR-30c-2-3p Regulation on Oncogenic Genes
Cancers 2020, 12(10), 2731; https://doi.org/10.3390/cancers12102731 - 23 Sep 2020
Cited by 1
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, and its prognosis is abysmal; only 25% of patients survive one year, and 5% live for five years. MicroRNA (miRNA) signature analysis of PDAC revealed that both strands of pre- [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer, and its prognosis is abysmal; only 25% of patients survive one year, and 5% live for five years. MicroRNA (miRNA) signature analysis of PDAC revealed that both strands of pre-miR-30c (miR-30c-5p, guide strand; miR-30c-2-3p, passenger strand) were significantly downregulated, suggesting they function as tumor-suppressors in PDAC cells. Ectopic expression assays demonstrated that these miRNAs attenuated the aggressiveness of PDAC cells, e.g., cell proliferation, migration, and invasiveness. Through a combination of in silico analyses and gene expression data, we identified 216 genes as putative oncogenic targets of miR-30c-5p and miR-30c-2-3p regulation in PDAC cells. Among these, the expression of 18 genes significantly predicted the 5-year survival rates of PDAC patients (p < 0.01). Importantly, the expression levels of 10 genes (YWHAZ, F3, TMOD3, NFE2L3, ENDOD1, ITGA3, RRAS, PRSS23, TOP2A, and LRRFIP1) were found to be independent prognostic factors for patient survival (p < 0.01). We focused on TOP2A (DNA Topoisomerase II Alpha) and investigated its potential as a therapeutic target for PDAC. The overexpression of TOP2A and its transcriptional activators (SP1 and HMGB2) was detected in PDAC clinical specimens. Moreover, the knockdown of TOP2A enhanced the sensitivity of PDAC cells to anticancer drugs. Our analyses of the PDAC miRNA signature and tumor-suppressive miRNAs provide important insights into the molecular pathogenesis of PDAC. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessArticle
Intracellular Porphyromonas gingivalis Promotes the Tumorigenic Behavior of Pancreatic Carcinoma Cells
Cancers 2020, 12(8), 2331; https://doi.org/10.3390/cancers12082331 - 18 Aug 2020
Cited by 3
Abstract
Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link P. gingivalis to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse [...] Read more.
Porphyromonas gingivalis is a member of the dysbiotic oral microbiome associated with oral inflammation and periodontal disease. Intriguingly, epidemiological studies link P. gingivalis to an increased risk of pancreatic cancer. Given that oral bacteria are detected in human pancreatic cancer, and both mouse and human pancreata harbor microbiota, we explored the involvement of P. gingivalis in pancreatic tumorigenesis using cell lines and a xenograft model. Live P. gingivalis induced proliferation of pancreatic cancer cells; however, surprisingly, this effect was independent of Toll-like receptor 2, the innate immune receptor that is engaged in response to P. gingivalis on other cancer and immune cells, and is required for P. gingivalis to induce alveolar bone resorption. Instead, we found that P. gingivalis survives inside pancreatic cancer cells, a trait that can be enhanced in vitro and is increased by hypoxia, a central characteristic of pancreatic cancer. Increased tumor cell proliferation was related to the degree of intracellular persistence, and infection of tumor cells with P. gingivalis led to enhanced growth in vivo. To the best of our knowledge, this study is the first to demonstrate the direct effect of exposure to P. gingivalis on the tumorigenic behavior of pancreatic cancer cell lines. Our findings shed light on potential mechanisms underlying the pancreatic cancer–periodontitis link. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessArticle
Actively Targeted Nanodelivery of Echinomycin Induces Autophagy-Mediated Death in Chemoresistant Pancreatic Cancer In Vivo
Cancers 2020, 12(8), 2279; https://doi.org/10.3390/cancers12082279 - 14 Aug 2020
Abstract
Pancreatic cancer remains a recalcitrant neoplasm associated with chemoresistance and high fatality. Because it is frequently resistant to apoptosis, exploiting autophagic cell death could offer a new treatment approach. We repurpose echinomycin, an antibiotic encapsulated within a syndecan-1 actively targeted nanoparticle, for treatment [...] Read more.
Pancreatic cancer remains a recalcitrant neoplasm associated with chemoresistance and high fatality. Because it is frequently resistant to apoptosis, exploiting autophagic cell death could offer a new treatment approach. We repurpose echinomycin, an antibiotic encapsulated within a syndecan-1 actively targeted nanoparticle, for treatment of pancreatic cancer. Tumor-specific uptake, biodistribution, efficacy of nanodelivered echinomycin, and mechanism of cell death were assessed in aggressive, metastatic models of pancreatic cancer. In these autophagic-dependent pancreatic cancer models, echinomycin treatment resulted in autophagic cell death noted by high levels of LC3 among other autophagy markers, but without hallmarks of apoptosis, e.g., caspase activation and chromatin fragmentation, or necrosis, e.g., plasma membrane degradation and chromatin condensation/degrading. In vivo, biodistribution of syndecan-1-targeted nanoparticles indicated preferential S2VP10 or S2CP9 tumor uptake compared to the liver and kidney (S2VP10 p = 0.0016, p = 0.00004 and S2CP9 p = 0.0009, p = 0.0001). Actively targeted nanodelivered echinomycin resulted in significant survival increases compared to Gemzar (S2VP10 p = 0.0003, S2CP9 p = 0.0017) or echinomycin only (S2VP10 p = 0.0096, S2CP9 p = 0.0073). We demonstrate that actively targeted nanodelivery of echinomycin results in autophagic cell death in pancreatic and potentially other high-autophagy, apoptosis-resistant tumors. Collectively, these findings support syndecan-1-targeted delivery of echinomycin and dysregulation of autophagy to induce cell death in pancreatic cancer. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessArticle
Induction of Lysosome Membrane Permeabilization as a Therapeutic Strategy to Target Pancreatic Cancer Stem Cells
Cancers 2020, 12(7), 1790; https://doi.org/10.3390/cancers12071790 - 04 Jul 2020
Cited by 2
Abstract
Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. [...] Read more.
Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessArticle
Myoferlin Is a Yet Unknown Interactor of the Mitochondrial Dynamics’ Machinery in Pancreas Cancer Cells
Cancers 2020, 12(6), 1643; https://doi.org/10.3390/cancers12061643 - 21 Jun 2020
Abstract
Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types including pancreas cancer. We have previously reported that myoferlin controls mitochondrial structure and function, [...] Read more.
Pancreas ductal adenocarcinoma is one of the deadliest cancers where surgery remains the main survival factor. Mitochondria were described to be involved in tumor aggressiveness in several cancer types including pancreas cancer. We have previously reported that myoferlin controls mitochondrial structure and function, and demonstrated that myoferlin depletion disturbs the mitochondrial dynamics culminating in a mitochondrial fission. In order to unravel the mechanism underlying this observation, we explored the myoferlin localization in pancreatic cancer cells and showed a colocalization with the mitochondrial dynamic machinery element: mitofusin. This colocalization was confirmed in several pancreas cancer cell lines and in normal cell lines as well. Moreover, in pancreas cancer cell lines, it appeared that myoferlin interacted with mitofusin. These discoveries open-up new research avenues aiming at modulating mitofusin function in pancreas cancer. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Review

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Open AccessReview
Targeting and Reprograming Cancer-Associated Fibroblasts and the Tumor Microenvironment in Pancreatic Cancer
Cancers 2021, 13(4), 697; https://doi.org/10.3390/cancers13040697 - 09 Feb 2021
Abstract
Pancreatic cancer is the fourth leading cause of cancer deaths in the United States both in female and male, and is projected to become the second deadliest cancer by 2030. The overall five-year survival rate remains at around 10%. Pancreatic cancer exhibits a [...] Read more.
Pancreatic cancer is the fourth leading cause of cancer deaths in the United States both in female and male, and is projected to become the second deadliest cancer by 2030. The overall five-year survival rate remains at around 10%. Pancreatic cancer exhibits a remarkable resistance to established therapeutic options such as chemotherapy and radiotherapy, due to dense stromal tumor microenvironment. Cancer-associated fibroblasts are the major stromal cell type and source of extracellular matrix proteins shaping a physical and metabolic barrier thereby reducing therapeutic efficacy. Targeting cancer-associated fibroblasts has been considered a promising therapeutic strategy. However, depleting cancer-associated fibroblasts may also have tumor-promoting effects due to their functional heterogeneity. Several subtypes of cancer-associated fibroblasts have been suggested to exhibit tumor-restraining function. This review article summarizes recent preclinical and clinical investigations addressing pancreatic cancer therapy through targeting specific subtypes of cancer-associated fibroblasts, deprogramming activated fibroblasts, administration of mesenchymal stem cells, as well as reprogramming tumor-promoting cancer-associated fibroblasts to tumor-restraining cancer-associated fibroblasts. Further, inter-cellular mediators between cancer-associated fibroblasts and the surrounding tissue microenvironment are discussed. It is important to increase our understanding of cancer-associated fibroblast heterogeneity and the tumor microenvironment for more specific and personalized therapies for pancreatic cancer patients in the future. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessReview
Diabetes and Pancreatic Cancer—A Dangerous Liaison Relying on Carbonyl Stress
Cancers 2021, 13(2), 313; https://doi.org/10.3390/cancers13020313 - 16 Jan 2021
Cited by 1
Abstract
Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is [...] Read more.
Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention and treatment, particularly in high-risk diabetic individuals. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessReview
Adjuvant Pancreatic Cancer Management: Towards New Perspectives in 2021
Cancers 2020, 12(12), 3866; https://doi.org/10.3390/cancers12123866 - 21 Dec 2020
Cited by 1
Abstract
Adjuvant chemotherapy is currently used in all patients with resected pancreatic cancer who are able to begin treatment within 3 months after surgery. Since the recent publication of the PRODIGE 24 trial results, modified FOLFIRINOX has become the standard-of-care in the non-Asian population [...] Read more.
Adjuvant chemotherapy is currently used in all patients with resected pancreatic cancer who are able to begin treatment within 3 months after surgery. Since the recent publication of the PRODIGE 24 trial results, modified FOLFIRINOX has become the standard-of-care in the non-Asian population with localized pancreatic adenocarcinoma following surgery. Nevertheless, there is still a risk of toxicity, and feasibility may be limited in heavily pre-treated patients. In more frail patients, gemcitabine-based chemotherapy remains a suitable option, for example gemcitabine or 5FU in monotherapy. In Asia, although S1-based chemotherapy is the standard of care it is not readily available outside Asia and data are lacking in non-Asiatic patients. In patients in whom resection is not initially possible, intensified schemes such as FOLFIRINOX or gemcitabine-nabpaclitaxel have been confirmed as options to enhance the response rate and resectability, promoting research in adjuvant therapy. In particular, should oncologists prescribe adjuvant treatment after a long sequence of chemotherapy +/– chemoradiotherapy and surgery? Should oncologists consider the response rate, the R0 resection rate alone, or the initial chemotherapy regimen? And finally, should they take into consideration the duration of the entire sequence, or the presence of limited toxicities of induction treatment? The aim of this review is to summarize adjuvant management of resected pancreatic cancer and to raise current and future concerns, especially the need for biomarkers and the best holistic care for patients. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
Open AccessReview
Cellular Heterogeneity of Pancreatic Stellate Cells, Mesenchymal Stem Cells, and Cancer-Associated Fibroblasts in Pancreatic Cancer
Cancers 2020, 12(12), 3770; https://doi.org/10.3390/cancers12123770 - 15 Dec 2020
Cited by 1
Abstract
Pancreatic cancer is projected to become the second deadliest cancer by 2030 in the United States, and the overall five-year survival rate stands still at around 9%. The stroma compartment can make up more than 90% of the pancreatic tumor mass, contributing to [...] Read more.
Pancreatic cancer is projected to become the second deadliest cancer by 2030 in the United States, and the overall five-year survival rate stands still at around 9%. The stroma compartment can make up more than 90% of the pancreatic tumor mass, contributing to the hypoxic tumor microenvironment. The dense stroma with extracellular matrix proteins can be a physical and metabolic barrier reducing therapeutic efficacy. Cancer-associated fibroblasts are a source of extracellular matrix proteins. Therefore, targeting these cells, or extracellular matrix proteins, have been considered as therapeutic strategies. However, several studies show that deletion of cancer-associated fibroblasts may have tumor-promoting effects. Cancer-associated fibroblasts are derived from a variety of different cell types, such as pancreatic stellate cells and mesenchymal stem cells, and constitute a diverse cell population consisting of several functionally heterogeneous subtypes. Several subtypes of cancer-associated fibroblasts exhibit a tumor-restraining function. This review article summarizes recent findings regarding origin and functional heterogeneity of tumor-promoting as well as tumor-restraining cancer-associated fibroblasts. A better understanding of cancer-associated fibroblast heterogeneity could provide more specific and personalized therapies for pancreatic cancer patients in the future. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessReview
Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer
Cancers 2020, 12(9), 2675; https://doi.org/10.3390/cancers12092675 - 19 Sep 2020
Cited by 1
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of the NF-κB transcription factors is a major mechanism that drives inflammation in PDAC. While targeting this pathway is widely supported as a promising therapeutic strategy, clinical success is elusive due to a lack of safe and effective anti-NF-κB pathway therapeutics. Furthermore, the cell type-specific contribution of this pathway, specifically in neoplastic cells, stromal fibroblasts, and immune cells, has not been critically appraised. In this article, we highlighted seminal and recent literature on molecular mechanisms that drive NF-κB activity in each of these major cell types in PDAC, focusing specifically on the innate immune Toll-like/IL-1 receptor pathway. We reviewed recent evidence on the signaling interplay between the NF-κB and oncogenic KRAS signaling pathways in PDAC cells and their collective contribution to cancer inflammation. Lastly, we reviewed clinical trials on agents that target the NF-κB pathway and novel therapeutic strategies that have been proposed in preclinical studies. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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Open AccessReview
Advanced Pancreatic Ductal Adenocarcinoma: Moving Forward
Cancers 2020, 12(7), 1955; https://doi.org/10.3390/cancers12071955 - 18 Jul 2020
Cited by 2
Abstract
Globally, the death rate of pancreatic ductal adenocarcinoma (PDAC) has doubled over 30 years and is likely to further increase, making PDAC a leading cause of cancer-related death in the coming years. PDAC is typically diagnosed at an advanced stage, and modified FOLFIRINOX [...] Read more.
Globally, the death rate of pancreatic ductal adenocarcinoma (PDAC) has doubled over 30 years and is likely to further increase, making PDAC a leading cause of cancer-related death in the coming years. PDAC is typically diagnosed at an advanced stage, and modified FOLFIRINOX or nab-paclitaxel and gemcitabine are the mainstay of systemic therapy. For elderly patients with good performance status, low-dose treatment can preserve quality of life without compromising cancer control or survival. Maintenance therapy should be considered in PDAC patients achieving disease control with systemic therapy. In particular, olaparib has demonstrated a progression-free survival benefit of 3.6 months in a subgroup of PDAC patients with germline BRCA1/2 mutations (ca. 10% of all PDAC). Pancreatic enzyme replacement therapy is often omitted in the treatment of patients with PDAC, with possibly deleterious consequences. Small intestinal bacterial overgrowth is highly prevalent in patients with PDAC and should be considered in the diagnostic algorithm of PDAC patients with bloating and diarrhea. Rivaroxaban has been associated with a reduced risk of thrombosis without an increase in major bleeding events, and its use should be considered in every patient with advanced PDAC undergoing systemic therapy. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)

Other

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Open AccessPerspective
Small Molecule KRAS Inhibitors: The Future for Targeted Pancreatic Cancer Therapy?
Cancers 2020, 12(5), 1341; https://doi.org/10.3390/cancers12051341 - 24 May 2020
Cited by 5
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors in the world. Currently, there are no approved targeted therapies for PDAC. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are known to be a major driver of PDAC [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors in the world. Currently, there are no approved targeted therapies for PDAC. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are known to be a major driver of PDAC progression, but it was considered an undruggable target until recently. Moreover, PDAC also suffers from drug delivery issues due to the highly fibrotic tumor microenvironment. In this perspective, we provide an overview of recent developments in targeting mutant KRAS and strategies to overcome drug delivery issues (e.g., nanoparticle delivery). Overall, we propose that the antitumor effects from novel KRAS inhibitors along with strategies to overcome drug delivery issues could be a new therapeutic way forward in PDAC. Full article
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)
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