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Cell and Molecular Biology of Pancreatic Disorders 2019

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 August 2019) | Viewed by 46809

Special Issue Editors

Department of Surgery, Division of Surgical Oncology, East Carolina University Brody School of Medicine, Greenville, NC 27834, USA
Interests: pancreas; liver; stomach; esophagus; gallbladder
1. Department of Molecular Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL 33612, USA
2. Department of Tumor Biology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, USA
Interests: calcium signaling; proteases in cancer; novel therapeutics in pancreatic cancer; cell cycle regulation; signal transduction; epithelial–mesenchymal transition; mechanisms of neurodegeneration; Alzheimer’s disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is a continuation of our 2018 Special Issue, “Cell and Molecular Biology of Pancreatic Disorders”.

Elucidation of the molecular mechanisms underlying the initiation and progression of a disease enables the development of targeted therapies to inhibit or delay the disease progression. Pancreatic disorders vary in nature, with pancreatic ductal adenocarcinoma being one of the most lethal cancers, with a dismal five-year survival rate of less than 6%. Due to a lack of non-invasive early detection methods, the cancer is detected at a late stage when it is aggressive and resistant to available therapies. Additionally, the tumor microenvironment—enriched with growth factors and cytokines—significantly supports the growth and metastasis of tumors, and hinders therapeutic efficacy. Secreted factors can act at the autocrine or paracrine level to promote or suppress cell growth in the microenvironment. Identification of the signaling mechanisms is important for targeted drug development. Furthermore, the role of cancer stem cells or tumor-initiating cells in the genesis and progression of pancreatic cancer is also not fully elucidated. This Special Issue is expected to cover the molecular and cellular mechanisms associated with pancreatic ductal adenocarcinomas, as well as the contribution of pancreatitis to the genesis of this disease. Other relevant aspects like the contribution of microenvironmental factors, cancer stem cells, behavior correlates such as smoking, and the role of environmental pollutants in the genesis and progression as well as responses to therapy will be covered in this Issue. We expect that this Special Issue will provide the latest information on the underlying mechanisms and treatment strategies associated with pancreatic disorders, and will be of interest to scientists and clinicians working in this area.

Prof. Dr. Emmanuel E. Zervos
Prof. Dr. Jaya Padmanabhan
Guest Editors

Manuscript Submission Information

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Keywords

  • Pancreatitis
  • Pancreatic ductal adenocarcinoma
  • Pancreatic neuroendocrine tumors
  • Pancreatic intraepithelial neoplasia
  • Intraductal papillary mucinous neoplasms
  • Pancreatic cancer stem cells
  • Pancreatic stromal cells
  • Pancreatic microenvironment
  • Genetic changes
  • Transcription and translation
  • Cell metabolism
  • Intracellular and intercellular signaling
  • Genomics/proteomics/lipidomics
  • Inflammation
  • Metastasis
  • Chronic pancreatitis
  • Acute necrotizing pancreatitis
  • SIRS
  • Sepsis

Published Papers (7 papers)

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Research

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8 pages, 1438 KiB  
Communication
The IL-17A/IL-17RA Axis Is Not Related to Overall Survival and Cancer Stem Cell Modulation in Pancreatic Cancer
by Jiahui Li, Christopher Betzler, Philipp Lohneis, Marie Christine Popp, Jiwei Qin, Thomas Kalinski, Thomas Wartmann, Christiane J. Bruns, Yue Zhao and Felix C. Popp
Int. J. Mol. Sci. 2020, 21(6), 2215; https://doi.org/10.3390/ijms21062215 - 23 Mar 2020
Cited by 3 | Viewed by 2658
Abstract
(1) Background: IL-17A accelerates pancreatic intraepithelial neoplasia (PanIN) progression. In this study, we examined whether IL-17A/IL-17RA promotes pancreatic ductal adenocarcinoma (PDAC) aggressiveness in terms of survival and cancer stem cell modulation. (2) Methods: In vitro, the wound-healing assay, the sphere formation assay, and [...] Read more.
(1) Background: IL-17A accelerates pancreatic intraepithelial neoplasia (PanIN) progression. In this study, we examined whether IL-17A/IL-17RA promotes pancreatic ductal adenocarcinoma (PDAC) aggressiveness in terms of survival and cancer stem cell modulation. (2) Methods: In vitro, the wound-healing assay, the sphere formation assay, and flow cytometry were applied to assess cancer stem cell features. In vivo, pancreatic tumors were induced in C57BL/6 mice using electroporation with oncogenic plasmids (P53-/- R172H; KrasG12V). Anti-IL-17 antibodies were administered as immunotherapy. We analyzed IL-17A/IL-17RA related survival using publicly available transcriptomic data (n = 903). (3) Results: IL-17A/IL-17RA expression was not related to survival in PDAC patients. IL-17A neither induces stem cell markers nor increases sphere formation and cell motility in vitro. Blocking the IL-17A/IL-17RA axis in a murine pancreatic cancer model did not improve the survival of mice, but reduced the tumor burden slightly. (4) Conclusions: IL-17A does not promote stem cell expansion in PDAC cell lines. Blocking IL-17A/IL-17RA signaling does not interfere with pancreatic cancer development and progression and may not be considered as a promising monotherapy for PDAC. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders 2019)
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21 pages, 6385 KiB  
Article
Fendiline Enhances the Cytotoxic Effects of Therapeutic Agents on PDAC Cells by Inhibiting Tumor-Promoting Signaling Events: A Potential Strategy to Combat PDAC
by Marwa Alhothali, Mevin Mathew, Geeta Iyer, Harshani R. Lawrence, Shengyu Yang, Srikumar Chellappan and Jaya Padmanabhan
Int. J. Mol. Sci. 2019, 20(10), 2423; https://doi.org/10.3390/ijms20102423 - 16 May 2019
Cited by 6 | Viewed by 3924
Abstract
The L-type calcium channel blocker fendiline has been shown to interfere with Ras-dependent signaling in K-Ras mutant cancer cells. Earlier studies from our lab had shown that treatment of pancreatic cancer cells with fendiline causes significant cytotoxicity and interferes with proliferation, survival, migration, [...] Read more.
The L-type calcium channel blocker fendiline has been shown to interfere with Ras-dependent signaling in K-Ras mutant cancer cells. Earlier studies from our lab had shown that treatment of pancreatic cancer cells with fendiline causes significant cytotoxicity and interferes with proliferation, survival, migration, invasion and anchorage independent growth. Currently there are no effective therapies to manage PDACs. As fendiline has been approved for treatment of patients with angina, we hypothesized that, if proven effective, combinatorial therapies using this agent would be easily translatable to clinic for testing in PDAC patients. Here we tested combinations of fendiline with gemcitabine, visudyne (a YAP1 inhibitor) or tivantinib (ARQ197, a c-Met inhibitor) for their effectiveness in overcoming growth and oncogenic characteristics of PDAC cells. The Hippo pathway component YAP1 has been shown to bypass K-Ras addiction, and allow tumor growth, in a Ras-null mouse model. Similarly, c-Met expression has been associated with poor prognosis and metastasis in PDAC patients. Our results presented here show that combinations of fendiline with these inhibitors show enhanced anti-tumor activity in Panc1, MiaPaCa2 and CD18/HPAF PDAC cells, as evident from the reduced viability, migration, anchorage-independent growth and self-renewal. Biochemical analysis shows that these agents interfere with various signaling cascades such as the activation of Akt and ERK, as well as the expression of c-Myc and CD44 that are altered in PDACs. These results imply that inclusion of fendiline may improve the efficacy of various chemotherapeutic agents that could potentially benefit PDAC patients. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders 2019)
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Review

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14 pages, 714 KiB  
Review
Stratifying Intraductal Papillary Mucinous Neoplasms by Cyst Fluid Analysis: Present and Future
by Scarlett Hao, Caitlin Takahashi, Rebecca A. Snyder and Alexander A. Parikh
Int. J. Mol. Sci. 2020, 21(3), 1147; https://doi.org/10.3390/ijms21031147 - 09 Feb 2020
Cited by 13 | Viewed by 3235
Abstract
A significant proportion of patients with intraductal papillary mucinous neoplasms (IPMNs) undergo surgical resection in order to prevent or treat pancreatic cancer at the risk of significant perioperative morbidity. Efforts have been made to stratify the potential risk of malignancy based on the [...] Read more.
A significant proportion of patients with intraductal papillary mucinous neoplasms (IPMNs) undergo surgical resection in order to prevent or treat pancreatic cancer at the risk of significant perioperative morbidity. Efforts have been made to stratify the potential risk of malignancy based on the clinical and radiographic features of IPMN to delineate which cysts warrant resection versus observation. An analysis of the cyst fluid obtained by preoperative endoscopic examination appears to be correlative of cyst type and risk, whereas serum markers and radiographic findings have not yet reached a level of sensitivity or specificity that proves they are clinically meaningful. In this review, we investigate the current cyst fluid analysis studies and present those that have shown promise in effectively stratifying high-risk versus low-risk lesions. While new cyst fluid markers continue to be identified, additional efforts in testing panels and marker composites in conjunction with clinical algorithms have also shown promise in distinguishing dysplasia and the risk of malignancy. These should be tested prospectively in order to determine their role in guiding the surveillance of low-risk lesions and to evaluate the new markers detected by proteomics and genetic sequencing. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders 2019)
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20 pages, 1290 KiB  
Review
β-Cell Maturation and Identity in Health and Disease
by Ciro Salinno, Perla Cota, Aimée Bastidas-Ponce, Marta Tarquis-Medina, Heiko Lickert and Mostafa Bakhti
Int. J. Mol. Sci. 2019, 20(21), 5417; https://doi.org/10.3390/ijms20215417 - 30 Oct 2019
Cited by 46 | Viewed by 7176
Abstract
The exponential increase of patients with diabetes mellitus urges for novel therapeutic strategies to reduce the socioeconomic burden of this disease. The loss or dysfunction of insulin-producing β-cells, in patients with type 1 and type 2 diabetes respectively, put these cells at the [...] Read more.
The exponential increase of patients with diabetes mellitus urges for novel therapeutic strategies to reduce the socioeconomic burden of this disease. The loss or dysfunction of insulin-producing β-cells, in patients with type 1 and type 2 diabetes respectively, put these cells at the center of the disease initiation and progression. Therefore, major efforts have been taken to restore the β-cell mass by cell-replacement or regeneration approaches. Implementing novel therapies requires deciphering the developmental mechanisms that generate β-cells and determine the acquisition of their physiological phenotype. In this review, we summarize the current understanding of the mechanisms that coordinate the postnatal maturation of β-cells and define their functional identity. Furthermore, we discuss different routes by which β-cells lose their features and functionality in type 1 and 2 diabetic conditions. We then focus on potential mechanisms to restore the functionality of those β-cell populations that have lost their functional phenotype. Finally, we discuss the recent progress and remaining challenges facing the generation of functional mature β-cells from stem cells for cell-replacement therapy for diabetes treatment. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders 2019)
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16 pages, 934 KiB  
Review
Wnt/β-Catenin Signaling: The Culprit in Pancreatic Carcinogenesis and Therapeutic Resistance
by Monish Ram Makena, Himavanth Gatla, Dattesh Verlekar, Sahithi Sukhavasi, Manoj K. Pandey and Kartick C. Pramanik
Int. J. Mol. Sci. 2019, 20(17), 4242; https://doi.org/10.3390/ijms20174242 - 30 Aug 2019
Cited by 100 | Viewed by 12936
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is responsible for 7.3% of all cancer deaths. Even though there is a steady increase in patient survival for most cancers over the decades, the patient survival rate for pancreatic cancer remains low with current therapeutic strategies. The Wnt/β-catenin pathway controls the maintenance of somatic stem cells in many tissues and organs and is implicated in pancreatic carcinogenesis by regulating cell cycle progression, apoptosis, epithelial-mesenchymal transition (EMT), angiogenesis, stemness, tumor immune microenvironment, etc. Further, dysregulated Wnt has been shown to cause drug resistance in pancreatic cancer. Although different Wnt antagonists are effective in pancreatic patients, limitations remain that must be overcome to increase the survival benefits associated with this emerging therapy. In this review, we have summarized the role of Wnt signaling in pancreatic cancer and suggested future directions to enhance the survival of pancreatic cancer patients. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders 2019)
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20 pages, 920 KiB  
Review
Potential Prognostic Markers of Acute Kidney Injury in the Early Phase of Acute Pancreatitis
by Justyna Wajda, Paulina Dumnicka, Małgorzata Maraj, Piotr Ceranowicz, Marek Kuźniewski and Beata Kuśnierz-Cabala
Int. J. Mol. Sci. 2019, 20(15), 3714; https://doi.org/10.3390/ijms20153714 - 30 Jul 2019
Cited by 33 | Viewed by 10675
Abstract
Acute kidney injury (AKI) is a serious complication of acute pancreatitis (AP), which occurs in up to 70% of patients with severe AP and significantly increases the risk of mortality. At present, AKI is diagnosed based on dynamic increase in serum creatinine and [...] Read more.
Acute kidney injury (AKI) is a serious complication of acute pancreatitis (AP), which occurs in up to 70% of patients with severe AP and significantly increases the risk of mortality. At present, AKI is diagnosed based on dynamic increase in serum creatinine and decreased urine output; however, there is a need for earlier and more accurate biomarkers. The aim of the study was to review current evidence on the laboratory tests that were studied as the potential biomarkers of AKI in AP. We also briefly summarized the knowledge coming from the studies including sepsis or ICU patients since severe acute pancreatitis is associated with systemic inflammation and organ failure. Serum cystatin C and serum or urine NGAL have been shown to predict or diagnose AKI in AP; however, this evidence come from the single center studies of low number of patients. Other markers, such as urinary kidney injury molecule-1, cell cycle arrest biomarkers (tissue inhibitor metalloproteinase-2 and urine insulin-like growth factor-binding protein 7), interleukin-18, liver-type fatty acid-binding protein, or calprotectin have been studied in other populations suffering from systemic inflammatory states. In AP, the potential markers of AKI may be significantly influenced by either dehydration or inflammation, and the impact of these factors may be difficult to distinguish from kidney injury. The subject of AKI complicating AP is understudied. More studies are needed, for both exploratory (to choose the best markers) and clinical (to evaluate the diagnostic accuracy of the chosen markers in real clinical settings). Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders 2019)
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16 pages, 509 KiB  
Review
Genomic Features and Clinical Management of Patients with Hereditary Pancreatic Cancer Syndromes and Familial Pancreatic Cancer
by Akihiro Ohmoto, Shinichi Yachida and Chigusa Morizane
Int. J. Mol. Sci. 2019, 20(3), 561; https://doi.org/10.3390/ijms20030561 - 29 Jan 2019
Cited by 33 | Viewed by 5684
Abstract
Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as [...] Read more.
Pancreatic cancer (PC) is one of the most devastating malignancies; it has a 5-year survival rate of only 9%, and novel treatment strategies are urgently needed. While most PC cases occur sporadically, PC associated with hereditary syndromes or familial PC (FPC; defined as an individual having two or more first-degree relatives diagnosed with PC) accounts for about 10% of cases. Hereditary cancer syndromes associated with increased risk for PC include Peutz-Jeghers syndrome, hereditary pancreatitis, familial atypical multiple mole melanoma, familial adenomatous polyposis, Lynch syndrome and hereditary breast and ovarian cancer syndrome. Next-generation sequencing of FPC patients has uncovered new susceptibility genes such as PALB2 and ATM, which participate in homologous recombination repair, and further investigations are in progress. Previous studies have demonstrated that some sporadic cases that do not fulfil FPC criteria also harbor similar mutations, and so genomic testing based on family history might overlook some susceptibility gene carriers. There are no established screening procedures for high-risk unaffected cases, and it is not clear whether surveillance programs would have clinical benefits. In terms of treatment, poly (ADP-ribose) polymerase inhibitors for BRCA-mutated cases or immune checkpoint inhibitors for mismatch repair deficient cases are promising, and clinical trials of these agents are underway. Full article
(This article belongs to the Special Issue Cell and Molecular Biology of Pancreatic Disorders 2019)
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