Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
3.7
4.7
Journals
Biomedicines
Special Issues
Pancreatic Cancer: From Mechanisms to Therapeutic Approaches
share announcement

Pancreatic Cancer: From Mechanisms to Therapeutic Approaches

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 49194

Special Issue Editor

Prof. Dr. Satoshi Wada

E-Mail Website
Guest Editor
Department of Clinical Diagnostic Oncology, Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, 6-11-11 Kita-Karasuyama, Setagaya-Ku, Tokyo 157-8577, Japan
Interests: cancer immunotherapy; biomarker; CAR-T; Immune checkpoint inhibitor; pancreatic cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Recent advances in cancer treatment research and development, especially the development of immune checkpoint inhibitors, have dramatically increased the life expectancy of patients diagnosed with cancer over the past decade. In addition, advances in comprehensive genetic analysis have made it possible to analyze abnormalities in driver genes that are important for the growth of cancer, and the development of specific therapeutic agents for such abnormalities has also progressed. Even under such circumstances, pancreatic cancer has not benefited from new therapeutic agents with little improvement in prognosis. Why does pancreatic cancer have a worse prognosis than other cancer types? Why are new therapeutic agents developed that do not work for pancreatic cancer? In order to solve these questions, this Special Issue explores the mechanisms that are unique to pancreatic cancer and aims to lead the development of novel therapeutic agents that can overcome these problems.

Dr. Satoshi Wada
Guest Editor

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 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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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 cancer
  • tumor microenvironment
  • biomarker
  • immune environment in pancreatic cancer

Published Papers (20 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

12 pages, 754 KiB  
Article
Comparison of Short-Term Surgical Outcomes According to Immediately Postoperative Serum Glucose Level in Non-Diabetic Pancreatic Resection Patients
by Okjoo Lee, Chang-Sup Lim, So Jeong Yoon, Ji Hye Jung, Sang Hyun Shin, Jin Seok Heo, Yong Chan Shin, Woohyun Jung and In Woong Han
Biomedicines 2022, 10(10), 2427; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10102427 - 28 Sep 2022
Viewed by 1217
Abstract
The adequate regulation of postoperative serum glucose level (SGL) is widely accepted; however, the effects for non-diabetic patients who underwent major pancreatic surgery have not yet been established. We discerned the relevance of the immediately postoperative SGL to short-term postoperative outcomes from major [...] Read more.
The adequate regulation of postoperative serum glucose level (SGL) is widely accepted; however, the effects for non-diabetic patients who underwent major pancreatic surgery have not yet been established. We discerned the relevance of the immediately postoperative SGL to short-term postoperative outcomes from major pancreatic surgery in non-diabetic patients. Between January 2007 and December 2016, 2259 non-diabetic patients underwent major pancreatic surgery at four tertiary medical centers in Republic of Korea. Based on a SGL of 200 mg/dL, patients were classified into two groups by averaging the results of four SGL tests taken on the first day after surgery, and their short-term postoperative outcomes were analyzed. A 1:1 propensity score matching method was conducted to establish the high SGL group (n = 568) and the normal SGL group (n = 568). The high SGL group experienced a significantly higher rate of level C complications in the Clavien-Dindo classification (CDc) than the normal SGL group (24.1% vs. 16.5%, p = 0.002). Additionally, an SGL of more than 200 mg/dL was associated with a significantly high risk of complications above level C CDc after adjusting for other risk factors (hazard ratio = 1.324, 95% confidence interval = 1.048–1.672, p = 0.019). The regulation of SGL of less than 200 mg/dL in non-diabetic patients early after major pancreatic surgery could be helpful for reducing postoperative complications. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

9 pages, 1984 KiB  
Article
Prognostic Significance of Initial Absolute Lymphocyte Count in Adjuvant Radiotherapy for Pancreatic Adenocarcinoma
by Jaesung Heo and O Kyu Noh
Biomedicines 2022, 10(9), 2190; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10092190 - 05 Sep 2022
Viewed by 1356
Abstract
Background: This study aimed to investigate the impact of absolute lymphocyte count (ALC) on clinical outcomes in patients treated with adjuvant RT with or without chemotherapy for pancreatic adenocarcinoma. Methods: From 2001 to 2015, 68 patients underwent curative surgery followed by adjuvant RT. [...] Read more.
Background: This study aimed to investigate the impact of absolute lymphocyte count (ALC) on clinical outcomes in patients treated with adjuvant RT with or without chemotherapy for pancreatic adenocarcinoma. Methods: From 2001 to 2015, 68 patients underwent curative surgery followed by adjuvant RT. Chemotherapy was administered concurrently or sequentially with RT. We analyzed the clinical impact of the initial ALC level on locoregional recurrence-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival (OS). Results: With a median follow-up of 13.7 months (range: 3.1–61.3), the 3 year OS, LRRFS, and DMFS are 25.4%, 40.0%, and 26.6%, respectively. The OS and LRRFS of the high initial ALC group (≥ 1540 × 106/L) are significantly higher than that of the group with lower initial ALC (3 year OS: 32.6% vs. 18.6%, p = 0.036; 3 year LRRFS: 53.5% vs. 27.0%, p = 0.031). In multivariable analyses, initial ALC level is the significant prognostic factor affecting LRRFS (HR = 0.457, p = 0.028) and OS (HR = 0.473, p = 0.026). Conclusions: Initial ALC could have potential prognostic significance in patients with pancreatic adenocarcinoma receiving adjuvant RT with or without chemotherapy. Further studies are warranted to investigate the role of adjuvant RT, considering the initial ALC. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

17 pages, 3102 KiB  
Article
Increased Stiffness Downregulates Focal Adhesion Kinase Expression in Pancreatic Cancer Cells Cultured in 3D Self-Assembling Peptide Scaffolds
by Nausika Betriu, Anna Andreeva, Anna Alonso and Carlos E. Semino
Biomedicines 2022, 10(8), 1835; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10081835 - 29 Jul 2022
Cited by 4 | Viewed by 1950
Abstract
The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that participates in integrin-mediated signal transduction and contributes to different biological processes, such as cell migration, survival, proliferation and angiogenesis. Moreover, FAK can be activated by autophosphorylation at position Y397 and trigger different [...] Read more.
The focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that participates in integrin-mediated signal transduction and contributes to different biological processes, such as cell migration, survival, proliferation and angiogenesis. Moreover, FAK can be activated by autophosphorylation at position Y397 and trigger different signaling pathways in response to increased extracellular matrix stiffness. In addition, FAK is overexpressed and/or hyperactivated in many epithelial cancers, and its expression correlates with tumor malignancy and invasion potential. One of the characteristics of solid tumors is an over deposition of ECM components, which generates a stiff microenvironment that promotes, among other features, sustained cell proliferation and survival. Researchers are, therefore, increasingly developing cell culture models to mimic the increased stiffness associated with these kinds of tumors. In the present work, we have developed a new 3D in vitro model to study the effect of matrix stiffness in pancreatic ductal adenocarcinoma (PDAC) cells as this kind of tumor is characterized by a desmoplastic stroma and an increased stiffness compared to its normal counterpart. For that, we have used a synthetic self-assembling peptide nanofiber matrix, RAD16-I, which does not suffer a significant degradation in vitro, thus allowing to maintain the same local stiffness along culture time. We show that increased matrix stiffness in synthetic 3D RAD16-I gels, but not in collagen type I scaffolds, promotes FAK downregulation at a protein level in all the cell lines analyzed. Moreover, even though it has classically been described that stiff 3D matrices promote an increase in pFAKY397/FAK proteins, we found that this ratio in soft and stiff RAD16-I gels is cell-type-dependent. This study highlights how cell response to increased matrix stiffness greatly depends on the nature of the matrix used for 3D culture. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Graphical abstract

19 pages, 2131 KiB  
Article
SOX9 Protein in Pancreatic Cancer Regulates Multiple Cellular Networks in a Cell-Specific Manner
by Eugene Kopantzev, Liya Kondratyeva, Marina Kopantseva, Kirill Kashkin, Dmitry Gnatenko, Elizaveta Grigorieva, Irina Alekseenko, Dina Safina and Igor Chernov
Biomedicines 2022, 10(7), 1466; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10071466 - 21 Jun 2022
Viewed by 2365
Abstract
SOX9 is upregulated in the majority of pancreatic ductal adenocarcinoma cases. It is hypothesized that the increased expression of SOX9 is necessary for the formation and maintenance of tumor phenotypes in pancreatic cancer cells. In our research, we studied six pancreatic cancer cell [...] Read more.
SOX9 is upregulated in the majority of pancreatic ductal adenocarcinoma cases. It is hypothesized that the increased expression of SOX9 is necessary for the formation and maintenance of tumor phenotypes in pancreatic cancer cells. In our research, we studied six pancreatic cancer cell lines, which displayed varying levels of differentiation and a range of oncogenic mutations. We chose the method of downregulation of SOX9 expression via siRNA transfection as the main method for investigating the functional role of the SOX9 factor in pancreatic cancer cells. We discovered that the downregulation of SOX9 expression in the cell lines leads to cell-line-specific changes in the expression levels of epithelial and mesenchymal protein markers. Additionally, the downregulation of SOX9 expression had a specific effect on the expression of pancreatic developmental master genes. SOX9 downregulation had the greatest effect on the expression levels of the protein regulators of cell proliferation. In three of the four cell lines studied, the transfection of siSOX9 led to a significant decrease in proliferative activity and to the activation of proapoptotic caspases in transfected cells. The acquired results demonstrate that the SOX9 protein exerts its multiple functions as a pleiotropic regulator of differentiation and a potential promoter of tumor growth in a cell-specific manner in pancreatic cancer cells. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

12 pages, 1196 KiB  
Article
Development of Nomograms for Predicting Prognosis of Pancreatic Cancer after Pancreatectomy: A Multicenter Study
by So Jeong Yoon, Boram Park, Jaewoo Kwon, Chang-Sup Lim, Yong Chan Shin, Woohyun Jung, Sang Hyun Shin, Jin Seok Heo and In Woong Han
Biomedicines 2022, 10(6), 1341; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061341 - 07 Jun 2022
Cited by 6 | Viewed by 1613
Abstract
Surgical resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Currently, the TNM classification system is considered the standard for predicting prognosis after surgery. However, the prognostic accuracy of the system remains limited. This study aimed to develop new predictive nomograms [...] Read more.
Surgical resection is the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). Currently, the TNM classification system is considered the standard for predicting prognosis after surgery. However, the prognostic accuracy of the system remains limited. This study aimed to develop new predictive nomograms for resected PDAC. The clinicopathological data of patients who underwent surgery for PDAC between 2006 and 2015 at five major institutions were retrospectively reviewed; 885 patients were included in the analysis. Cox regression analysis was performed to investigate prognostic factors for recurrence and survival, and statistically significant factors were used for creating nomograms. The nomogram for predicting recurrence-free survival included nine factors: sarcopenic obesity, elevated carbohydrate antigen 19–9, platelet-to-lymphocyte ratio, preoperatively-identified arterial abutment, estimated blood loss (EBL), tumor differentiation, size, lymph node ratio, and tumor necrosis. The nomogram for predicting overall survival included 10 variables: age, underlying liver disease, chronic kidney disease, preoperatively found portal vein invasion, portal vein resection, EBL, tumor differentiation, size, lymph node metastasis, and tumor necrosis. The time-dependent area under the receiver operating characteristic curve for both nomograms exceeded 0.70. Nomograms were developed for predicting survival after resection of PDAC, and the platforms showed fair predictive performance. These new comprehensive nomograms provide information on disease status and are useful for determining further treatment for PDAC patients. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

11 pages, 1946 KiB  
Article
Prognostic Implications of Portal Venous Circulating Tumor Cells in Resectable Pancreatic Cancer
by Young Hoon Choi, Tae Ho Hong, Seung Bae Yoon, In Seok Lee, Myung Ah Lee, Ho Joong Choi, Moon Hyung Choi and Eun Sun Jung
Biomedicines 2022, 10(6), 1289; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061289 - 31 May 2022
Cited by 7 | Viewed by 1530
Abstract
Circulating tumor cells (CTCs) are a promising prognostic biomarker for cancers. However, the paucity of CTCs in peripheral blood in early-stage cancer is a major challenge. Our study aimed to investigate whether portal venous CTCs can be a biomarker for early recurrence and [...] Read more.
Circulating tumor cells (CTCs) are a promising prognostic biomarker for cancers. However, the paucity of CTCs in peripheral blood in early-stage cancer is a major challenge. Our study aimed to investigate whether portal venous CTCs can be a biomarker for early recurrence and poor prognosis in pancreatic cancer. Patients who underwent upfront curative surgery for resectable pancreatic cancer were consecutively enrolled in this prospective study. Intraoperatively, 7.5 mL of portal and peripheral blood was collected, and CTC detection and identification were performed using immunofluorescence staining. Peripheral blood CTC sampling was performed in 33 patients, of which portal vein CTC sampling was performed in 28. The median portal venous CTCs (2.5, interquartile ranges (IQR) 1–7.75) were significantly higher than the median peripheral venous CTCs (1, IQR 0–2, p < 0.001). Higher stage and regional lymph node metastasis were related with a larger number of CTCs (≥3) in portal venous blood. Patients with low portal venous CTCs (≤2) showed better overall (p = 0.002) and recurrence-free (p = 0.007) survival than those with high portal venous CTCs (≥3). If validated, portal CTCs can be used as a prognostic biomarker in patients with resectable pancreatic cancer. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

22 pages, 6648 KiB  
Article
Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
by Patricia Guerrero-Ochoa, Raquel Ibáñez-Pérez, Germán Berbegal-Pinilla, Diederich Aguilar, Isabel Marzo, Francisco Corzana, Martha Minjárez-Sáenz, Javier Macías-León, Blanca Conde, Javier Raso, Ramón Hurtado-Guerrero and Alberto Anel
Biomedicines 2022, 10(6), 1223; https://doi.org/10.3390/biomedicines10061223 - 24 May 2022
Cited by 2 | Viewed by 2200
Abstract
Two granulysin (GRNLY) based immunotoxins were generated, one containing the scFv of the SM3 mAb (SM3GRNLY) and the other the scFv of the AR20.5 mAb (AR20.5GRNLY). These mAb recognize different amino acid sequences of aberrantly O-glycosylated MUC1, also known as the Tn antigen, [...] Read more.
Two granulysin (GRNLY) based immunotoxins were generated, one containing the scFv of the SM3 mAb (SM3GRNLY) and the other the scFv of the AR20.5 mAb (AR20.5GRNLY). These mAb recognize different amino acid sequences of aberrantly O-glycosylated MUC1, also known as the Tn antigen, expressed in a variety of tumor cell types. We first demonstrated the affinity of these immunotoxins for their antigen using surface plasmon resonance for the purified antigen and flow cytometry for the antigen expressed on the surface of living tumor cells. The induction of cell death of tumor cell lines of different origin positive for Tn antigen expression was stronger in the cases of the immunotoxins than that induced by GRNLY alone. The mechanism of cell death induced by the immunotoxins was studied, showing that the apoptotic component demonstrated previously for GRNLY was also present, but that cell death induced by the immunotoxins included also necroptotic and necrotic components. Finally, we demonstrated the in vivo tumor targeting by the immunotoxins after systemic injection using a xenograft model of the human pancreatic adenocarcinoma CAPAN-2 in athymic mice. While GRNLY alone did not have a therapeutic effect, SM3GRNLY and AR20.5GRNLY reduced tumor volume by 42 and 60%, respectively, compared with untreated tumor-bearing mice, although the results were not statistically significant in the case of AR20.5GRNLY. Histological studies of tumors obtained from treated mice demonstrated reduced cellularity, nuclear morphology compatible with apoptosis induction and active caspase-3 detection by immunohistochemistry. Overall, our results exemplify that these immunotoxins are potential drugs to treat Tn-expressing cancers. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

12 pages, 2868 KiB  
Article
Alloferon Affects the Chemosensitivity of Pancreatic Cancer by Regulating the Expression of SLC6A14
by Hyejung Jo, Dahae Lee, Cheolhyeon Go, Yoojin Jang, Suhyun Bae, Tomoyo Agura, Jiye Hong, Dongmin Kang, Yejin Kim and Jae Seung Kang
Biomedicines 2022, 10(5), 1113; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10051113 - 11 May 2022
Cited by 3 | Viewed by 2160
Abstract
Pancreatic cancer (PCa), one of the most malignant solid tumors, has a high mortality rate. Although there have been many trials of chemotherapeutic drugs such as gemcitabine, the mortality rates remain significantly higher than for other types of cancer. Therefore, more effective ways [...] Read more.
Pancreatic cancer (PCa), one of the most malignant solid tumors, has a high mortality rate. Although there have been many trials of chemotherapeutic drugs such as gemcitabine, the mortality rates remain significantly higher than for other types of cancer. Therefore, more effective ways of improving conventional therapy for PCa are needed. Cancer cells take up large amounts of glutamine to drive their rapid proliferation. Recent studies show that the amino acid transporter SLC6A14 is upregulated in some cancers alongside glutamine metabolism. Alloferon, a peptide isolated from the insect immune system, exerts anti-viral and anti-inflammatory effects via its immunomodulatory function. In addition, it has anti-tumoral effects, although the underlying mechanisms are largely unknown. Therefore, we investigated the effects of alloferon on the PCa cell lines Panc-1 and AsPC-1. Exposure of these cells to alloferon for 3 weeks led to the downregulation of SLC6A14 expression and decreased glutamine uptake. Given that SLC6A14 plays a role in tumor progression and survival by promoting glutamine uptake into cancer cells, alloferon could be a potential adjuvant for the chemotherapeutic drug gemcitabine. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

25 pages, 4886 KiB  
Article
Triazole Modified Tetraiodothyroacetic Acid Conjugated to Polyethylene Glycol, a Thyrointegrin αvβ3 Antagonist as a Radio- and Chemo-Sensitizer in Pancreatic Cancer
by Thangirala Sudha, Kavitha Godugu, Gennadi V. Glinsky and Shaker A. Mousa
Biomedicines 2022, 10(4), 795; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040795 - 29 Mar 2022
Cited by 3 | Viewed by 1811
Abstract
Thyroid hormone L thyroxine stimulates pancreatic carcinoma cell proliferation via thyrointegrin αvβ3 receptors, and antagonist tetraiodothyroacetic acid (tetrac) inhibits cancer cell growth. Chemically modified bis-triazole-tetrac conjugated with polyethylene glycol (P-bi-TAT) has higher binding affinity to αvβ3 receptors compared to tetrac. We investigated the [...] Read more.
Thyroid hormone L thyroxine stimulates pancreatic carcinoma cell proliferation via thyrointegrin αvβ3 receptors, and antagonist tetraiodothyroacetic acid (tetrac) inhibits cancer cell growth. Chemically modified bis-triazole-tetrac conjugated with polyethylene glycol (P-bi-TAT) has higher binding affinity to αvβ3 receptors compared to tetrac. We investigated the antiproliferation effect of P-bi-TAT in pancreatic cancer cells (SUIT2) and its radio- and chemo-sensitizing roles in a mouse model of pancreatic cancer. P-bi-TAT treatment increased tumor-targeted radiation-induced cell death and decreased tumor size. P-bi-TAT acted as a chemo-sensitizer and enhanced the 5-fluorouracil (5FU) effect in decreasing pancreatic tumor weight compared to 5FU monotherapy. Withdrawal of treatment continued the tumor regression; however, the 5FU group showed tumor regrowth. The mechanisms of the anti-cancer activity of P-bi-TAT on SUIT2 cells were assessed by microarray experiments, and genome-wide profiling identified significant alterations of 1348 genes’ expression. Both down-regulated and up-regulated transcripts suggest that a molecular interference at the signaling pathway-associated gene expression is the prevalent mode of P-bi-TAT anti-cancer activity. Our data indicate that non-cytotoxic P-bi-TAT is not only an anti-cancer agent but also a radio-sensitizer and chemo-sensitizer that acts on the extracellular domain of the cell surface αvβ3 receptor. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

16 pages, 14846 KiB  
Article
The Class I HDAC Inhibitor Valproic Acid Strongly Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Immune System Activation
by Amber Blaauboer, Peter M. van Koetsveld, Dana A. M. Mustafa, Jasper Dumas, Fadime Dogan, Suzanne van Zwienen, Casper H. J. van Eijck and Leo J. Hofland
Biomedicines 2022, 10(3), 517; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10030517 - 22 Feb 2022
Cited by 8 | Viewed by 2270
Abstract
Background: Gemcitabine efficacy in pancreatic cancer is often impaired due to limited intracellular uptake and metabolic activation. Epi-drugs target gene expression patterns and represent a promising approach to reverse chemoresistance. In this study, we investigate the chemosensitizing effect of different epi-drugs when combined [...] Read more.
Background: Gemcitabine efficacy in pancreatic cancer is often impaired due to limited intracellular uptake and metabolic activation. Epi-drugs target gene expression patterns and represent a promising approach to reverse chemoresistance. In this study, we investigate the chemosensitizing effect of different epi-drugs when combined with gemcitabine in pancreatic cancer. Methods: Mouse KPC3 cells were used for all experiments. Five different epi-drugs were selected for combination therapy: 5-aza-2′-deoxycytidine, hydralazine, mocetinostat, panobinostat, and valproic acid (VPA). Treatment effects were determined by cell proliferation and colony forming assays. Expression of genes were assessed by real-time quantitative PCR. The most promising epi-drug for combination therapy was studied in immune competent mice. Intratumor changes were defined using NanoString PanCancer panel IO360. Results: All epi-drugs, except hydralazine, potentiated the gemcitabine response in KPC3 cells (range decrease IC50 value 1.7–2-fold; p < 0.001). On colony formation, the cytotoxic effect of 0.5 ng/mL gemcitabine was 1.4 to 6.3 times stronger (p < 0.01). Two out of three drug-transporter genes were strongly upregulated following epi-drug treatment (a range fold increase of 17–124 and 9–60 for Slc28a1 and Slc28a3, respectively; all p < 0.001). VPA combined with gemcitabine significantly reduced tumor size with 74% compared to vehicle-treated mice and upregulated expression of immune-related pathways (range pathway score 0.86–1.3). Conclusions: These results provide a strong rationale for combining gemcitabine with VPA treatment. For the first time, we present intratumor changes and show activation of the immune system. Clinical trials are warranted to assess efficacy and safety of this novel combination in pancreatic cancer patients. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

21 pages, 8506 KiB  
Article
PTML Modeling for Pancreatic Cancer Research: In Silico Design of Simultaneous Multi-Protein and Multi-Cell Inhibitors
by Valeria V. Kleandrova and Alejandro Speck-Planche
Biomedicines 2022, 10(2), 491; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020491 - 18 Feb 2022
Cited by 12 | Viewed by 2570
Abstract
Pancreatic cancer (PANC) is a dangerous type of cancer that is a major cause of mortality worldwide and exhibits a remarkably poor prognosis. To date, discovering anti-PANC agents remains a very complex and expensive process. Computational approaches can accelerate the search for anti-PANC [...] Read more.
Pancreatic cancer (PANC) is a dangerous type of cancer that is a major cause of mortality worldwide and exhibits a remarkably poor prognosis. To date, discovering anti-PANC agents remains a very complex and expensive process. Computational approaches can accelerate the search for anti-PANC agents. We report for the first time two models that combined perturbation theory with machine learning via a multilayer perceptron network (PTML-MLP) to perform the virtual design and prediction of molecules that can simultaneously inhibit multiple PANC cell lines and PANC-related proteins, such as caspase-1, tumor necrosis factor-alpha (TNF-alpha), and the insulin-like growth factor 1 receptor (IGF1R). Both PTML-MLP models exhibited accuracies higher than 78%. Using the interpretation from one of the PTML-MLP models as a guideline, we extracted different molecular fragments desirable for the inhibition of the PANC cell lines and the aforementioned PANC-related proteins and then assembled some of those fragments to form three new molecules. The two PTML-MLP models predicted the designed molecules as potentially versatile anti-PANC agents through inhibition of the three PANC-related proteins and multiple PANC cell lines. Conclusions: This work opens new horizons for the application of the PTML modeling methodology to anticancer research. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

23 pages, 2605 KiB  
Article
An In Vitro Investigation into Cryoablation and Adjunctive Cryoablation/Chemotherapy Combination Therapy for the Treatment of Pancreatic Cancer Using the PANC-1 Cell Line
by John M. Baust, Kimberly L. Santucci, Robert G. Van Buskirk, Isaac Raijman, William E. Fisher, John G. Baust and Kristi K. Snyder
Biomedicines 2022, 10(2), 450; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020450 - 15 Feb 2022
Cited by 10 | Viewed by 2673
Abstract
As the incidence of pancreatic ductal adenocarcinoma (PDAC) continues to grow, so does the need for new strategies for treatment. One such area being evaluated is cryoablation. While promising, studies remain limited and questions surrounding basic dosing (minimal lethal temperature) coupled with technological [...] Read more.
As the incidence of pancreatic ductal adenocarcinoma (PDAC) continues to grow, so does the need for new strategies for treatment. One such area being evaluated is cryoablation. While promising, studies remain limited and questions surrounding basic dosing (minimal lethal temperature) coupled with technological issues associated with accessing PDAC tumors and tumor proximity to vasculature and bile ducts, among others, have limited the use of cryoablation. Additionally, as chemotherapy remains the first-line of attack for PDAC, there is limited information on the impact of combining freezing with chemotherapy. As such, this study investigated the in vitro response of a PDAC cell line to freezing, chemotherapy, and the combination of chemotherapy pre-treatment and freezing. PANC-1 cells and PANC-1 tumor models were exposed to cryoablation (freezing insult) and compared to non-frozen controls. Additionally, PANC-1 cells were exposed to varying sub-clinical doses of gemcitabine or oxaliplatin alone and in combination with freezing. The results show that freezing to −10 °C did not affect viability, whereas −15 °C and −20 °C resulted in a reduction in 1 day post-freeze viability to 85% and 20%, respectively, though both recovered to controls by day 7. A complete cell loss was found following a single freeze below −25 °C. The combination of 100 nM gemcitabine (1.1 mg/m2) pre-treatment and a single freeze at −15 °C resulted in near-complete cell death (<5% survival) over the 7-day assessment interval. The combination of 8.8 µM oxaliplatin (130 mg/m2) pre-treatment and a single −15 °C freeze resulted in a similar trend of increased PANC-1 cell death. In summary, these in vitro results suggest that freezing alone to temperatures in the range of −25 °C results in a high degree of PDAC destruction. Further, the data support a potential combinatorial chemo/cryo-therapeutic strategy for the treatment of PDAC. These results suggest that a reduction in chemotherapeutic dose may be possible when offered in combination with freezing for the treatment of PDAC. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

12 pages, 1148 KiB  
Article
Macrophage C/EBPδ Drives Gemcitabine, but Not 5-FU or Paclitaxel, Resistance of Pancreatic Cancer Cells in a Deoxycytidine-Dependent Manner
by C. Arnold Spek, Hella L. Aberson and JanWillem Duitman
Biomedicines 2022, 10(2), 219; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10020219 - 20 Jan 2022
Cited by 4 | Viewed by 2235
Abstract
Treatment of pancreatic ductal adenocarcinoma (PDAC), a dismal disease with poor survival rates, is hampered by the high prevalence of chemotherapy resistance. Resistance is accompanied by macrophage infiltration into the tumor microenvironment, and infiltrated macrophages are key players in chemotherapy resistance. In the [...] Read more.
Treatment of pancreatic ductal adenocarcinoma (PDAC), a dismal disease with poor survival rates, is hampered by the high prevalence of chemotherapy resistance. Resistance is accompanied by macrophage infiltration into the tumor microenvironment, and infiltrated macrophages are key players in chemotherapy resistance. In the current manuscript, we identify CCAAT/enhancer-binding protein delta (C/EBPδ) as an important transcription factor driving macrophage-dependent gemcitabine resistance. We show that conditioned medium obtained from wild type macrophages largely diminishes gemcitabine-induced cytotoxicity of PDAC cells, whereas conditioned medium obtained from C/EBPδ-deficient macrophages only minimally affects gemcitabine-induced PDAC cell death. Subsequent analysis of RNA-Seq data identified the pyrimidine metabolism pathway amongst the most significant pathways down-regulated in C/EBPδ-deficient macrophages and size filtration experiments indeed showed that the low molecular weight and free metabolite fraction most effectively induced gemcitabine resistance. In line with a role for pyrimidines, we next show that supplementing macrophage conditioned medium with deoxycytidine overruled the effect of macrophage conditioned media on gemcitabine resistance. Consistently, macrophage C/EBPδ-dependent resistance is specific for gemcitabine and does not affect paclitaxel or 5-FU-induced cytotoxicity. Overall, we thus show that C/EBPδ-dependent deoxycytidine biosynthesis in macrophages induces gemcitabine resistance of pancreatic cancer cells. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

18 pages, 4873 KiB  
Article
Azadirachtin Attenuates Lipopolysaccharide-Induced ROS Production, DNA Damage, and Apoptosis by Regulating JNK/Akt and AMPK/mTOR-Dependent Pathways in Rin-5F Pancreatic Beta Cells
by Annie John and Haider Raza
Biomedicines 2021, 9(12), 1943; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9121943 - 18 Dec 2021
Cited by 9 | Viewed by 2623
Abstract
Pancreatic inflammation and the resulting cellular responses have been implicated in pancreatitis, diabetes, and pancreatic cancer. Inflammatory responses due to the bacterial endotoxin, lipopolysaccharide (LPS), have been demonstrated to alter cellular metabolism, autophagy, apoptosis, and cell proliferation in different cell populations, and hence [...] Read more.
Pancreatic inflammation and the resulting cellular responses have been implicated in pancreatitis, diabetes, and pancreatic cancer. Inflammatory responses due to the bacterial endotoxin, lipopolysaccharide (LPS), have been demonstrated to alter cellular metabolism, autophagy, apoptosis, and cell proliferation in different cell populations, and hence increases the risks for organ toxicity including cancer. The exact molecular mechanism is however not clear. In the present study, we investigated the role and mechanism of an antioxidant, azadirachtin (AZD), a limonoid extracted from the neem tree (Azadirachta indica), against LPS-induced oxidative stress in the pancreatic β-cell line, Rin-5F. We demonstrated that cells treated with LPS (1 µg/mL for 24 h) showed increased reactive oxygen species (ROS) production, DNA damage, cell cycle arrest, and apoptosis. Our results also showed that LPS induced alterations in the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathways, suppressing autophagy and augmenting apoptosis. Treatment with Azadirachtin (25 µM for 24 h), on the other hand, rendered some degree of protection to the pancreatic cells from apoptosis by inducing the autophagy signals required for cell survival. These results may have significance in elucidating the mechanisms of pancreatic β-cell survival and death by balancing the molecular communication between autophagy and apoptosis under inflammatory and pathological conditions. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

16 pages, 3335 KiB  
Article
Validation of Serum Biomarkers That Complement CA19-9 in Detecting Early Pancreatic Cancer Using Electrochemiluminescent-Based Multiplex Immunoassays
by Jin Song, Lori J. Sokoll, Daniel W. Chan and Zhen Zhang
Biomedicines 2021, 9(12), 1897; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9121897 - 14 Dec 2021
Cited by 7 | Viewed by 2716
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy; its early detection is critical for improving prognosis. Electrochemiluminescent-based multiplex immunoassays were developed with high analytical performance. All proteins were analyzed in sera of patients diagnosed with PDAC (n = 138), benign pancreatic conditions [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy; its early detection is critical for improving prognosis. Electrochemiluminescent-based multiplex immunoassays were developed with high analytical performance. All proteins were analyzed in sera of patients diagnosed with PDAC (n = 138), benign pancreatic conditions (111), and healthy controls (70). The clinical performance of these markers was evaluated individually or in combination for their complementarity to CA19-9 in detecting early PDAC. Logistic regression modeling including sex and age as cofactors identified a two-marker panel of CA19-9 and CA-125 that significantly improved the performance of CA19-9 alone in discriminating PDAC (AUC: 0.857 vs. 0.766), as well as early stage PDAC (0.805 vs. 0.702) from intraductal papillary mucinous neoplasm (IPMN). At a fixed specificity of 80%, the panel significantly improved sensitivities (78% vs. 41% or 72% vs. 59%). A two-marker panel of HE4 and CEA significantly outperformed CA19-9 in separating IPMN from chronic pancreatitis (0.841 vs. 0.501). The biomarker panels evaluated by assays demonstrated potential complementarity to CA19-9 in detecting early PDAC, warranting additional clinical validation to determine their role in the early detection of pancreatic cancer. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

14 pages, 2200 KiB  
Article
Comparison of Characteristics and Survival Rates of Resectable Pancreatic Ductal Adenocarcinoma according to Tumor Location
by Min Kyu Sung, Yejong Park, Bong Jun Kwak, Eunsung Jun, Woohyung Lee, Ki Byung Song, Jae Hoon Lee, Dae Wook Hwang and Song Cheol Kim
Biomedicines 2021, 9(11), 1706; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9111706 - 17 Nov 2021
Cited by 5 | Viewed by 1601
Abstract
The impact of tumor location on patient survival in pancreatic ductal adenocarcinoma (PDAC) remains controversial. This study investigated the association between primary tumor location and survival rates for resectable PDAC. Additionally, we assessed if this association remains consistent across categories of the Tumor-Node-Metastasis [...] Read more.
The impact of tumor location on patient survival in pancreatic ductal adenocarcinoma (PDAC) remains controversial. This study investigated the association between primary tumor location and survival rates for resectable PDAC. Additionally, we assessed if this association remains consistent across categories of the Tumor-Node-Metastasis staging system. We analyzed 2471 patients who underwent surgical resection between 2000 and 2018 at a single center. Subgroup analysis was performed according to the Tumor-Node-Metastasis staging system. Among the group, 67.9% (1677 patients) had pancreatic head cancer (PHC) and 32.1% (794 patients) had pancreatic body/tail cancer (PBTC). Patients with PHC had worse overall survival and worse disease-free survival than those with PBTC. Patients with PHC had worse survival in stage IB and stage IIB than those with PBTC. No significant difference was observed for stages IA, IIA, and III. Multivariate analysis showed that elevated CA 19-9, mGPS, a longer hospital stay, complication, accompanying vein resection, larger tumor size, worse differentiation, higher TNM stage (stage IIB, III, IV), presence of LVI, and positive resection margin were risk factors for poor survival after resection. In resectable PDAC, patients with PHC had worse overall and disease-free survival than those with PBTC. However, tumor location was not an independent prognostic factor for PDAC. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

14 pages, 1004 KiB  
Article
Clinical Outcome of RAMPS for Left-Sided Pancreatic Ductal Adenocarcinoma: A Comparison of Anterior RAMPS versus Posterior RAMPS for Patients without Periadrenal Infiltration
by Jaewoo Kwon, Yejong Park, Eunsung Jun, Woohyung Lee, Ki Byung Song, Jae Hoon Lee, Dae Wook Hwang and Song Cheol Kim
Biomedicines 2021, 9(10), 1291; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9101291 - 22 Sep 2021
Cited by 7 | Viewed by 2228
Abstract
Radical antegrade modular pancreatosplenectomy (RAMPS) is considered an effective procedure for left-sided pancreatic ductal adenocarcinoma (PDAC). However, whether there are differences in perioperative outcomes, pathologies, or survival outcomes between anterior RAMPS (aRAMPS) and posterior RAMPS (pRAMPS) has not been reported previously. We retrospectively [...] Read more.
Radical antegrade modular pancreatosplenectomy (RAMPS) is considered an effective procedure for left-sided pancreatic ductal adenocarcinoma (PDAC). However, whether there are differences in perioperative outcomes, pathologies, or survival outcomes between anterior RAMPS (aRAMPS) and posterior RAMPS (pRAMPS) has not been reported previously. We retrospectively reviewed and compared the demographic, perioperative, histopathologic, and survival data of patients who underwent aRAMPS or pRAMPS for PDAC. We also compared these two groups among patients without periadrenal infiltration or adrenal invasion. A total of 112 aRAMPS patients and 224 pRAMPS patients were evaluated. Periadrenal infiltration, neoadjuvant treatment, and concurrent vessel resection were more prevalent in the pRAMPS group. After excluding patients with periadrenal infiltration, 106 aRAMPS patients were compared with 157 pRAMPS patients. There were no significant differences between the aRAMPS and pRAMPS groups in the pathologic tumor size, resection margin, proportion of tangential margin in the R1 resection, and number of harvested lymph nodes. The median overall survival and disease-free survival also did not differ significantly between the two groups. We cautiously suggest that pRAMPS will not necessarily provide more beneficial histopathologic outcomes and survival rates for left-sided PDAC cases without periadrenal infiltration. If periadrenal infiltration is not suspected, aRAMPS alone should be sufficiently effective. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

Review

Jump to: Research

16 pages, 966 KiB  
Review
Obesity and Pancreatic Cancer: Recent Progress in Epidemiology, Mechanisms and Bariatric Surgery
by Shuhei Shinoda, Naohiko Nakamura, Brett Roach, David A. Bernlohr, Sayeed Ikramuddin and Masato Yamamoto
Biomedicines 2022, 10(6), 1284; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10061284 - 31 May 2022
Cited by 7 | Viewed by 2573
Abstract
More than 30% of people in the United States (US) are classified as obese, and over 50% are considered significantly overweight. Importantly, obesity is a risk factor not only for the development of metabolic syndrome but also for many cancers, including pancreatic ductal [...] Read more.
More than 30% of people in the United States (US) are classified as obese, and over 50% are considered significantly overweight. Importantly, obesity is a risk factor not only for the development of metabolic syndrome but also for many cancers, including pancreatic ductal adenocarcinoma (PDAC). PDAC is the third leading cause of cancer-related death, and 5-year survival of PDAC remains around 9% in the U.S. Obesity is a known risk factor for PDAC. Metabolic control and bariatric surgery, which is an effective treatment for severe obesity and allows massive weight loss, have been shown to reduce the risk of PDAC. It is therefore clear that elucidating the connection between obesity and PDAC is important for the identification of a novel marker and/or intervention point for obesity-related PDAC risk. In this review, we discussed recent progress in obesity-related PDAC in epidemiology, mechanisms, and potential cancer prevention effects of interventions, including bariatric surgery with preclinical and clinical studies. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

19 pages, 1247 KiB  
Review
The Trinity: Interplay among Cancer Cells, Fibroblasts, and Immune Cells in Pancreatic Cancer and Implication of CD8+ T Cell-Orientated Therapy
by Yu-Hsuan Hung, Li-Tzong Chen and Wen-Chun Hung
Biomedicines 2022, 10(4), 926; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10040926 - 18 Apr 2022
Cited by 1 | Viewed by 2413
Abstract
The microenvironment in tumors is complicated and is constituted by different cell types and stromal proteins. Among the cell types, the abundance of cancer cells, fibroblasts, and immune cells is high and these cells work as the “Trinity” in promoting tumorigenesis. Although unidirectional [...] Read more.
The microenvironment in tumors is complicated and is constituted by different cell types and stromal proteins. Among the cell types, the abundance of cancer cells, fibroblasts, and immune cells is high and these cells work as the “Trinity” in promoting tumorigenesis. Although unidirectional or bidirectional crosstalk between two independent cell types has been well characterized, the multi-directional interplays between cancer cells, fibroblasts, and immune cells in vitro and in vivo are still unclear. We summarize recent studies in addressing the interaction of the “Trinity” members in the tumor microenvironment and propose a functional network for how these members communicate with each other. In addition, we discuss the underlying mechanisms mediating the interplay. Moreover, correlations of the alterations in the distribution and functionality of cancer cells, fibroblasts, and immune cells under different circumstances are reviewed. Finally, we point out the future application of CD8+ T cell-oriented therapy in the treatment of pancreatic cancer. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Graphical abstract

17 pages, 4360 KiB  
Review
Fatty Pancreas-Centered Metabolic Basis of Pancreatic Adenocarcinoma: From Obesity, Diabetes and Pancreatitis to Oncogenesis
by Ming-Ling Chang
Biomedicines 2022, 10(3), 692; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10030692 - 17 Mar 2022
Cited by 14 | Viewed by 6887
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer, and it is currently the third most common cause of cancer death in the U.S.A. Progress in the fight against PDAC has been hampered by an inability to detect it early [...] Read more.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer, and it is currently the third most common cause of cancer death in the U.S.A. Progress in the fight against PDAC has been hampered by an inability to detect it early in the overwhelming majority of patients, and also by the reduced oxygen levels and nutrient perfusion caused by new matrix formation through the activation of stromal cells in the context of desmoplasia. One harbinger of PDAC is excess intrapancreatic fat deposition, namely, fatty pancreas, which specifically affects the tumor macro- and microenvironment in the organ. Over half of PDAC patients have diabetes mellitus (DM) at the time of diagnosis, and fatty pancreas is associated with subsequent DM development. Moreover, there is a strong association between fatty pancreas and fatty liver through obesity, and a higher intrapancreatic fat percentage has been noted in acute pancreatitis patients with DM than in those without DM. All these findings suggest that the link between fatty pancreas and PDAC might occur through metabolic alterations, either DM-related or non-DM-related. Based on clinical, in vivo and in vitro evidence, the current review highlights the etiologies of fatty pancreas (including fatty infiltration and replacement) and the fatty pancreas-associated metabolic alterations involved in oncogenesis to provide crucial targets to prevent, detect, and/or effectively treat PDAC. Full article
(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-20
Back to TopTop