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 Therapeutics".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 45610

Special Issue 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
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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

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Keywords

  • pancreatic cancer
  • tumor microenvironment
  • biomarker
  • immune environment in pancreatic cancer

Published Papers (20 papers)

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12 pages, 754 KiB  
Article
Comparison of Short-Term Surgical Outcomes According to Immediately Postoperative Serum Glucose Level in Non-Diabetic Pancreatic Resection Patients
Biomedicines 2022, 10(10), 2427; https://doi.org/10.3390/biomedicines10102427 - 28 Sep 2022
Viewed by 1129
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)
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9 pages, 1984 KiB  
Article
Prognostic Significance of Initial Absolute Lymphocyte Count in Adjuvant Radiotherapy for Pancreatic Adenocarcinoma
Biomedicines 2022, 10(9), 2190; https://doi.org/10.3390/biomedicines10092190 - 05 Sep 2022
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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)
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17 pages, 3102 KiB  
Article
Increased Stiffness Downregulates Focal Adhesion Kinase Expression in Pancreatic Cancer Cells Cultured in 3D Self-Assembling Peptide Scaffolds
Biomedicines 2022, 10(8), 1835; https://doi.org/10.3390/biomedicines10081835 - 29 Jul 2022
Cited by 3 | Viewed by 1676
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)
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19 pages, 2131 KiB  
Article
SOX9 Protein in Pancreatic Cancer Regulates Multiple Cellular Networks in a Cell-Specific Manner
Biomedicines 2022, 10(7), 1466; https://doi.org/10.3390/biomedicines10071466 - 21 Jun 2022
Viewed by 2180
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)
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12 pages, 1196 KiB  
Article
Development of Nomograms for Predicting Prognosis of Pancreatic Cancer after Pancreatectomy: A Multicenter Study
Biomedicines 2022, 10(6), 1341; https://doi.org/10.3390/biomedicines10061341 - 07 Jun 2022
Cited by 6 | Viewed by 1480
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)
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11 pages, 1946 KiB  
Article
Prognostic Implications of Portal Venous Circulating Tumor Cells in Resectable Pancreatic Cancer
Biomedicines 2022, 10(6), 1289; https://doi.org/10.3390/biomedicines10061289 - 31 May 2022
Cited by 6 | Viewed by 1416
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)
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22 pages, 6648 KiB  
Article
Preclinical Studies of Granulysin-Based Anti-MUC1-Tn Immunotoxins as a New Antitumoral Treatment
Biomedicines 2022, 10(6), 1223; https://doi.org/10.3390/biomedicines10061223 - 24 May 2022
Cited by 2 | Viewed by 2057
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)
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