Research

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13 pages, 14117 KiB

Open AccessArticle

Immunohistochemical Evaluation of the Expression of Specific Membrane Antigens in Patients with Pancreatic Ductal Adenocarcinoma

by Alberto Nicoletti, Federica Vitale, Giuseppe Quero, Mattia Paratore, Claudio Fiorillo, Marcantonio Negri, Angela Carlino, Frediano Inzani, Antonio Gasbarrini, Sergio Alfieri and Lorenzo Zileri Dal Verme

Cancers 2023, 15(18), 4586; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15184586 - 15 Sep 2023

Cited by 1 | Viewed by 948

Abstract

(1) Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. The lack of validated disease biomarkers makes timely diagnosis challenging in most cases. Cell membrane and surface proteins play a crucial role in several routes of oncogenesis. The aim of [...] Read more.

(1) Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. The lack of validated disease biomarkers makes timely diagnosis challenging in most cases. Cell membrane and surface proteins play a crucial role in several routes of oncogenesis. The aim of this study was to evaluate the expression of six membrane antigens on PDAC (CA 19-9, mucin 1 and 4 (MUC1, MUC4), mesothelin (MSLN), Annexin A10 (ANXA10), Glypican-1 (GPC-1)) and their correlation with oncologic outcomes. (2) Methods: Immunohistochemical staining for CA 19.9, MUC1, MUC4, MSLN, ANXA10, and GPC-1 of surgical samples of 50 consecutive patients with PDAC was performed. Antigen expression for tumor, ductal, and acinar tissues was classified according to the histo-score (H-score) by two pathologists. (3) Results: Recurrence rate was 47% and 18 patients (36%) deceased (median follow-up 21.5 months). Immunostaining for CA 19-9 and MUC1 showed a significantly higher expression in the neoplastic tissue compared to non-tumor ductal and acinar tissues (p < 0.001). MUC4, MSLN, ANXA10, and GPC-1 were selectively expressed in the neoplastic tissue (p < 0.001). A CA 19-9 H-score value >270 was independently associated with a worse overall survival (p = 0.05) and disease-free survival (p = 0.05). (4) Conclusions: CA 19-9 and MUC1 are highly expressed in PDAC cells. The histological expression of CA 19-9 may predict prognosis. MUC4, MSLN, ANXA10, and GPC-1 are selectively expressed by neoplastic tissue and may represent a potential histological biomarker of disease. Full article

(This article belongs to the Special Issue Future Trends and Therapies of Pancreatic Cancer—Where Are We Going from Here On?)

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17 pages, 4610 KiB

Open AccessArticle

Antiproliferative Activity of Krukovine by Regulating Transmembrane Protein 139 (TMEM139) in Oxaliplatin-Resistant Pancreatic Cancer Cells

by Jee-Hyung Lee, Sang-Hyub Lee, Sang-Kook Lee, Jin-Ho Choi, Seohyun Lim, Min-Song Kim, Kyung-Min Lee, Min-Woo Lee, Ja-Lok Ku, Dae-Hyun Kim, In-Rae Cho, Woo-Hyun Paik, Ji-Kon Ryu and Yong-Tae Kim

Cancers 2023, 15(9), 2642; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15092642 - 07 May 2023

Cited by 2 | Viewed by 1725

Abstract

Krukovine (KV) is an alkaloid isolated from the bark of Abuta grandifolia (Mart.) Sandw. (Menispermaceae) with anticancer potential in some cancers with KRAS mutations. In this study, we explored the anticancer efficacy and mechanism of KV in oxaliplatin-resistant pancreatic cancer cells and patient-derived [...] Read more.

Krukovine (KV) is an alkaloid isolated from the bark of Abuta grandifolia (Mart.) Sandw. (Menispermaceae) with anticancer potential in some cancers with KRAS mutations. In this study, we explored the anticancer efficacy and mechanism of KV in oxaliplatin-resistant pancreatic cancer cells and patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutation. After treatment with KV, mRNA and protein levels were determined by RNA-seq and Western blotting, respectively. Cell proliferation, migration, and invasion were measured by MTT, scratch wound healing assay, and transwell analysis, respectively. Patient-derived pancreatic cancer organoids (PDPCOs) with KRAS mutations were treated with KV, oxaliplatin (OXA), and a combination of KV and OXA. KV suppresses tumor progression via the downregulation of the Erk-RPS6K-TMEM139 and PI3K-Akt-mTOR pathways in oxaliplatin-resistant AsPC-1 cells. Furthermore, KV showed an antiproliferative effect in PDPCOs, and the combination of OXA and KV inhibited PDPCO growth more effectively than either drug alone. Full article

(This article belongs to the Special Issue Future Trends and Therapies of Pancreatic Cancer—Where Are We Going from Here On?)

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14 pages, 5033 KiB

Open AccessArticle

VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

by David Digomann, Johannes Strack, Max Heiduk, Ioana Plesca, Luise Rupp, Charlotte Reiche, Simone Nicolaus, Carolin Beer, Ulrich Sommer, Marc Schmitz, Marius Distler, Jürgen Weitz, Adrian M. Seifert and Lena Seifert

Cancers 2023, 15(8), 2326; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15082326 - 17 Apr 2023

Cited by 4 | Viewed by 1981

Abstract

Immunotherapy has shown promising results in multiple solid tumors and hematological malignancies. However, pancreatic ductal adenocarcinoma (PDAC) has been largely refractory to current clinical immunotherapies. The V-domain Ig suppressor of T-cell activation (VISTA) inhibits T-cell effector function and maintains peripheral tolerance. Here, we [...] Read more.

Immunotherapy has shown promising results in multiple solid tumors and hematological malignancies. However, pancreatic ductal adenocarcinoma (PDAC) has been largely refractory to current clinical immunotherapies. The V-domain Ig suppressor of T-cell activation (VISTA) inhibits T-cell effector function and maintains peripheral tolerance. Here, we determine VISTA expression in nontumorous pancreatic (n = 5) and PDAC tissue using immunohistochemistry (n = 76) and multiplex immunofluorescence staining (n = 67). Additionally, VISTA expression on tumor-infiltrating immune cells and matched blood samples (n = 13) was measured with multicolor flow cytometry. Further, the effect of recombinant VISTA on T-cell activation was investigated in vitro, and VISTA blockade was tested in an orthotopic PDAC mouse model in vivo. PDAC showed significantly higher VISTA expression compared to that of a nontumorous pancreas. Patients with a high density of VISTA-expressing tumor cells had reduced overall survival. The VISTA expression of CD4⁺ and CD8⁺ T cells was increased after stimulation and particularly after a coculture with tumor cells. We detected a higher level of proinflammatory cytokine (TNFα and IFNγ) expression by CD4⁺ and CD8⁺ T cells, which was reversed with the addition of recombinant VISTA. A VISTA blockade reduced tumor weights in vivo. The VISTA expression of tumor cells has clinical relevance, and its blockade may be a promising immunotherapeutic strategy for PDAC. Full article

(This article belongs to the Special Issue Future Trends and Therapies of Pancreatic Cancer—Where Are We Going from Here On?)

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9 pages, 692 KiB

Open AccessCommunication

Regulatory T Cells in Pancreatic Cancer: Of Mice and Men

by Carmen Mota Reyes, Elke Demir, Kaan Çifcibaşı, Rouzanna Istvanffy, Helmut Friess and Ihsan Ekin Demir

Cancers 2022, 14(19), 4582; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14194582 - 21 Sep 2022

Cited by 5 | Viewed by 1965

Abstract

Regulatory T cells (Treg) are one of the major immunosuppressive cell subsets in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells mechanisms form a partially redundant [...] Read more.

Regulatory T cells (Treg) are one of the major immunosuppressive cell subsets in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells mechanisms form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these complex compensatory mechanisms may be the tumors of patients who underwent neoTx. Here, we observed a parallel decrease in the numbers of both intratumoral Tregs and MDSC after neoTx even in locally advanced PCa. NeoTx also led to decreased amounts of αSMA⁺ myofibroblastic cancer-associated fibroblasts (myCAF) and increased proportions of CD8⁺ cytotoxic T lymphocytes in the tumor. In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform. Full article

(This article belongs to the Special Issue Future Trends and Therapies of Pancreatic Cancer—Where Are We Going from Here On?)

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21 pages, 4262 KiB

Open AccessArticle

IL-17B/RB Activation in Pancreatic Stellate Cells Promotes Pancreatic Cancer Metabolism and Growth

by Jiahui Li, Xiaolin Wu, Lars Schiffmann, Thomas MacVicar, Chenghui Zhou, Zhefang Wang, Dai Li, Oscar Velazquez Camacho, Reiner Heuchel, Margarete Odenthal, Axel Hillmer, Alexander Quaas, Yue Zhao, Christiane J. Bruns and Felix C. Popp

Cancers 2021, 13(21), 5338; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13215338 - 24 Oct 2021

Cited by 9 | Viewed by 2268

Abstract

In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) [...] Read more.

In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions. Full article

(This article belongs to the Special Issue Future Trends and Therapies of Pancreatic Cancer—Where Are We Going from Here On?)

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Review

Jump to: Research

23 pages, 986 KiB

Open AccessReview

State-of-the-Art and Upcoming Innovations in Pancreatic Cancer Care: A Step Forward to Precision Medicine

by Tommaso Schepis, Sara Sofia De Lucia, Antonio Pellegrino, Angelo del Gaudio, Rossella Maresca, Gaetano Coppola, Michele Francesco Chiappetta, Antonio Gasbarrini, Francesco Franceschi, Marcello Candelli and Enrico Celestino Nista

Cancers 2023, 15(13), 3423; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15133423 - 30 Jun 2023

Cited by 6 | Viewed by 2126

Abstract

Pancreatic cancer remains a social and medical burden despite the tremendous advances that medicine has made in the last two decades. The incidence of pancreatic cancer is increasing, and it continues to be associated with high mortality and morbidity rates. The difficulty of [...] Read more.

Pancreatic cancer remains a social and medical burden despite the tremendous advances that medicine has made in the last two decades. The incidence of pancreatic cancer is increasing, and it continues to be associated with high mortality and morbidity rates. The difficulty of early diagnosis (the lack of specific symptoms and biomarkers at early stages), the aggressiveness of the disease, and its resistance to systemic therapies are the main factors for the poor prognosis of pancreatic cancer. The only curative treatment for pancreatic cancer is surgery, but the vast majority of patients with pancreatic cancer have advanced disease at the time of diagnosis. Pancreatic surgery is among the most challenging surgical procedures, but recent improvements in surgical techniques, careful patient selection, and the availability of minimally invasive techniques (e.g., robotic surgery) have dramatically reduced the morbidity and mortality associated with pancreatic surgery. Patients who are not candidates for surgery may benefit from locoregional and systemic therapy. In some cases (e.g., patients for whom marginal resection is feasible), systemic therapy may be considered a bridge to surgery to allow downstaging of the cancer; in other cases (e.g., metastatic disease), systemic therapy is considered the standard approach with the goal of prolonging patient survival. The complexity of patients with pancreatic cancer requires a personalized and multidisciplinary approach to choose the best treatment for each clinical situation. The aim of this article is to provide a literature review of the available treatments for the different stages of pancreatic cancer. Full article

(This article belongs to the Special Issue Future Trends and Therapies of Pancreatic Cancer—Where Are We Going from Here On?)

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23 pages, 1005 KiB

Open AccessReview

The Liver Pre-Metastatic Niche in Pancreatic Cancer: A Potential Opportunity for Intervention

by Peter Gumberger, Bergthor Bjornsson, Per Sandström, Linda Bojmar and Constantinos P. Zambirinis

Cancers 2022, 14(12), 3028; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14123028 - 20 Jun 2022

Cited by 6 | Viewed by 3264

Abstract

Cancer-related mortality is primarily a consequence of metastatic dissemination and associated complications. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and tends to metastasize early, especially in the liver. Emerging evidence suggests that organs that develop metastases exhibit microscopic changes [...] Read more.

Cancer-related mortality is primarily a consequence of metastatic dissemination and associated complications. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and tends to metastasize early, especially in the liver. Emerging evidence suggests that organs that develop metastases exhibit microscopic changes that favor metastatic growth, collectively known as “pre-metastatic niches”. By definition, a pre-metastatic niche is chronologically established before overt metastatic outgrowth, and its generation involves the release of tumor-derived secreted factors that modulate cells intrinsic to the recipient organ, as well as recruitment of additional cells from tertiary sites, such as bone marrow—all orchestrated by the primary tumor. The pre-metastatic niche is characterized by tumor-promoting inflammation with tumor-supportive and immune-suppressive features, remodeling of the extracellular matrix, angiogenic modulation and metabolic alterations that support growth of disseminated tumor cells. In this paper, we review the current state of knowledge of the hepatic pre-metastatic niche in PDAC and attempt to create a framework to guide future diagnostic and therapeutic studies. Full article

(This article belongs to the Special Issue Future Trends and Therapies of Pancreatic Cancer—Where Are We Going from Here On?)

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14 pages, 301 KiB

Open AccessReview

Management of Pancreatic Cancer and Its Microenvironment: Potential Impact of Nano-Targeting

by Nardeen Perko and Shaker A. Mousa

Cancers 2022, 14(12), 2879; https://doi.org/10.3390/cancers14122879 - 10 Jun 2022

Cited by 1 | Viewed by 2062

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is rare and difficult to treat, making it a complicated diagnosis for every patient. These patients have a low survival rate along with a poor quality of life under current pancreatic cancer therapies that adversely affect healthy cells due [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is rare and difficult to treat, making it a complicated diagnosis for every patient. These patients have a low survival rate along with a poor quality of life under current pancreatic cancer therapies that adversely affect healthy cells due to the lack of precise drug targeting. Additionally, chemoresistance and radioresistance are other key challenges in PDAC, which might be due in part to the lack of tumor-targeted delivery of sufficient levels of different chemotherapies because of their low therapeutic index. Thus, instead of leaving a trail of off-target damage when killing these cancer cells, it is best to find a way that targets them directly. More seriously, metastatic relapse often occurs after surgery, and therefore, achieving improved outcomes in the management of PDAC in the absence of strategies preventing metastasis is likely to be impossible. Nano-targeting of the tumor and its microenvironment has shown promise for treating various cancers, which might be a promising approach for PDAC. This review updates the advancements in treatment modalities for pancreatic cancer and highlights future directions that warrant further investigation to increase pancreatic patients’ overall survival. Full article

(This article belongs to the Special Issue Future Trends and Therapies of Pancreatic Cancer—Where Are We Going from Here On?)

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Graphical abstract

13 pages, 1512 KiB

Open AccessReview

Current and Future Therapies for Pancreatic Ductal Adenocarcinoma

by Áine Sally, Ryan McGowan, Karen Finn and Brian Michael Moran

Cancers 2022, 14(10), 2417; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102417 - 13 May 2022

Cited by 12 | Viewed by 3178

Abstract

Pancreatic cancer is one of the leading causes of cancer-related death worldwide. This is due to delayed diagnosis and resistance to traditional chemotherapy. Delayed diagnosis is often due to the broad range of non-specific symptoms that are associated with the disease. Resistance to [...] Read more.

Pancreatic cancer is one of the leading causes of cancer-related death worldwide. This is due to delayed diagnosis and resistance to traditional chemotherapy. Delayed diagnosis is often due to the broad range of non-specific symptoms that are associated with the disease. Resistance to current chemotherapies, such as gemcitabine, develops due to genetic mutations that are either intrinsic or acquired. This has resulted in poor patient prognosis and, therefore, justifies the requirement for new targeted therapies. A synthetic lethality approach, that targets specific loss-of-function mutations in cancer cells, has shown great potential in pancreatic ductal adenocarcinoma (PDAC). Immunotherapies have also yielded promising results in the development of new treatment options, with several currently undergoing clinical trials. The utilisation of monoclonal antibodies, immune checkpoint inhibitors, adoptive cell transfer, and vaccines have shown success in several neoplasms such as breast cancer and B-cell malignancies and, therefore, could hold the same potential in PDAC treatment. These therapeutic strategies could have the potential to be at the forefront of pancreatic cancer therapy in the future. This review focuses on currently approved therapies for PDAC, the challenges associated with them, and future directions of therapy including synthetically lethal approaches, immunotherapy, and current clinical trials. Full article

(This article belongs to the Special Issue Future Trends and Therapies of Pancreatic Cancer—Where Are We Going from Here On?)

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