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Cancers
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Targeting the Tumor Microenvironment (Volume II)
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Targeting the Tumor Microenvironment (Volume II)

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

Deadline for manuscript submissions: 30 April 2025 | Viewed by 14141

Special Issue Editors

Prof. Dr. Georgios Giamas

E-Mail Website
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
Prof. Dr. Teresa Gagliano

E-Mail Website
Guest Editor
Department of Medicine, University of Udine, 33100 Udine, Italy
Interests: protein kinase c; tumor; tgf-beta; pituitary adenoma cells; adrenocortical tumors; medullary thyroid carcinoma cells; tumor microenvironment; medullary thyroid carcinoma; fibroblast
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This collection is the second edition of the Special Issue “Targeting the Tumor Microenvironment” (https://www.mdpi.com/journal/cancers/special_issues/TME).

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 outcomes. Recently introduced cancer therapies target 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 advances 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. We invite authors to contribute cutting-edge studies to this Special Issue, entitled “Targeting the Tumor Microenvironment (Volume II)”, to further highlight the involvement of TME in cancer progression and treatment.

Prof. Dr. Georgios Giamas
Prof. 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 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

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Published Papers (9 papers)

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Research

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23 pages, 5448 KiB  
Article
Casein Kinase 2 Inhibitor, CX-4945, Induces Apoptosis and Restores Blood-Brain Barrier Homeostasis in In Vitro and In Vivo Models of Glioblastoma
by Valentina Bova, Deborah Mannino, Ayomide E. Salako, Emanuela Esposito, Alessia Filippone and Sarah A. Scuderi
Cancers 2024, 16(23), 3936; https://doi.org/10.3390/cancers16233936 - 24 Nov 2024
Viewed by 737
Abstract
Background: In oncology, casein kinase 2 (CK2), a serine/threonine kinase, has a dual action, regulating cellular processes and acting as an oncogenic promoter. Methods: This study examined the effect of CX-4945, a selective CK2 inhibitor, in a human U-87 glioblastoma (GBM) cell [...] Read more.
Background: In oncology, casein kinase 2 (CK2), a serine/threonine kinase, has a dual action, regulating cellular processes and acting as an oncogenic promoter. Methods: This study examined the effect of CX-4945, a selective CK2 inhibitor, in a human U-87 glioblastoma (GBM) cell line, treated with CX-4945 (5, 10, and 15 μM) for 24 h. Similarly, the hCMEC/D3 cell line was used to mimic the blood–brain barrier (BBB), examining the ability of CX-4945 to restore BBB homeostasis, after stimulation with lipopolysaccharide (LPS) and then treated with CX-4945 (5, 10, and 15 μM). Results: We reported that CX-4945 reduced the proliferative activity and modulated the main pathways involved in tumor progression including apoptosis. Furthermore, in confirmation of the in vitro study, performing a xenograft model, we demonstrated that CX-4945 exerted promising antiproliferative effects, also restoring the tight junctions’ expression. Conclusions: These new insights into the molecular signaling of CK2 in GBM and BBB demonstrate that CX-4945 could be a promising approach for future GBM therapy, not only in the tumor microenvironment but also at the BBB level. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))
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17 pages, 2450 KiB  
Article
TGF-β Signaling Loop in Pancreatic Ductal Adenocarcinoma Activates Fibroblasts and Increases Tumor Cell Aggressiveness
by Noemi di Miceli, Chiara Baioni, Linda Barbieri, Davide Danielli, Emiliano Sala, Lucia Salvioni, Stefania Garbujo, Miriam Colombo, Davide Prosperi, Metello Innocenti and Luisa Fiandra
Cancers 2024, 16(21), 3705; https://doi.org/10.3390/cancers16213705 - 1 Nov 2024
Viewed by 1073
Abstract
Background: The interaction between cancer cells and cancer-associated fibroblasts (CAFs) is a key determinant of the rapid progression, high invasiveness, and chemoresistance of aggressive desmoplastic cancers such as pancreatic ductal adenocarcinoma (PDAC). Tumor cells are known to reprogram fibroblasts into CAFs by secreting [...] Read more.
Background: The interaction between cancer cells and cancer-associated fibroblasts (CAFs) is a key determinant of the rapid progression, high invasiveness, and chemoresistance of aggressive desmoplastic cancers such as pancreatic ductal adenocarcinoma (PDAC). Tumor cells are known to reprogram fibroblasts into CAFs by secreting transforming growth factor beta (TGF-β), amongst other cytokines. In turn, CAFs produce soluble factors that promote tumor-cell invasiveness and chemoresistance, including TGF-β itself, which has a major role in myofibroblastic CAFs. Such a high level of complexity has hampered progress toward a clear view of the TGFβ signaling loop between stromal fibroblasts and PDAC cells. Methods: Here, we tackled this issue by using co-culture settings that allow paracrine signaling alone (transwell systems) or paracrine and contact-mediated signaling (3D spheroids). Results: We found that TGF-β is critically involved in the activation of normal human fibroblasts into alpha-smooth muscle actin (α-SMA)-positive CAFs. The TGF-β released by CAFs accounted for the enhanced proliferation and resistance to gemcitabine of PDAC cells. This was accompanied by a partial epithelial-to-mesenchymal transition in PDAC cells, with no increase in their migratory abilities. Nevertheless, 3D heterospheroids comprising PDAC cells and fibroblasts allowed monitoring the pro-invasive effects of CAFs on cancer cells, possibly due to combined paracrine and physical contact-mediated signals. Conclusions: We conclude that TGF-β is only one of the players that mediates the communication between PDAC cells and fibroblasts and controls the acquisition of aggressive phenotypes. Hence, these advanced in vitro models may be exploited to further investigate these events and to design innovative anti-PDAC therapies. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))
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20 pages, 5729 KiB  
Article
Combined PET Radiotracer Approach Reveals Insights into Stromal Cell-Induced Metabolic Changes in Pancreatic Cancer In Vitro and In Vivo
by Alina Doctor, Markus Laube, Sebastian Meister, Oliver C. Kiss, Klaus Kopka, Sandra Hauser and Jens Pietzsch
Cancers 2024, 16(19), 3393; https://doi.org/10.3390/cancers16193393 - 4 Oct 2024
Viewed by 1162
Abstract
Background/Objective Pancreatic stellate cells (PSCs) in pancreatic adenocarcinoma (PDAC) are producing extracellular matrix, which promotes the formation of a dense fibrotic microenvironment. This makes PDAC a highly heterogeneous tumor-stroma-driven entity, associated with reduced perfusion, limited oxygen supply, high interstitial fluid pressure, and limited [...] Read more.
Background/Objective Pancreatic stellate cells (PSCs) in pancreatic adenocarcinoma (PDAC) are producing extracellular matrix, which promotes the formation of a dense fibrotic microenvironment. This makes PDAC a highly heterogeneous tumor-stroma-driven entity, associated with reduced perfusion, limited oxygen supply, high interstitial fluid pressure, and limited bioavailability of therapeutic agents. Methods In this study, spheroid and tumor xenograft models of human PSCs and PanC-1 cells were characterized radiopharmacologically using a combined positron emission tomography (PET) radiotracer approach. [18F]FDG, [18F]FMISO, and [18F]FAPI-74 were employed to monitor metabolic activity, hypoxic metabolic state, and functional expression of fibroblast activation protein alpha (FAPα), a marker of activated PSCs. Results In vitro, PanC-1 and multi-cellular tumor spheroids demonstrated comparable glucose uptake and hypoxia, whereas FAPα expression was significantly higher in PSC spheroids. In vivo, glucose uptake as well as the transition to hypoxia were comparable in PanC-1 and multi-cellular xenograft models. In mice injected with PSCs, FAPα expression decreased over a period of four weeks post-injection, which was attributed to the successive death of PSCs. In contrast, FAPα expression increased in both PanC-1 and multi-cellular xenograft models over time due to invasion of mouse fibroblasts. Conclusion The presented models are suitable for subsequently characterizing stromal cell-induced metabolic changes in tumors using noninvasive molecular imaging techniques. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))
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17 pages, 7399 KiB  
Article
Lactate Oxidase Disrupts Lactate-Activated RAS and PI3K Oncogenic Signaling
by Chandler R. Keller, Steve R. Martinez, Alexys Keltz, Michelle Chen and Weimin Li
Cancers 2024, 16(16), 2817; https://doi.org/10.3390/cancers16162817 - 10 Aug 2024
Viewed by 1027
Abstract
LOX was recently shown to inhibit cancer cell proliferation and tumor growth. The mechanism of this inhibition, however, has been exclusively attributed to LOX depletion of TME lactate, a cancer cell energy source, and production of H2O2, an oxidative [...] Read more.
LOX was recently shown to inhibit cancer cell proliferation and tumor growth. The mechanism of this inhibition, however, has been exclusively attributed to LOX depletion of TME lactate, a cancer cell energy source, and production of H2O2, an oxidative stressor. We report that TME lactate triggers the assembly of the lactate receptor hydroxycarboxylic acid receptor 1 (HCAR1)-associated protein complex, which includes GRB2, SOS1, KRAS, GAB1, and PI3K, for the activation of both the RAS and the PI3K oncogenic signaling pathways in breast cancer (BCa) cells. LOX treatment decreased the levels of the proteins in the protein complex via induction of their proteasomal degradation. In addition, LOX inhibited lactate-stimulated expression of the lactate transporters MCT1 and MCT4. Our data suggest that HCAR1 activation by lactate is crucial for the assembly and function of the RAS and PI3K signaling nexus. Shutting down lactate signaling by disrupting this nexus could be detrimental to cancer cells. HCAR1 is therefore a promising target for the control of the RAS and the PI3K signaling required for BCa progression. Thus, our study provides insights into lactate signaling regulation of cancer progression and extends our understanding of LOX’s functional mechanisms that are fundamental for exploring its therapeutic potential. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))
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18 pages, 3675 KiB  
Article
A Metastatic Cancer Expression Generator (MetGen): A Generative Contrastive Learning Framework for Metastatic Cancer Generation
by Zhentao Liu, Yu-Chiao Chiu, Yidong Chen and Yufei Huang
Cancers 2024, 16(9), 1653; https://doi.org/10.3390/cancers16091653 - 25 Apr 2024
Viewed by 1309
Abstract
Despite significant advances in tumor biology and clinical therapeutics, metastasis remains the primary cause of cancer-related deaths. While RNA-seq technology has been used extensively to study metastatic cancer characteristics, challenges persist in acquiring adequate transcriptomic data. To overcome this challenge, we propose MetGen, [...] Read more.
Despite significant advances in tumor biology and clinical therapeutics, metastasis remains the primary cause of cancer-related deaths. While RNA-seq technology has been used extensively to study metastatic cancer characteristics, challenges persist in acquiring adequate transcriptomic data. To overcome this challenge, we propose MetGen, a generative contrastive learning tool based on a deep learning model. MetGen generates synthetic metastatic cancer expression profiles using primary cancer and normal tissue expression data. Our results demonstrate that MetGen generates comparable samples to actual metastatic cancer samples, and the cancer and tissue classification yields performance rates of 99.8 ± 0.2% and 95.0 ± 2.3%, respectively. A benchmark analysis suggests that the proposed model outperforms traditional generative models such as the variational autoencoder. In metastatic subtype classification, our generated samples show 97.6% predicting power compared to true metastatic samples. Additionally, we demonstrate MetGen’s interpretability using metastatic prostate cancer and metastatic breast cancer. MetGen has learned highly relevant signatures in cancer, tissue, and tumor microenvironments, such as immune responses and the metastasis process, which can potentially foster a more comprehensive understanding of metastatic cancer biology. The development of MetGen represents a significant step toward the study of metastatic cancer biology by providing a generative model that identifies candidate therapeutic targets for the treatment of metastatic cancer. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))
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16 pages, 3738 KiB  
Article
Limited Effects of Class II Transactivator-Based Immunotherapy in Murine and Human Glioblastoma
by A. Katherine Tan, Aurelie Henry, Nicolas Goffart, Sofie van Logtestijn, Vincent Bours, Elly M. Hol and Pierre A. Robe
Cancers 2024, 16(1), 193; https://doi.org/10.3390/cancers16010193 - 30 Dec 2023
Cited by 2 | Viewed by 1426
Abstract
Background: The major histocompatibility complex type II is downregulated in glioblastoma (GB) due to the silencing of the major transcriptional regulator class II transactivator (CIITA). We investigated the pro-immunogenic potential of CIITA overexpression in mouse and human GB. Methods: The intracerebral growth of [...] Read more.
Background: The major histocompatibility complex type II is downregulated in glioblastoma (GB) due to the silencing of the major transcriptional regulator class II transactivator (CIITA). We investigated the pro-immunogenic potential of CIITA overexpression in mouse and human GB. Methods: The intracerebral growth of wildtype GL261-WT cells was assessed following contralateral injection of GL261-CIITA cells or flank injections with GL261-WT or GL261-CIITA cells. Splenocytes obtained from mice implanted intracerebrally with GL261-WT, GL261-CIITA cells or phosphate buffered saline (PBS) were transferred to other mice and subsequently implanted intracerebrally with GL261-WT. Human GB cells and (syngeneic) GB-infiltrating immune cells were isolated from surgical samples and co-cultured with GB cells expressing CIITA or not, followed by RT-qPCR assessment of the expression of key immune regulators. Results: Intracerebral vaccination of GL261-CIITA significantly reduced the subsequent growth of GL261-WT cells implanted contralaterally. Vaccination with GL261-WT or -CIITA subcutaneously, however, equivalently retarded the intracerebral growth of GL261 cells. Adoptive cell transfer experiments showed a similar antitumor potential of lymphocytes harvested from mice implanted intracerebrally with GL261-WT or -CIITA. Human GB-infiltrating myeloid cells and lymphocytes were not activated when cultured with CIITA-expressing GB cells. Tumor-infiltrating NK cells remained mostly inactivated when in co-culture with GB cells, regardless of CIITA. Conclusion: these results question the therapeutic potential of CIITA-mediated immunotherapy in glioblastoma. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))
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Review

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13 pages, 866 KiB  
Review
The Crosstalk between Nerves and Cancer—A Poorly Understood Phenomenon and New Possibilities
by David Benzaquen, Yaacov R. Lawrence, Daniel Taussky, Daniel Zwahlen, Christoph Oehler and Ambroise Champion
Cancers 2024, 16(10), 1875; https://doi.org/10.3390/cancers16101875 - 15 May 2024
Cited by 1 | Viewed by 1947
Abstract
Introduction: Crosstalk occurs between nerve and cancer cells. These interactions are important for cancer homeostasis and metabolism. Nerve cells influence the tumor microenvironment (TME) and participate in metastasis through neurogenesis, neural extension, and axonogenesis. We summarized the past and current literature on the [...] Read more.
Introduction: Crosstalk occurs between nerve and cancer cells. These interactions are important for cancer homeostasis and metabolism. Nerve cells influence the tumor microenvironment (TME) and participate in metastasis through neurogenesis, neural extension, and axonogenesis. We summarized the past and current literature on the interaction between nerves and cancer, with a special focus on pancreatic ductal adenocarcinoma (PDAC), prostate cancer (PCa), and the role of the nerve growth factor (NGF) in cancer. Materials/Methods: We reviewed PubMed and Google Scholar for the relevant literature on the relationship between nerves, neurotrophins, and cancer in general and specifically for both PCa and PDAC. Results: The NGF helped sustain cancer cell proliferation and evade immune defense. It is a neuropeptide involved in neurogenic inflammation through the activation of several cells of the immune system by several proinflammatory cytokines. Both PCa and PDAC employ different strategies to evade immune defense. The prostate is richly innervated by both the sympathetic and parasympathetic nerves, which helps in both growth control and homeostasis. Newly formed autonomic nerve fibers grow into cancer cells and contribute to cancer initiation and progression through the activation of β-adrenergic and muscarinic cholinergic signaling. Surgical or chemical sympathectomy prevents the development of prostate cancer. Beta-blockers have a high therapeutic potential for cancer, although current clinical data have been contradictory. With a better understanding of the beta-receptors, one could identify specific receptors that could have an effect on prostate cancer development or act as therapeutic agents. Conclusion: The bidirectional crosstalk between the nervous system and cancer cells has emerged as a crucial regulator of cancer and its microenvironment. Denervation has been shown to be promising in vitro and in animal models. Additionally, there is a potential relationship between cancer and psychosocial biology through neurotransmitters and neurotrophins. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))
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16 pages, 1600 KiB  
Review
Decoding the Tumour Microenvironment: Molecular Players, Pathways, and Therapeutic Targets in Cancer Treatment
by Eleonora Malavasi, Manuel Adamo, Elisa Zamprogno, Viviana Vella, Georgios Giamas and Teresa Gagliano
Cancers 2024, 16(3), 626; https://doi.org/10.3390/cancers16030626 - 31 Jan 2024
Viewed by 1984
Abstract
The tumour microenvironment (TME) is a complex and constantly evolving collection of cells and extracellular components. Cancer cells and the surrounding environment influence each other through different types of processes. Characteristics of the TME include abnormal vasculature, altered extracellular matrix, cancer-associated fibroblast and [...] Read more.
The tumour microenvironment (TME) is a complex and constantly evolving collection of cells and extracellular components. Cancer cells and the surrounding environment influence each other through different types of processes. Characteristics of the TME include abnormal vasculature, altered extracellular matrix, cancer-associated fibroblast and macrophages, immune cells, and secreted factors. Within these components, several molecules and pathways are altered and take part in the support of the tumour. Epigenetic regulation, kinases, phosphatases, metabolic regulators, and hormones are some of the players that influence and contribute to shaping the tumour and the TME. All these characteristics contribute significantly to cancer progression, metastasis, and immune escape, and may be the target for new approaches for cancer treatment. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))
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29 pages, 3322 KiB  
Review
Chimeric Antigen Receptor T Cell and Chimeric Antigen Receptor NK Cell Therapy in Pediatric and Adult High-Grade Glioma—Recent Advances
by Adrian Kowalczyk, Julia Zarychta, Anna Marszołek, Joanna Zawitkowska and Monika Lejman
Cancers 2024, 16(3), 623; https://doi.org/10.3390/cancers16030623 - 31 Jan 2024
Cited by 5 | Viewed by 2583
Abstract
High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with [...] Read more.
High-grade gliomas (HGG) account for approximately 10% of central nervous system (CNS) tumors in children and 25% of CNS tumors in adults. Despite their rare occurrence, HGG are a significant clinical problem. The standard therapeutic procedure in both pediatric and adult patients with HGG is the surgical resection of the tumor combined with chemotherapy and radiotherapy. Despite intensive treatment, the 5-year overall survival in pediatric patients is below 20–30%. This rate is even lower for the most common HGG in adults (glioblastoma), at less than 5%. It is, therefore, essential to search for new therapeutic methods that can extend the survival rate. One of the therapeutic options is the use of immune cells (T lymphocytes/natural killer (NK) cells) expressing a chimeric antigen receptor (CAR). The objective of the following review is to present the latest results of preclinical and clinical studies evaluating the efficacy of CAR-T and CAR-NK cells in HGG therapy. Full article
(This article belongs to the Special Issue Targeting the Tumor Microenvironment (Volume II))
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