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Tumor Necrosis Factor: Molecular Insights and Clinical Implications

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 20210

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Special Issue Editor

Dr. Lorraine A. O'Reilly

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Guest Editor

The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia
Interests: inflammation-associated cancers; relationship between cytokines, the JAK/STAT and NF-kB signaling pathways in upper gastrointestinal cancers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Tumour necrosis factor-alpha (TNF/TNFa) as the foremost pro-inflammatory cytokine is a pivotal regulator of conventional innate and adaptive immune responses, with diverse functions in cellular processes such as differentiation, proliferation, inflammation, apoptosis and necroptosis. Since its discovery nearly 40 years ago, the TNF superfamily has grown to 19 members, with 29 interacting receptors and multiple scaffolding proteins. Binding of TNF to either TNFR1 or TNFR2 mediates the activation of tightly regulated and complex downstream signalling cascades, resulting in cell death or activation of the transcription factors NF-kB (Nuclear Factor-KappaB) and AP-1 (Activation Protein-1). Dysregulation of these signalling pathways are associated with a multitude of inflammatory conditions and increased risk for several cancers, although the exact role TNF plays in cancer is contradictory and much debated. TNF biologics, while established therapeutically for inflammatory/autoimmune diseases, have been disappointing for cancer therapy.

In this Special Issue we would like to comprehensively address the role of the molecular complexities of TNF signalling, particularly in relation to inflammation as a cancer driver. To additionally address these concepts, we welcome original publications or reviews on recent insights into the control of TNF superfamily activity and its manipulation to curtail cancer development. Finally, we would like to highlight and discuss the success and challenges of newer therapeutic approaches aimed at manipulating TNF signalling for cancer therapy. Such therapies are not limited to IAP inhibitors, antagonistic TNFR2 antibodies and various combinative approaches with immunotherapies or therapy related to TNF or other members of the TNF superfamily to improve clinical outcomes.

We therefore invite colleagues to submit their contributions in the topic to this Special Issue.

I look forward to receiving your contributions.

Dr. Lorraine A. O'Reilly
Guest Editor

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

TNF
cancer
cell death
inflammation
clinical
therapy
immunotherapy

Published Papers (7 papers)

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Research

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20 pages, 6704 KiB

Open AccessArticle

The Impact of TRAIL on the Immunological Milieu during the Early Stage of Abdominal Sepsis

by Ann-Kathrin Berg, Elisabeth M. Hahn, Fiona Speichinger-Hillenberg, Annemaria Silvana Grube, Nina A. Hering, Ani K. Stoyanova and Katharina Beyer

Cancers 2023, 15(6), 1773; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061773 - 15 Mar 2023

Viewed by 1209

Abstract

Despite intensive scientific efforts, the therapy of peritonitis is presently limited to symptomatic measures, including infectious source control and broad-spectrum antibiotics. Promising therapeutic approaches to reduce morbidity and mortality are still missing. Within the early phase of abdominal sepsis, apoptosis of neutrophil granulocytes is inhibited, which is linked to tissue damage and septic shock. TNF-related apoptosis-inducing ligand (TRAIL) is a promising agent to stimulate neutrophil apoptosis. However, the underlying mechanisms have not been elucidated so far. The objective of the present study was to characterize the molecular mechanisms of TRAIL-stimulated apoptosis in early abdominal sepsis. Therefore, the murine sepsis model Colon ascendens stent peritonitis (CASP) was applied in wild type (WT) and TRAIL knock-out (TRAIL–/–) C57/BL6j mice. Neutrophil granulocytes were isolated from spleen, blood, bone marrow, and peritoneal lavage using magnetic-activated cell sorting. Neutrophil maturation was analyzed by light microscopy, and apoptotic neutrophils were quantified by fluorescence-activated cell sorting (FACS). Western blot and FACS were used to investigate expression changes in apoptotic proteins and TRAIL receptors. The impact of TRAIL-induced apoptosis was studied in vitro. In septic mice (CASP 6 h), the number of neutrophils in the BM was reduced but increased in the blood and peritoneal lavage. This was paralleled by an increased maturation of neutrophils from rod-shaped to segmented neutrophils (right shift). In vitro, extrinsic TRAIL stimulation did not alter the apoptosis level of naïve neutrophils but stimulated apoptosis in neutrophils derived from septic WT and TRAIL–/– mice. Neutrophils of the bone marrow and spleen showed enhanced protein expression of anti-apoptotic Flip, c-IAP1, and McL-1 and reduced expression levels of pro-apoptotic Bax in neutrophils, which might correlate with apoptosis inhibition in these cells. CASP increased the expression of intrinsic TRAIL in neutrophils derived from the bone marrow and spleen. This might be explained by an increased expression of the TRAIL receptors DR5, DcR1, and DcR2 on neutrophils in sepsis. No differences were observed between septic or naïve WT and TRAIL–/– mice. In conclusion, the present study shows that neutrophil granulocytes are sensitive to TRAIL-stimulated apoptosis in the early stage of abdominal sepsis, emphasizing the promising role of TRAIL as a therapeutic agent. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor: Molecular Insights and Clinical Implications)

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18 pages, 6837 KiB

Open AccessArticle

Immune Phenotypic Characterization of a TRAIL-Knockout Mouse

by Ani K. Stoyanova, Arne Sattler, Elisabeth M. Hahn, Nina A. Hering, Marco Arndt, Johannes Christian Lauscher, Fiona Speichinger-Hillenberg, Katja Kotsch, Ann-Kathrin Berg and Katharina Beyer

Cancers 2023, 15(5), 1475; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051475 - 25 Feb 2023

Cited by 1 | Viewed by 1748

Abstract

The TNF-superfamily member TRAIL is known to mediate selective apoptosis in tumor cells suggesting this protein as a potential antitumor drug target. However, initial successful pr-clinical results could not be translated into the clinic. Reasons for the ineffectiveness of TRAIL-targeting in tumor therapies could include acquired TRAIL resistance. A tumor cell acquires TRAIL resistance, for example, by upregulation of antiapoptotic proteins. In addition, TRAIL can also influence the immune system and thus, tumor growth. We were able to show in our previous work that TRAIL^−/− mice show improved survival in a mouse model of pancreatic carcinoma. Therefore, in this study we aimed to immunologically characterize the TRAIL^−/− mice. We observed no significant differences in the distribution of CD3⁺, CD4⁺, CD8⁺ T-cells, Tregs, and central memory CD4⁺ and CD8⁺ cells. However, we provide evidence for relevant differences in the distribution of effector memory T-cells and CD8⁺CD122⁺ cells but also in dendritic cells. Our findings suggest that T-lymphocytes of TRAIL^−/− mice proliferate at a lower rate, and that the administration of recombinant TRAIL significantly increases their proliferation, while regulatory T-cells (Tregs) from TRAIL^−/− mice are less suppressive. Regarding the dendritic cells, we found more type-2 conventional dendritic cells (DC2s) in the TRAIL^−/− mice. For the first time (to the best of our knowledge), we provide a comprehensive characterization of the immunological landscape of TRAIL-deficient mice. This will establish an experimental basis for future investigations of TRAIL-mediated immunology. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor: Molecular Insights and Clinical Implications)

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Review

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18 pages, 1603 KiB

Open AccessReview

Tumor Necrosis Factor-Alpha and Adiponectin in Nonalcoholic Fatty Liver Disease-Associated Hepatocellular Carcinoma

by Ilias D. Vachliotis, Ioannis Valsamidis and Stergios A. Polyzos

Cancers 2023, 15(21), 5306; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15215306 - 06 Nov 2023

Cited by 3 | Viewed by 1294

Abstract

Nonalcoholic fatty liver disease (NAFLD) is emerging as an important risk factor for hepatocellular carcinoma (HCC), whose prevalence is rising. Although the mechanisms of progression from NAFLD to HCC are not fully elucidated, tumor necrosis factor-α (TNF-α) and adiponectin, as well as their interplay, which seems to be antagonistic, may contribute to the pathophysiology of NAFLD-associated HCC. TNF-α initially aims to protect against hepatocarcinogenesis, but during the progression of NAFLD, TNF-α is increased, thus probably inducing hepatocarcinogenesis in the long-term, when NAFLD is not resolved. On the other hand, adiponectin, which is expected to exert anti-tumorigenic effects, is decreased during the progression of the disease, a trend that may favor hepatocarcinogenesis, but is paradoxically increased at end stage disease, i.e., cirrhosis and HCC. These observations render TNF-α and adiponectin as potentially diagnostic biomarkers and appealing therapeutic targets in the setting of NAFLD-associated HCC, possibly in combination with systematic therapy. In this regard, combination strategy, including immune checkpoint inhibitors (ICIs) with anti-TNF biologics and/or adiponectin analogs or medications that increase endogenous adiponectin, may warrant investigation against NAFLD-associated HCC. This review aims to summarize evidence on the association between TNF-α and adiponectin with NAFLD-associated HCC, based on experimental and clinical studies, and to discuss relevant potential therapeutic considerations. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor: Molecular Insights and Clinical Implications)

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17 pages, 1354 KiB

Open AccessReview

Tumour Necrosis Factor Alpha (TNF-α) and Oral Squamous Cell Carcinoma

by Gary Brierly, Antonio Celentano, Omar Breik, Elham Moslemivayeghan, Romeo Patini, Michael McCullough and Tami Yap

Cancers 2023, 15(6), 1841; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061841 - 19 Mar 2023

Cited by 6 | Viewed by 2964

Abstract

Uncovering the inflammatory mechanisms underpinning initiation, progression, and promotion of oral squamous cell carcinoma (OSCC) development is fundamental to the rational pursuit of targeted therapeutics. Here we present a review of the current knowledge of the role of TNF-α in the aetiology, pathogenesis, and potential therapies with regards to OSCC. TNF-α is worthy of particular attention in OSCC, with its presence demonstrated to enhance cell proliferation and its downregulation demonstrated to inhibit proliferation and migration in other carcinomas in both in vitro and in vivo models and oral cancer patients. Increased TNF-α in the OSCC tumour microenvironment has been demonstrated to favour invasion through promotion of firstly the pro-inflammatory, pro-invasive phenotypes of OSCC cells and secondly its paracrine mechanism mediating recruitment and activation of inflammatory cells. Polymorphisms affecting the gene expression of TNF-α have been strongly associated with an increased risk for oral squamous cell carcinoma. A number of studies have considered TNF-α within biofluids, including saliva and serum, as a potential biomarker for the early detection of OSCC, as well as its staging, differentiation, and prognosis. The broad and multifaceted role that TNF-α plays in many inflammatory states presents an obvious confounder, particularly with demonstrated increased TNF-α levels in common oral disease states. Lastly, biologic agents targeting TNF-α are currently in clinical use for immune-mediated inflammatory rheumatological and gastrointestinal diseases. There is the potential that these biological agents might have an adjunctive role in OSCC prevention and treatment. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor: Molecular Insights and Clinical Implications)

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32 pages, 1797 KiB

Open AccessReview

The BAFF-APRIL System in Cancer

by Md Ashik Ullah and Fabienne Mackay

Cancers 2023, 15(6), 1791; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061791 - 16 Mar 2023

Cited by 9 | Viewed by 4844

Abstract

B cell-activating factor (BAFF; also known as CD257, TNFSF13B, BLyS) and a proliferation-inducing ligand (APRIL; also known as CD256, TNFSF13) belong to the tumor necrosis factor (TNF) family. BAFF was initially discovered as a B-cell survival factor, whereas APRIL was first identified as a protein highly expressed in various cancers. These discoveries were followed by over two decades of extensive research effort, which identified overlapping signaling cascades between BAFF and APRIL, controlling immune homeostasis in health and driving pathogenesis in autoimmunity and cancer, the latter being the focus of this review. High levels of BAFF, APRIL, and their receptors have been detected in different cancers and found to be associated with disease severity and treatment response. Here, we have summarized the role of the BAFF-APRIL system in immune cell differentiation and immune tolerance and detailed its pathogenic functions in hematological and solid cancers. We also highlight the emerging therapeutics targeting the BAFF-APRIL system in different cancer types. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor: Molecular Insights and Clinical Implications)

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27 pages, 1170 KiB

Open AccessReview

Tumor Necrosis Factor Alpha: Implications of Anesthesia on Cancers

by Wei-Cheng Tseng, Hou-Chuan Lai, Yi-Hsuan Huang, Shun-Ming Chan and Zhi-Fu Wu

Cancers 2023, 15(3), 739; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030739 - 25 Jan 2023

Cited by 1 | Viewed by 1899

Abstract

Cancer remains a major public health issue and a leading cause of death worldwide. Despite advancements in chemotherapy, radiation therapy, and immunotherapy, surgery is the mainstay of cancer treatment for solid tumors. However, tumor cells are known to disseminate into the vascular and lymphatic systems during surgical manipulation. Additionally, surgery-induced stress responses can produce an immunosuppressive environment that is favorable for cancer relapse. Up to 90% of cancer-related deaths are the result of metastatic disease after surgical resection. Emerging evidence shows that the interactions between tumor cells and the tumor microenvironment (TME) not only play decisive roles in tumor initiation, progression, and metastasis but also have profound effects on therapeutic efficacy. Tumor necrosis factor alpha (TNF-α), a pleiotropic cytokine contributing to both physiological and pathological processes, is one of the main mediators of inflammation-associated carcinogenesis in the TME. Because TNF-α signaling may modulate the course of cancer, it can be therapeutically targeted to ameliorate clinical outcomes. As the incidence of cancer continues to grow, approximately 80% of cancer patients require anesthesia during cancer care for diagnostic, therapeutic, or palliative procedures, and over 60% of cancer patients receive anesthesia for primary surgical resection. Numerous studies have demonstrated that perioperative management, including surgical manipulation, anesthetics/analgesics, and other supportive care, may alter the TME and cancer progression by affecting inflammatory or immune responses during cancer surgery, but the literature about the impact of anesthesia on the TNF-α production and cancer progression is limited. Therefore, this review summarizes the current knowledge of the implications of anesthesia on cancers from the insights of TNF-α release and provides future anesthetic strategies for improving oncological survival. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor: Molecular Insights and Clinical Implications)

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22 pages, 1232 KiB

Open AccessReview

Tumor Necrosis Factor Receptor 2 (TNFR2): An Emerging Target in Cancer Therapy

by Juliane Medler, Kirstin Kucka and Harald Wajant

Cancers 2022, 14(11), 2603; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14112603 - 25 May 2022

Cited by 9 | Viewed by 5407

Abstract

Despite the great success of TNF blockers in the treatment of autoimmune diseases and the identification of TNF as a factor that influences the development of tumors in many ways, the role of TNFR2 in tumor biology and its potential suitability as a therapeutic target in cancer therapy have long been underestimated. This has been fundamentally changed with the identification of TNFR2 as a regulatory T-cell (Treg)-stimulating factor and the general clinical breakthrough of immunotherapeutic approaches. However, considering TNFR2 as a sole immunosuppressive factor in the tumor microenvironment does not go far enough. TNFR2 can also co-stimulate CD8⁺ T-cells, sensitize some immune and tumor cells to the cytotoxic effects of TNFR1 and/or acts as an oncogene. In view of the wide range of cancer-associated TNFR2 activities, it is not surprising that both antagonists and agonists of TNFR2 are considered for tumor therapy and have indeed shown overwhelming anti-tumor activity in preclinical studies. Based on a brief summary of TNFR2 signaling and the immunoregulatory functions of TNFR2, we discuss here the main preclinical findings and insights gained with TNFR2 agonists and antagonists. In particular, we address the question of which TNFR2-associated molecular and cellular mechanisms underlie the observed anti-tumoral activities of TNFR2 agonists and antagonists. Full article

(This article belongs to the Special Issue Tumor Necrosis Factor: Molecular Insights and Clinical Implications)

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