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Targeting the Tumor Microenvironment

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Tumor Microenvironment".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 38848

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Prof. Dr. Georgios Giamas

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Guest Editor

School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK
Interests: signaling; cancer; breast cancer; glioblastoma; microenvironment; exosomes; kinases
Special Issues, Collections and Topics in MDPI journals

Dr. Teresa Gagliano

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Guest Editor

School of Life Sciences, University of Sussex, Brighton BN1 9QG, UK
Interests: signalling; cancer; breast cancer; microenvironment; endocrine cancers; kinases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

The tumor microenvironment (TME) plays a pivotal role in different types of cancer. The interactions that occur within the TME are fundamental in tumor-induced suppression of the immune system and metastatic dissemination of cancer cells, and these mechanisms may ultimately affect tumor progression and treatment outcome. Recently introduced cancer therapies are targeting the interaction between tumors and the TME. However, stromal components of the tumor niche may extensively affect drug response in tumor cells. Furthermore, stroma-targeted strategies have emerged as a new treatment option for many types of cancer. Despite, the recent advancement in cancer treatment a proportion of patients remain resistant, thus, it is necessary to develop innovative therapeutic approaches by investigating the fundamental role of TME. In this Special Issue, “Targeting the Tumor Microenvironment”, authors are invited to contribute cutting-edge studies that will further highlight the involvement of TME in cancer progression and treatment

Prof. Georgios Giamas
Dr. Teresa Gagliano
Guest Editors

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. Cancers is an international peer-reviewed open access semimonthly 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 2900 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

microenvironment
cancer treatment
resistance to treatment
metastasis
immune response
immune cells
fibroblasts
angiogenesis
EVs
signalling

Published Papers (12 papers)

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Research

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26 pages, 5186 KiB

Open AccessArticle

Claudin-Low Breast Cancer Inflammatory Signatures Support Polarization of M1-Like Macrophages with Protumoral Activity

by Mayra Cecilia Suárez-Arriaga, Alfonso Méndez-Tenorio, Vadim Pérez-Koldenkova and Ezequiel M. Fuentes-Pananá

Cancers 2021, 13(9), 2248; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092248 - 07 May 2021

Cited by 7 | Viewed by 3357

Abstract

We previously reported that triple-negative breast cancer (BRCA) cells overexpress the cytokines GM-CSF, G-CSF, MCP-1, and RANTES, and when monocytes were 3-D co-cultured with them, M1-like macrophages were generated with the ability to induce aggressive features in luminal BRCA cell lines. These include upregulation of mesenchymal and stemness markers and invasion. In this study, we stimulated peripheral blood monocytes with the four cytokines and confirmed their capacity to generate protumoral M1-like macrophages. Using the METABRIC BRCA database, we observed that GM-CSF, MCP-1, and RANTES are associated with triple-negative BRCA and reduced overall survival, particularly in patients under 55 years of age. We propose an extended M1-like macrophage proinflammatory signature connected with these three cytokines. We found that the extended M1-like macrophage signature coexists with monocyte/macrophage, Th1 immune response, and immunosuppressive signatures, and all are enriched in claudin-low BRCA samples, and correlate with reduced patient overall survival. Furthermore, we observed that all these signatures are also present in mesenchymal carcinomas of the colon (COAD) and bladder (BLCA). The claudin-low tumor subtype has an adverse clinical outcome and remains poorly understood. This study places M1 macrophages as potential protumoral drivers in already established cancers, and as potential contributors to claudin-low aggressiveness and poor prognosis. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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18 pages, 3082 KiB

Open AccessArticle

Hyperglycemia-Induced miR-467 Drives Tumor Inflammation and Growth in Breast Cancer

by Jasmine Gajeton, Irene Krukovets, Santoshi Muppala, Dmitriy Verbovetskiy, Jessica Zhang and Olga Stenina-Adognravi

Cancers 2021, 13(6), 1346; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061346 - 16 Mar 2021

Cited by 12 | Viewed by 2230

Abstract

The tumor microenvironment contains the parenchyma, blood vessels, and infiltrating immune cells, including tumor-associated macrophages (TAMs). TAMs affect the developing tumor and drive cancer inflammation. We used mouse models of hyperglycemia and cancer and specimens from hyperglycemic breast cancer (BC) patients to demonstrate that miR-467 mediates the effects of high blood glucose on cancer inflammation and growth. Hyperglycemic patients have a higher risk of developing breast cancer. We have identified a novel miRNA-dependent pathway activated by hyperglycemia that promotes BC angiogenesis and inflammation supporting BC growth. miR-467 is upregulated in endothelial cells (EC), macrophages, BC cells, and in BC tumors. A target of miR-467, thrombospondin-1 (TSP-1), inhibits angiogenesis and promotes resolution of inflammation. Systemic injections of a miR-467 antagonist in mouse models of hyperglycemia resulted in decreased BC growth (p < 0.001). Tumors from hyperglycemic mice had a two-fold increase in macrophage accumulation compared to normoglycemic controls (p < 0.001), and TAM infiltration was prevented by the miR-467 antagonist (p < 0.001). BC specimens from hyperglycemic patients had increased miR-467 levels, increased angiogenesis, decreased levels of TSP-1, and increased TAM infiltration in malignant breast tissue in hyperglycemic vs. normoglycemic patients (2.17-fold, p = 0.002) and even in normal breast tissue from hyperglycemic patients (2.18-fold increase, p = 0.04). In malignant BC tissue, miR-467 levels were upregulated 258-fold in hyperglycemic patients compared to normoglycemic patients (p < 0.001) and increased 56-fold in adjacent normal tissue (p = 0.008). Our results suggest that miR-467 accelerates tumor growth by inducing angiogenesis and promoting the recruitment of TAMs to drive hyperglycemia-induced cancer inflammation. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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16 pages, 8082 KiB

Open AccessArticle

Tuberculous Fibrosis Enhances Tumorigenic Potential via the NOX4–Autophagy Axis

by Seong Ji Woo, Youngmi Kim, Harry Jung, Jae Jun Lee and Ji Young Hong

Cancers 2021, 13(4), 687; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040687 - 08 Feb 2021

Cited by 7 | Viewed by 2068

Abstract

While a higher incidence of lung cancer in subjects with previous tuberculous infection has been reported in epidemiologic data, the mechanism by which previous tuberculosis affects lung cancer remains unclear. We investigated the role of NOX4 in tuberculous pleurisy-assisted tumorigenicity both in vitro and in vivo.Heat-killed Mycobacterium tuberculosis-stimulated mesothelial cells augmented the migrationand invasive potential of lung cancer cells in a NOX4-dependent manner. Mice with Mycobacterium bovis bacillus Calmette–Guérin (BCG) pleural infection exhibited increased expression of NOX4 and enhanced malignant potential of lung cancer compared to mice with intrathoracic injection of phosphate-buffered saline. The BCG+ KLN205 (KLN205 cancer cell injection after BCG treatment) NOX4 KO mice group showed reduced tuberculous fibrosis-promoted metastatic potential of lung cancer, increased autophagy, and decreased expression of TGF-β, IL-6, and TNF-α compared to the BCG+KLN205 WT mice group. Finally, NOX4 silencing mitigated the malignant potential of A549 cells that was enhanced by tuberculous pleural effusion and restored autophagy signaling. Our results suggest that the NOX4–autophagy axis regulated by tuberculous fibrosis could result in enhanced tumorigenic potential and that NOX4-P62 might serve as a target for tuberculous fibrosis-induced lung cancer. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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16 pages, 4327 KiB

Open AccessArticle

The Oxygen-Generating Calcium Peroxide-Modified Magnetic Nanoparticles Attenuate Hypoxia-Induced Chemoresistance in Triple-Negative Breast Cancer

by Fong-Yu Cheng, Chia-Hsin Chan, Bour-Jr Wang, Ya-Ling Yeh, Ying-Jan Wang and Hui-Wen Chiu

Cancers 2021, 13(4), 606; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040606 - 03 Feb 2021

Cited by 21 | Viewed by 3702

Abstract

Cancer response to chemotherapy is regulated not only by intrinsic sensitivity of cancer cells but also by tumor microenvironment. Tumor hypoxia, a condition of low oxygen level in solid tumors, is known to increase the resistance of cancer cells to chemotherapy. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Due to lack of target in TNBC, chemotherapy is the only approved systemic treatment. We evaluated the effect of hypoxia on chemotherapy resistance in TNBC in a series of in vitro and in vivo experiments. Furthermore, we synthesized the calcium peroxide-modified magnetic nanoparticles (CaO₂-MNPs) with the function of oxygen generation to improve and enhance the therapeutic efficiency of doxorubicin treatment in the hypoxia microenvironment of TNBC. The results of gene set enrichment analysis (GSEA) software showed that the hypoxia and autophagy gene sets are significantly enriched in TNBC patients. We found that the chemical hypoxia stabilized the expression of hypoxia-inducible factor 1α (HIF-1α) protein and increased doxorubicin resistance in TNBC cells. Moreover, hypoxia inhibited the induction of apoptosis and autophagy by doxorubicin. In addition, CaO₂-MNPs promoted ubiquitination and protein degradation of HIF-1α. Furthermore, CaO₂-MNPs inhibited autophagy and induced apoptosis in TNBC cells. Our animal studies with an orthotopic mouse model showed that CaO₂-MNPs in combination with doxorubicin exhibited a stronger tumor-suppressive effect on TNBC, compared to the doxorubicin treatment alone. Our findings suggest that combined with CaO₂-MNPs and doxorubicin attenuates HIF-1α expression to improve the efficiency of chemotherapy in TNBC. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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24 pages, 4644 KiB

Open AccessArticle

Heterogeneity Matters: Different Regions of Glioblastoma Are Characterized by Distinctive Tumor-Supporting Pathways

by Ivana Manini, Federica Caponnetto, Emiliano Dalla, Tamara Ius, Giuseppe Maria Della Pepa, Enrico Pegolo, Anna Bartolini, Giuseppe La Rocca, Grazia Menna, Carla Di Loreto, Alessandro Olivi, Miran Skrap, Giovanni Sabatino and Daniela Cesselli

Cancers 2020, 12(10), 2960; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102960 - 13 Oct 2020

Cited by 20 | Viewed by 2303

Abstract

The glioblastoma microenvironment plays a substantial role in glioma biology. However, few studies have investigated its spatial heterogeneity. Exploiting 5-ALA Fluorescence Guided Surgery (FGS), we were able to distinguish between the tumor core (ALA+), infiltrating area (ALA-PALE) and healthy tissue (ALA−) of the glioblastoma, based on the level of accumulated fluorescence. The aim of this study was to investigate the properties of the microenvironments associated with these regions. For this purpose, we isolated glioma-associated stem cells (GASC), resident in the glioma microenvironment, from ALA+, ALA-PALE and ALA− samples and compared them in terms of growth kinetic, phenotype and for the expression of 84 genes associated with cancer inflammation and immunity. Differentially expressed genes were correlated with transcriptomic datasets from TCGA/GTEX. Our results show that GASC derived from the three distinct regions, despite a similar phenotype, were characterized by different transcriptomic profiles. Moreover, we identified a GASC-based genetic signature predictive of overall survival and disease-free survival. This signature, highly expressed in ALA+ GASC, was also well represented in ALA PALE GASC. 5-ALA FGS allowed to underline the heterogeneity of the glioma microenvironments. Deepening knowledge of these differences can contribute to develop new adjuvant therapies targeting the crosstalk between tumor and its supporting microenvironment. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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15 pages, 1975 KiB

Open AccessArticle

G-CSF and G-CSFR Induce a Pro-Tumorigenic Macrophage Phenotype to Promote Colon and Pancreas Tumor Growth

by Ioannis Karagiannidis, Eliane de Santana Van Vilet, Erika Said Abu Egal, Brandon Phinney, Damian Jacenik, Eric R. Prossnitz and Ellen J. Beswick

Cancers 2020, 12(10), 2868; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102868 - 06 Oct 2020

Cited by 20 | Viewed by 3133

Abstract

Tumor-associated macrophages (TAMs) in the gastrointestinal tumor microenvironment (TME) are known to polarize into populations exhibiting pro- or anti-tumoral activity in response to stimuli such as growth factors and cytokines. Our previous work has recognized granulocyte colony-stimulating factor (G-CSF) as a cytokine capable of influencing immune cells of the TME exhibiting pro-tumoral activity. Here, we aimed to focus on how G-CSF regulates TAM phenotype and function and the effects on gastrointestinal (GI) tumor progression. Thus, wildtype (WT) and G-CSFR^−/− macrophages were examined for cytokine production, gene expression, and transcription factor activity. Adoptive transfer of WT or G-CSFR^−/− macrophages into tumor-bearing mice was performed to study their influence in the progression of colon (MC38) and pancreatic (PK5L1940) tumor mouse models. Finally, the difference in cytotoxic potential between WT and G-CSFR^−/− macrophages was examined both in vitro and in vivo. Our results indicate that G-CSF promotes increased IL-10 production and decreased IL-12 production, which was reversed in G-CSFR^−/− macrophages for a pro-inflammatory phenotype. Furthermore, G-CSFR^−/− macrophages were characterized by higher levels of NOS2 expression and NO production, which led to greater tumor related cytotoxicity both in vitro and in vivo. Our results suggest that in the absence of G-CSFR, macrophage-related tumor cytotoxicity was amplified. These findings, along with our previous reports, pinpoint G-CSF /G-CSFR as a prominent target for possible clinical applications that aim to control the TME and the GI tumor progression. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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16 pages, 2170 KiB

Open AccessArticle

CXCR4 Inhibition Enhances Efficacy of FLT3 Inhibitors in FLT3-Mutated AML Augmented by Suppressed TGF-β Signaling

by Bo-Reum Kim, Seung-Hyun Jung, A-Reum Han, Gyeongsin Park, Hee-Je Kim, Bin Yuan, Venkata Lokesh Battula, Michael Andreeff, Marina Konopleva, Yeun-Jun Chung and Byung-Sik Cho

Cancers 2020, 12(7), 1737; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12071737 - 30 Jun 2020

Cited by 11 | Viewed by 3171

Abstract

Given the proven importance of the CXCL12/CXCR4 axis in the stroma–acute myeloid leukemia (AML) interactions and the rapid emergence of resistance to FLT3 inhibitors, we investigated the efficacy and safety of a novel CXCR4 inhibitor, LY2510924, in combination with FLT3 inhibitors in preclinical models of AML with FLT3-ITD mutations (FLT3-ITD-AML). Quizartinib, a potent FLT3 inhibitor, induced apoptosis in FLT3-ITD-AML, while LY2510924 blocked surface CXCR4 without inducing apoptosis. LY2510924 significantly reversed stroma-mediated resistance against quizartinib mainly through the MAPK pathway. In mice with established FLT3-ITD-AML, LY2510924 induced durable mobilization and differentiation of leukemia cells, resulting in enhanced anti-leukemia effects when combined with quizartinib, whereas transient effects were seen on non-leukemic blood cells in immune-competent mice. Sequencing of the transcriptome of the leukemic cells surviving in vivo treatment with quizartinib and LY2510924 revealed that genes related to TGF-β signaling may confer resistance against the drug combination. In co-culture experiments of FLT3-ITD-AML and stromal cells, both silencing of TGF-β in stromal cells or TGF-β-receptor kinase inhibitor enhanced apoptosis by combined treatment. Disruption of the CXCL12/CXCR4 axis in FLT3-ITD-AML by LY2510924 and its negligible effects on normal immunocytes could safely enhance the potency of quizartinib, which may be further improved by blockade of TGF-β signaling. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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15 pages, 13463 KiB

Open AccessArticle

Anti-EGFR Therapy Induces EGF Secretion by Cancer-Associated Fibroblasts to Confer Colorectal Cancer Chemoresistance

by Colleen M. Garvey, Roy Lau, Alyssa Sanchez, Ren X. Sun, Emma J. Fong, Michael E. Doche, Oscar Chen, Anthony Jusuf, Heinz-Josef Lenz, Brent Larson and Shannon M. Mumenthaler

Cancers 2020, 12(6), 1393; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061393 - 28 May 2020

Cited by 33 | Viewed by 4329

Abstract

Targeted agents have improved the efficacy of chemotherapy for cancer patients, however, there remains a lack of understanding of how these therapies affect the unsuspecting bystanders of the stromal microenvironment. Cetuximab, a monoclonal antibody therapy targeting the epidermal growth factor receptor (EGFR), is given in combination with chemotherapy as the standard of care for a subset of metastatic colorectal cancer patients. The overall response to this treatment is underwhelming and, while genetic mutations that confer resistance have been identified, it is still not known why this drug is ineffective for some patients. We discovered that cancer-associated fibroblasts (CAFs), a major cellular subset of the tumor stroma, can provide a source of cancer cell resistance. Specifically, we observed that upon treatment with cetuximab, CAFs increased their secretion of EGF, which was sufficient to render neighboring cancer cells resistant to cetuximab treatment through sustained mitogen-activated protein kinases (MAPK) signaling. Furthermore, we show the cetuximab-induced EGF secretion to be specific to CAFs and not to cancer cells or normal fibroblasts. Altogether, this work emphasizes the importance of the tumor microenvironment and considering the potential unintended consequences of therapeutically targeting cancer-driving proteins on non-tumorigenic cell types. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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Review

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15 pages, 16900 KiB

Open AccessReview

Epigenetic Mechanisms beyond Tumour–Stroma Crosstalk

by Teresa Gagliano and Claudio Brancolini

Cancers 2021, 13(4), 914; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040914 - 22 Feb 2021

Cited by 9 | Viewed by 2335

Abstract

Despite cancer having been usually considered the result of genetic mutations, it is now well established that epigenetic dysregulations play pivotal roles in cancer onset and progression. Hence, inactivation of tumour suppressor genes can be gained not only by genetic mutations, but also by epigenetic mechanisms such as DNA methylation and histone modifications. To occur, epigenetic events need to be triggered by genetic alterations of the epigenetic regulators, or they can be mediated by intracellular and extracellular stimuli. In this last setting, the tumour microenvironment (TME) plays a fundamental role. Therefore, to decipher how epigenetic changes are associated with TME is a challenge still open. The complex signalling between tumour cells and stroma is currently under intensive investigation, and most of the molecules and pathways involved still need to be identified. Neoplastic initiation and development are likely to involve a back-and-forth crosstalk among cancer and stroma cells. An increasing number of studies have highlighted that the cancer epigenome can be influenced by tumour microenvironment and vice versa. Here, we discuss about the recent literature on tumour–stroma interactions that focus on epigenetic mechanisms and the reciprocal regulation between cancer and TME cells. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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18 pages, 7177 KiB

Open AccessReview

Noncoding RNAs in the Interplay between Tumor Cells and Cancer-Associated Fibroblasts: Signals to Catch and Targets to Hit

by Martina Tassinari and Paolo Gandellini

Cancers 2021, 13(4), 709; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040709 - 09 Feb 2021

Cited by 8 | Viewed by 3290

Abstract

Cancer development and progression are not solely cell-autonomous and genetically driven processes. Dynamic interaction of cancer cells with the surrounding microenvironment, intended as the chemical/physical conditions as well as the mixture of non-neoplastic cells of the tumor niche, drive epigenetic changes that are pivotal for the acquisition of malignant traits. Cancer-associated fibroblasts (CAF), namely fibroblasts that, corrupted by cancer cells, acquire a myofibroblast-like reactive phenotype, are able to sustain tumor features by the secretion of soluble paracrine signals and the delivery extracellular vesicles. In such diabolic liaison, a major role has been ascribed to noncoding RNAs. Defined as RNAs that are functional though not being translated into proteins, noncoding RNAs predominantly act as regulators of gene expression at both the transcriptional and post-transcriptional levels. In this review, we summarize the current knowledge of microRNAs and long noncoding RNAs that act intracellularly in either CAFs or cancer cells to sustain tumor-stroma interplay. We also report on the major role of extracellular noncoding RNAs that are bidirectionally transferred between either cell type. Upon presenting a comprehensive view of the existing literature, we provide our critical opinion regarding the possible clinical utility of tumor-stroma related noncoding RNAs as therapeutic target/tools or prognostic/predictive biomarkers. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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23 pages, 11803 KiB

Open AccessReview

Extracellular Vesicles Orchestrate Immune and Tumor Interaction Networks

by Kevin Ho Wai Yim, Ala’a Al Hrout, Simone Borgoni and Richard Chahwan

Cancers 2020, 12(12), 3696; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12123696 - 09 Dec 2020

Cited by 11 | Viewed by 3374

Abstract

Extracellular vesicles (EVs) are emerging as potent and intricate intercellular communication networks. From their first discovery almost forty years ago, several studies have bolstered our understanding of these nano-vesicular structures. EV subpopulations are now characterized by differences in size, surface markers, cargo, and biological effects. Studies have highlighted the importance of EVs in biology and intercellular communication, particularly during immune and tumor interactions. These responses can be equally mediated at the proteomic and epigenomic levels through surface markers or nucleic acid cargo signaling, respectively. Following the exponential growth of EV studies in recent years, we herein synthesize new aspects of the emerging immune–tumor EV-based intercellular communications. We also discuss the potential role of EVs in fundamental immunological processes under physiological conditions, viral infections, and tumorigenic conditions. Finally, we provide insights on the future prospects of immune–tumor EVs and suggest potential avenues for the use of EVs in diagnostics and therapeutics. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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21 pages, 1349 KiB

Open AccessReview

Cold Atmospheric Plasma Treatment for Pancreatic Cancer–The Importance of Pancreatic Stellate Cells

by Ruben Verloy, Angela Privat-Maldonado, Evelien Smits and Annemie Bogaerts

Cancers 2020, 12(10), 2782; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12102782 - 28 Sep 2020

Cited by 20 | Viewed by 4139

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with low five-year survival rates of 8% by conventional treatment methods, e.g., chemotherapy, radiotherapy, and surgery. PDAC shows high resistance towards chemo- and radiotherapy and only 15–20% of all patients can have surgery. This disease is predicted to become the third global leading cause of cancer death due to its significant rise in incidence. Therefore, the development of an alternative or combinational method is necessary to improve current approaches. Cold atmospheric plasma (CAP) treatments could offer multiple advantages to this emerging situation. The plasma-derived reactive species can induce oxidative damage and a cascade of intracellular signaling pathways, which could lead to cell death. Previous reports have shown that CAP treatment also influences cells in the tumor microenvironment, such as the pancreatic stellate cells (PSCs). These PSCs, when activated, play a crucial role in the propagation, growth and survival of PDAC tumors. However, the effect of CAP on PSCs is not yet fully understood. This review focuses on the application of CAP for PDAC treatment and the importance of PSCs in the response to treatment. Full article

(This article belongs to the Special Issue Targeting the Tumor Microenvironment)

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