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Pancreatic Cancer: From Mechanisms to Therapeutic Approaches 2.0

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 9806

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Special Issue Editor

Prof. Dr. Satoshi Wada

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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
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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 (6 papers)

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Research

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21 pages, 3410 KiB

Open AccessArticle

Hyperthermia Influences the Secretion Signature of Tumor Cells and Affects Endothelial Cell Sprouting

by Wisdom O. Maduabuchi, Felista L. Tansi, Regine Heller and Ingrid Hilger

Biomedicines 2023, 11(8), 2256; https://doi.org/10.3390/biomedicines11082256 - 12 Aug 2023

Cited by 1 | Viewed by 1001

Abstract

Tumors are a highly heterogeneous mass of tissue showing distinct therapy responses. In particular, the therapeutic outcome of tumor hyperthermia treatments has been inconsistent, presumably due to tumor versus endothelial cell cross-talks related to the treatment temperature and the tumor tissue environment. Here, we investigated the impact of the average or strong hyperthermic treatment (43 °C or 47 °C for 1 h) of the human pancreatic adenocarcinoma cell line (PANC-1 and BxPC-3) on endothelial cells (HUVECs) under post-treatment normoxic or hypoxic conditions. Immediately after the hyperthermia treatment, the distinct repression of secreted pro-angiogenic factors (e.g., VEGF, PDGF-AA, PDGF-BB, M-CSF), intracellular HIF-1α and the enhanced phosphorylation of ERK1/2 in tumor cells were detectable (particularly for strong hyperthermia, 2D cell monolayers). Notably, there was a significant increase in endothelial sprouting when 3D self-organized pancreatic cancer cells were treated with strong hyperthermia and the post-treatment conditions were hypoxic. Interestingly, for the used treatment temperatures, the intracellular HIF-1α accumulation in tumor cells seems to play a role in MAPK/ERK activation and mediator secretion (e.g., VEGF, PDGF-AA, Angiopoietin-2), as shown by inhibition experiments. Taken together, the hyperthermia of pancreatic adenocarcinoma cells in vitro impacts endothelial cells under defined environmental conditions (cell-to-cell contact, oxygen status, treatment temperature), whereby HIF-1α and VEGF secretion play a role in a complex context. Our observations could be exploited for the hyperthermic treatment of pancreatic cancer in the future. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches 2.0)

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20 pages, 5415 KiB

Open AccessArticle

Multifaceted Effects of Kinase Inhibitors on Pancreatic Cancer Cells Reveals Pivotal Entities with Therapeutic Implications

by Yoo Na Kim, Ketki Patil, Jeonghwa Ma, Griffin A. Dufek and S. Balakrishna Pai

Biomedicines 2023, 11(6), 1716; https://doi.org/10.3390/biomedicines11061716 - 15 Jun 2023

Cited by 1 | Viewed by 1707

Abstract

Pancreatic cancer is one of the most aggressive forms of cancer and is the seventh leading cause of cancer deaths worldwide. Pancreatic ductal adenocarcinoma (PDAC) accounts for over 90% of pancreatic cancers. Most pancreatic cancers are recalcitrant to radiation, chemotherapy, and immunotherapy, highlighting the urgent need for novel treatment options for this deadly disease. To this end, we screened a library of kinase inhibitors in the PDAC cell lines PANC-1 and BxPC-3 and identified two highly potent molecules: Aurora kinase inhibitor AT 9283 (AT) and EGFR kinase inhibitor WZ 3146 (WZ). Both AT and WZ exhibited a dose-dependent inhibition of viability in both cell lines. Thus, we conducted an in-depth multilevel (cellular, molecular, and proteomic) analysis with AT and WZ in PANC-1 cells, which harbor KRAS mutation and exhibit quasimesenchymal properties representing pancreatic cancer cells as having intrinsic chemoresistance and the potential for differential response to therapy. Elucidation of the molecular mechanism of action of AT and WZ revealed an impact on the programmed cell death pathway with an increase in apoptotic, multicaspase, and caspase 3/7 positive cells. Additionally, the key survival molecule Bcl-2 was impacted. Moreover, cell cycle arrest was observed with both kinase inhibitors. Additionally, an increase in superoxide radicals was observed in the AT-treated group. Importantly, proteomic profiling revealed differentially regulated key entities with multifaceted effects, which could have a deleterious impact on PDAC. These findings suggest potential targets for efficacious treatment, including a possible increase in the efficacy of immunotherapy using PD-L1 antibody due to the upregulation of lactoferrin and radixin. Furthermore, combination therapy outcomes with gemcitabine/platinum drugs may also be more effective due to an increase in the NADH dehydrogenase complex. Notably, protein–protein interaction analysis (STRING) revealed possible enrichment of reactome pathway entities. Additionally, novel therapy options, such as vimentin-antibody--drug conjugates, could be explored. Therefore, future studies with the two kinases as monotherapy/combination therapy are warranted. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches 2.0)

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19 pages, 5724 KiB

Open AccessArticle

CCR4 Blockade Diminishes Intratumoral Macrophage Recruitment and Augments Survival of Syngeneic Pancreatic Cancer-Bearing Mice

by Aydar Khabipov, Dung Nguyen Trung, Julia van der Linde, Lea Miebach, Maik Lenz, Felix Erne, Wolfram von Bernstorff, Tobias Schulze, Stephan Kersting, Sander Bekeschus and Lars Ivo Partecke

Biomedicines 2023, 11(6), 1517; https://doi.org/10.3390/biomedicines11061517 - 24 May 2023

Cited by 1 | Viewed by 1482

Abstract

Pancreatic cancer is known for its tumor microenvironment (TME), which is rich in stromal and immune cells supporting cancer growth and therapy resistance. In particular, tumor-associated macrophages (TAMs) are known for their angiogenesis- and metastasis-promoting properties, which lead to the failure of conventional therapies for pancreatic cancer. Hence, treatment options targeting TAMs are needed. The C-C chemokine receptor type 4 (CCR4) is critical for immune cell recruitment into the TME, and in this paper we explore the effects of its genetic or immunotherapeutic blockade in pancreatic-cancer-bearing mice. Murine PDA6606 pancreatic cancer cells and murine peritoneal macrophages were used for in vitro migration assays. In vivo, a syngeneic, orthotropic pancreatic cancer model was established. Tumor growth and survival were monitored under prophylactic and therapeutic application of a CCR4 antagonist (AF-399/420/18025) in wildtype (CCR4^wt) and CCR4-knockout (CCR4^−/−) mice. Immune infiltration was monitored in tumor tissue sections and via flow cytometry of lysed tumors. PDA6606 cells induced less migration in CCR4^−/− than in CCR4^wt macrophages in vitro. Pancreatic TAM infiltration was higher, and survival was reduced in CCR4^wt mice compared to CCR4^−/− mice. Antagonizing CCR4 in wildtype mice revealed similar results as in CCR4^−/− mice without antagonization. Prophylactic CCR4 antagonist application in wildtype mice was more efficient than therapeutic antagonization. CCR4 seems to be critically involved in TAM generation and tumor progression in pancreatic cancer. CCR4 blockade may help prolong the relapse-free period after curative surgery in pancreatic cancer and improve prognosis. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches 2.0)

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13 pages, 731 KiB

Open AccessArticle

Impact of Aspirin Intake on Postoperative Survival after Primary Pancreatic Resection of Pancreatic Ductal Adenocarcinoma—A Single-Center Evaluation

by Danilo Hackner, Mirianna Hobbs, Susanne Merkel, Christian Krautz, Georg F. Weber, Robert Grützmann and Maximilian Brunner

Biomedicines 2023, 11(5), 1466; https://doi.org/10.3390/biomedicines11051466 - 17 May 2023

Viewed by 1096

Abstract

(1) Background: The intake of aspirin (ASS) has been demonstrated to have a relevant impact on the pathogenesis, incidence and outcome in different solid gastrointestinal tumors. However, data on the effect of ASS on the short-term outcome and the long-term survival in patients with pancreatic carcinoma are still limited. (2) Methods: A total of 213 patients who underwent primary resection of PDAC at the University Hospital of Erlangen from January 2000 to December 2018 were included in this retrospective single-center study in total. Patients were stratified according to the aspirin intake into three groups: continuous aspirin intake (cASS), perioperatively interrupted aspirin intake (iASS) and no aspirin intake (no ASS) at the timepoint of surgery. The postoperative outcome as well as long-term survival were compared between the groups. (3) Results: There were no differences regarding postoperative morbidity (iASS: 54% vs. cASS: 53% vs. no ASS: 64%, p = 0.448) and in-hospital mortality (iASS: 4% vs. cASS: 10% vs. no ASS: 3%, p = 0.198) between the groups. The overall survival (OS) and disease-free survival (DFS) did not differ in the groups when comparing the ASS-intake status (OS: iASS 17.8 months vs. cASS 19.6 months vs. no ASS 21.6 months, p = 0.489; DFS: iASS 14.0 months vs. cASS 18.3 months vs. no ASS 14.7 months, p = 0.957). Multivariate analysis revealed that age (hazard ratio (HR) 2.2, p < 0.001), lymph node-positive status (HR 2.0, p < 0.001), R status 1 or 2 (HR 2.8, p < 0.001) and differentiation with a grading of 3 (HR 1.7, p = 0.005) were significant independent prognostic factors regarding the OS. Moreover, age (HR 1.5, p = 0.040), lymph node-positive status (HR 1.8, p = 0.002) and high-grade (G3) carcinomas (HR 1.5, p = 0.037) could be identified as independent prognostic parameters for DFS. (4) Conclusions: In patients undergoing primary surgery for curative resection of pancreatic carcinoma, the perioperative intake of ASS had no significant impact on postoperative outcome, overall and disease-free survival. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches 2.0)

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10 pages, 3715 KiB

Open AccessArticle

Endoscopic Ultrasound-Guided Pancreatic Interstitial Laser Ablation Using a Cylindrical Laser Diffuser: A Long-Term Follow-Up Study

by Jungnam Lee, Youjeong Seo, Van Gia Truong, Hye Jung Jeong, Jung-Hyun Lim, Seonghee Lim, Hyun Wook Kang and Jin-Seok Park

Biomedicines 2022, 10(11), 2895; https://doi.org/10.3390/biomedicines10112895 - 11 Nov 2022

Cited by 2 | Viewed by 1482

Abstract

Background and Aims: Local ablative treatment is another option for improving outcomes and has been evaluated for locally advanced pancreatic cancer. We previously suggested endoscopic ultrasound (EUS)-guided interstitial laser ablation using a cylindrical laser diffuser (CILA) might be a feasible therapeutic option based on experiments performed on pancreatic cancer cell lines and porcine model with a short follow-up (3 days). The aim of this study was to investigate the safety of EUS-CILA performed using optimal settings in porcine pancreas with a long-term follow-up (2 weeks). Methods: EUS-CILA (laser energy of 450 J; 5 W for 90 s) was applied to normal pancreatic tissue in porcine (n = 5) under EUS guidance. Animals were observed clinically for 2 weeks after EUS-CILA to evaluate complications. Computed tomography and laboratory tests were carried out to evaluate safety. Two weeks after EUS-CILA, all pigs were sacrificed, and histopathological safety and efficacy evaluations were conducted. Results: EUS-CILA was technically successful in all five cases. No major complications occurred during the follow-up period. Body weight of porcine did not change during the study period without any significant change in feed intake. Animals remained in excellent condition throughout the experimental period, and laboratory tests and computed tomography (CT) scans provided no evidence of a major complication. Histopathological evaluation showed complete ablation in the ablated area with clear delineation of surrounding normal pancreatic tissue. Mean ablated volume was 55.5 mm² × 29.0 mm and mean ablated areas in the pancreatic sections of the five pigs were not significantly different (p = 0.368). Conclusions: In conclusion, our experimental study suggests that EUS-CILA is safe and has the potential to be an effective local treatment modality. No major morbidity or mortality occurred during the study period. Further evaluations are warranted before clinical application. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches 2.0)

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Review

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23 pages, 955 KiB

Open AccessReview

An Insight on Functioning Pancreatic Neuroendocrine Neoplasms

by Michele Bevere, Anastasios Gkountakos, Filippo Maria Martelli, Aldo Scarpa, Claudio Luchini and Michele Simbolo

Biomedicines 2023, 11(2), 303; https://doi.org/10.3390/biomedicines11020303 - 21 Jan 2023

Cited by 6 | Viewed by 2350

Abstract

Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms arising from islets of the Langerhans in the pancreas. They can be divided into two groups, based on peptide hormone secretion, functioning and nonfunctioning PanNENs. The first group is characterized by different secreted peptides causing specific syndromes and is further classified into subgroups: insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma and tumors producing serotonin and adrenocorticotrophic hormone. Conversely, the second group does not release peptides and is usually associated with a worse prognosis. Today, although the efforts to improve the therapeutic approaches, surgery remains the only curative treatment for patients with PanNENs. The development of high-throughput techniques has increased the molecular knowledge of PanNENs, thereby allowing us to understand better the molecular biology and potential therapeutic vulnerabilities of PanNENs. Although enormous advancements in therapeutic and molecular aspects of PanNENs have been achieved, there is poor knowledge about each subgroup of functioning PanNENs.Therefore, we believe that combining high-throughput platforms with new diagnostic tools will allow for the efficient characterization of the main differences among the subgroups of functioning PanNENs. In this narrative review, we summarize the current landscape regarding diagnosis, molecular profiling and treatment, and we discuss the future perspectives of functioning PanNENs. Full article

(This article belongs to the Special Issue Pancreatic Cancer: From Mechanisms to Therapeutic Approaches 2.0)

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