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Role of Cytokines and Other Soluble Factors in Tumor Development:...
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Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 March 2023) | Viewed by 44934

Special Issue Editors

Dr. Graziana Digiacomo

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
Interests: cell culture; oncology; molecular and cell biology; signaling pathways; hepatocarcinoma; lung cancer; CDK4/6-inhibitors; macrophages; angiogenesis; cell migration and invasion; target therapy; western blot analysis; gene expression
Special Issues, Collections and Topics in MDPI journals
Dr. Andrea Cavazzoni

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
Interests: cell culture; oncology; molecular and cell biology; signaling pathways; lung cancer; angiogenesis; cell migration and invasion; immune checkpoint inhibitors; target therapy

Special Issue Information

Dear Colleagues,

The process that involves the formation of new blood vessels from the preexisting vasculature is known as angiogenesis. It occurs during both physiologic and pathologic processes, such as embryonic development and tumor progression, respectively. Physiological angiogenesis is a complex process that is regulated by a balance of pro-angiogenic and anti-angiogenic cytokines.

Tumor and stromal cells secrete high levels of pro-angiogenic factors, which can create an abnormal vasculature resulting in poorly perfused tumors. The formation of immature endothelial sprouts is promoted by angiogenic factors, including vascular endothelial growth factor (VEGF) and angiopoietins. The first described cytokine contributing to tumor angiogenesis was VEGF-A. Successively, many other cytokines have been described to regulate the process of angiogenesis in tumors.

It is known that several inflammatory mediators, such as TNF-α, IL-6, TGF-β, and IL-10, are involved in both the initiation and progression of cancer. 

Further studies to test novel approaches that target the signaling pathways regulated by both angiogenetic activators and inhibitors constitute one of the main strategies for anti-angiogenic therapies, as a single agent or coupled with other molecular approaches, such as the immune checkpoint inhibitors.

This Special Issue aims to publish original research or reviews concerning the role of cytokines and other soluble factors in cancer progression, with the aim to propose new pharmacological approaches.

Dr. Graziana Digiacomo
Dr. Andrea Cavazzoni
Guest Editors

Manuscript Submission Information

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Keywords

  • angiogenesis
  • cytokines
  • cancer
  • metastasis
  • tumor progression

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Published Papers (11 papers)

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Editorial

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4 pages, 186 KiB  
Editorial
Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies
by Andrea Cavazzoni and Graziana Digiacomo
Cells 2023, 12(21), 2532; https://doi.org/10.3390/cells12212532 - 27 Oct 2023
Cited by 4 | Viewed by 1033
Abstract
Many cytokines control tumor development by directly lowering cancer cell proliferation and inducing apoptotic cell death, or indirectly by activating the antitumoral activity of specific immune cells such as NK or CD8+ T-lymphocytes [...] Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)

Research

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21 pages, 6141 KiB  
Article
Tumor Microenvironmental Cytokines Drive NSCLC Cell Aggressiveness and Drug-Resistance via YAP-Mediated Autophagy
by Paola Matarrese, Rosa Vona, Barbara Ascione, Camilla Cittadini, Annalisa Tocci and Anna Maria Mileo
Cells 2023, 12(7), 1048; https://doi.org/10.3390/cells12071048 - 30 Mar 2023
Cited by 4 | Viewed by 2838
Abstract
Dynamic reciprocity between cellular components of the tumor microenvironment and tumor cells occurs primarily through the interaction of soluble signals, i.e., cytokines produced by stromal cells to support cancer initiation and progression by regulating cell survival, differentiation and immune cell functionality, as well [...] Read more.
Dynamic reciprocity between cellular components of the tumor microenvironment and tumor cells occurs primarily through the interaction of soluble signals, i.e., cytokines produced by stromal cells to support cancer initiation and progression by regulating cell survival, differentiation and immune cell functionality, as well as cell migration and death. In the present study, we focused on the analysis of the functional response of non-small cell lung cancer cell lines elicited by the treatment with some crucial stromal factors which, at least in part, mimic the stimulus exerted in vivo on tumor cells by microenvironmental components. Our molecular and functional results highlight the role played by the autophagic machinery in the cellular response in terms of the invasive capacity, stemness and drug resistance of two non-small lung cancer cell lines treated with stromal cytokines, also highlighting the emerging role of the YAP pathway in the mutual and dynamic crosstalk between tumor cells and tumor microenvironment elements. The results of this study provide new insights into the YAP-mediated autophagic mechanism elicited by microenvironmental cytokines on non-small cell lung cancer cell lines and may suggest new potential strategies for future cancer therapeutic interventions. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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Review

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15 pages, 2175 KiB  
Review
Exploiting an Interleukin-15 Heterodimeric Agonist (N803) for Effective Immunotherapy of Solid Malignancies
by Grace Lui, Christine M. Minnar, Patrick Soon-Shiong, Jeffrey Schlom and Sofia R. Gameiro
Cells 2023, 12(12), 1611; https://doi.org/10.3390/cells12121611 - 12 Jun 2023
Cited by 6 | Viewed by 3946
Abstract
Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune checkpoint inhibitors. Interleukin-15 (IL-15) is a promising cytokine for the treatment of cancer as it stimulates NK and CD8+ lymphocytes. However, [...] Read more.
Identifying effective immunotherapies for solid tumors remains challenging despite the significant clinical responses observed in subsets of patients treated with immune checkpoint inhibitors. Interleukin-15 (IL-15) is a promising cytokine for the treatment of cancer as it stimulates NK and CD8+ lymphocytes. However, unfavorable pharmacokinetics and safety concerns render recombinant IL-15 (rIL-15) a less attractive modality. These shortcomings were addressed by the clinical development of heterodimeric IL-15 agonists, including N803. In preclinical tumor models, N803 elicited significant Th1 immune activation and tumor suppressive effects, primarily mediated by NK and CD8+ T lymphocytes. In addition, multiple clinical studies have demonstrated N803 to be safe for the treatment of cancer patients. The combination of N803 with the immune checkpoint inhibitor nivolumab demonstrated encouraging clinical responses in nivolumab-naïve and nivolumab-refractory patients with non-small cell lung cancer. In a recent Phase II/III clinical study, most Bacillus Calmette–Guerin (BCG)-refractory bladder cancer patients treated with N803 plus BCG experienced durable complete responses. Currently, N803 is being evaluated preclinically and clinically in combination with various agents, including chemotherapeutics, immune checkpoint inhibitors, vaccines, and other immuno-oncology agents. This report will review the mechanism(s) of action of N803 and how it relates to the preclinical and clinical studies of N803. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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15 pages, 1710 KiB  
Review
Interleukin-33: Friend or Foe in Gastrointestinal Tract Cancers?
by Laura Francesca Pisani, Isabella Teani, Maurizio Vecchi and Luca Pastorelli
Cells 2023, 12(11), 1481; https://doi.org/10.3390/cells12111481 - 26 May 2023
Cited by 7 | Viewed by 2337
Abstract
Accumulating evidence suggests that Interleukin-33 (IL-33), a member of the IL-1 family, has crucial roles in tissue homeostasis and repair, type 2 immunity, inflammation, and viral infection. IL-33 is a novel contributing factor in tumorigenesis and plays a critical role in regulating angiogenesis [...] Read more.
Accumulating evidence suggests that Interleukin-33 (IL-33), a member of the IL-1 family, has crucial roles in tissue homeostasis and repair, type 2 immunity, inflammation, and viral infection. IL-33 is a novel contributing factor in tumorigenesis and plays a critical role in regulating angiogenesis and cancer progression in a variety of human cancers. The partially unraveled role of IL-33/ST2 signaling in gastrointestinal tract cancers is being investigated through the analysis of patients’ samples and by studies in murine and rat models. In this review, we discuss the basic biology and mechanisms of release of the IL-33 protein and its involvement in gastrointestinal cancer onset and progression. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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9 pages, 854 KiB  
Review
Rethinking Oncologic Treatment Strategies with Interleukin-2
by Brian Ko, Naoko Takebe, Omozusi Andrews, Monish Ram Makena and Alice P. Chen
Cells 2023, 12(9), 1316; https://doi.org/10.3390/cells12091316 - 5 May 2023
Cited by 9 | Viewed by 3840
Abstract
High-dose recombinant human IL-2 (rhIL-2, aldesleukin) emerged as an important treatment option for selected patients with metastatic melanoma and metastatic renal cell carcinoma, producing durable and long-lasting antitumor responses in a small fraction of patients and heralding the potential of cancer immunotherapy. However, [...] Read more.
High-dose recombinant human IL-2 (rhIL-2, aldesleukin) emerged as an important treatment option for selected patients with metastatic melanoma and metastatic renal cell carcinoma, producing durable and long-lasting antitumor responses in a small fraction of patients and heralding the potential of cancer immunotherapy. However, the adoption of high-dose rhIL-2 has been restricted by its severe treatment-related adverse event (TRAE) profile, which necessitates highly experienced clinical providers familiar with rhIL-2 administration and readily accessible critical care medicine support. Given the comparatively wide-ranging successes of immune checkpoint inhibitors and chimeric antigen receptor T cell therapies, there have been concerted efforts to significantly improve the efficacy and toxicities of IL-2-based immunotherapeutic approaches. In this review, we highlight novel drug development strategies, including biochemical modifications and engineered IL-2 variants, to expand the narrow therapeutic window of IL-2 by leveraging downstream activation of the IL-2 receptor to selectively expand anti-tumor CD8-positive T cells and natural killer cells. These modified IL-2 cytokines improve single-agent activity in solid tumor malignancies beyond the established United States Food and Drug Administration (FDA) indications of metastatic melanoma and renal cell carcinoma, and may also be safer in rational combinations with established treatment modalities, including anti-PD-(L)1 and anti-CTLA-4 immunotherapy, chemotherapies, and targeted therapy approaches. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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35 pages, 3227 KiB  
Review
The Cytokine Network in Colorectal Cancer: Implications for New Treatment Strategies
by Heidi Braumüller, Bernhard Mauerer, Johanna Andris, Christopher Berlin, Thomas Wieder and Rebecca Kesselring
Cells 2023, 12(1), 138; https://doi.org/10.3390/cells12010138 - 29 Dec 2022
Cited by 27 | Viewed by 5320
Abstract
Colorectal cancer (CRC) is one of the most frequent tumor entities worldwide with only limited therapeutic options. CRC is not only a genetic disease with several mutations in specific oncogenes and/or tumor suppressor genes such as APC, KRAS, PIC3CA, BRAF, SMAD4 or TP53 [...] Read more.
Colorectal cancer (CRC) is one of the most frequent tumor entities worldwide with only limited therapeutic options. CRC is not only a genetic disease with several mutations in specific oncogenes and/or tumor suppressor genes such as APC, KRAS, PIC3CA, BRAF, SMAD4 or TP53 but also a multifactorial disease including environmental factors. Cancer cells communicate with their environment mostly via soluble factors such as cytokines, chemokines or growth factors to generate a favorable tumor microenvironment (TME). The TME, a heterogeneous population of differentiated and progenitor cells, plays a critical role in regulating tumor development, growth, invasion, metastasis and therapy resistance. In this context, cytokines from cancer cells and cells of the TME influence each other, eliciting an inflammatory milieu that can either enhance or suppress tumor growth and metastasis. Additionally, several lines of evidence exist that the composition of the microbiota regulates inflammatory processes, controlled by cytokine secretion, that play a role in carcinogenesis and tumor progression. In this review, we discuss the cytokine networks between cancer cells and the TME and microbiome in colorectal cancer and the related treatment strategies, with the goal to discuss cytokine-mediated strategies that could overcome the common therapeutic resistance of CRC tumors. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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19 pages, 753 KiB  
Review
Relationship between Tumor Infiltrating Immune Cells and Tumor Metastasis and Its Prognostic Value in Cancer
by Huan-Xiang Li, Shu-Qi Wang, Zheng-Xing Lian, Shou-Long Deng and Kun Yu
Cells 2023, 12(1), 64; https://doi.org/10.3390/cells12010064 - 23 Dec 2022
Cited by 22 | Viewed by 3676
Abstract
Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME [...] Read more.
Tumor metastasis is an important reason for the difficulty of tumor treatment. Besides the tumor cells themselves, the tumor microenvironment plays an important role in the process of tumor metastasis. Tumor infiltrating immune cells (TIICs) are one of the main components of TME and plays an important role in every link of tumor metastasis. This article mainly reviews the role of tumor-infiltrating immune cells in epithelial mesenchymal transformation, extracellular matrix remodeling, tumor angiogenesis and formation of pre-metastatic niche. The value of TIICs in the prognosis of cervical cancer, lung cancer and breast cancer was also discussed. We believe that accurate prognosis of cancer treatment outcomes is conducive to further improving treatment regimens, determining personalized treatment strategies, and ultimately achieving successful cancer treatment. This paper elucidates the relationship between tumor and TIICs in order to explore the function of immune cells in different diseases and provide new ideas for the treatment of cancer. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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23 pages, 4341 KiB  
Review
The Role of IL-6 in Cancer Cell Invasiveness and Metastasis—Overview and Therapeutic Opportunities
by Magdalena Rašková, Lukáš Lacina, Zdeněk Kejík, Anna Venhauerová, Markéta Skaličková, Michal Kolář, Milan Jakubek, Daniel Rosel, Karel Smetana, Jr. and Jan Brábek
Cells 2022, 11(22), 3698; https://doi.org/10.3390/cells11223698 - 21 Nov 2022
Cited by 79 | Viewed by 7090
Abstract
Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role [...] Read more.
Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role of IL-6 signalling pathways in cancer biology, with particular emphasis on cancer cell invasiveness and metastasis formation. Targeting principal components of IL-6 signalling (e.g., IL-6Rs, gp130, STAT3, NF-κB) is an intensively studied approach in preclinical cancer research. It is of significant translational potential; numerous studies strongly imply the remarkable potential of IL-6 signalling inhibitors, especially in metastasis suppression. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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19 pages, 2008 KiB  
Review
Tumor Microenvironment Immunosuppression: A Roadblock to CAR T-Cell Advancement in Solid Tumors
by Abigail Cheever, Michelle Townsend and Kim O’Neill
Cells 2022, 11(22), 3626; https://doi.org/10.3390/cells11223626 - 16 Nov 2022
Cited by 20 | Viewed by 4426
Abstract
Chimeric antigen receptor (CAR) T cells are an exciting advancement in cancer immunotherapy, with striking success in hematological cancers. However, in solid tumors, the unique immunosuppressive elements of the tumor microenvironment (TME) contribute to the failure of CAR T cells. This review discusses [...] Read more.
Chimeric antigen receptor (CAR) T cells are an exciting advancement in cancer immunotherapy, with striking success in hematological cancers. However, in solid tumors, the unique immunosuppressive elements of the tumor microenvironment (TME) contribute to the failure of CAR T cells. This review discusses the cell populations, cytokine/chemokine profile, and metabolic immunosuppressive elements of the TME. This immunosuppressive TME causes CAR T-cell exhaustion and influences failure of CAR T cells to successfully infiltrate solid tumors. Recent advances in CAR T-cell development, which seek to overcome aspects of the TME immunosuppression, are also reviewed. Novel discoveries overcoming immunosuppressive limitations of the TME may lead to the success of CAR T cells in solid tumors. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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18 pages, 1141 KiB  
Review
Transforming Growth Factor-Beta Signaling in Cancer-Induced Cachexia: From Molecular Pathways to the Clinics
by Rita Balsano, Zita Kruize, Martina Lunardi, Annalisa Comandatore, Mara Barone, Andrea Cavazzoni, Andrea David Re Cecconi, Luca Morelli, Hanneke Wilmink, Marcello Tiseo, Ingrid Garajovà, Lia van Zuylen, Elisa Giovannetti and Rosanna Piccirillo
Cells 2022, 11(17), 2671; https://doi.org/10.3390/cells11172671 - 28 Aug 2022
Cited by 14 | Viewed by 4847
Abstract
Cachexia is a metabolic syndrome consisting of massive loss of muscle mass and function that has a severe impact on the quality of life and survival of cancer patients. Up to 20% of lung cancer patients and up to 80% of pancreatic cancer [...] Read more.
Cachexia is a metabolic syndrome consisting of massive loss of muscle mass and function that has a severe impact on the quality of life and survival of cancer patients. Up to 20% of lung cancer patients and up to 80% of pancreatic cancer patients are diagnosed with cachexia, leading to death in 20% of them. The main drivers of cachexia are cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), macrophage inhibitory cytokine 1 (MIC-1/GDF15) and transforming growth factor-beta (TGF-β). Besides its double-edged role as a tumor suppressor and activator, TGF-β causes muscle loss through myostatin-based signaling, involved in the reduction in protein synthesis and enhanced protein degradation. Additionally, TGF-β induces inhibin and activin, causing weight loss and muscle depletion, while MIC-1/GDF15, a member of the TGF-β superfamily, leads to anorexia and so, indirectly, to muscle wasting, acting on the hypothalamus center. Against this background, the blockade of TGF-β is tested as a potential mechanism to revert cachexia, and antibodies against TGF-β reduced weight and muscle loss in murine models of pancreatic cancer. This article reviews the role of the TGF-β pathway and to a minor extent of other molecules including microRNA in cancer onset and progression with a special focus on their involvement in cachexia, to enlighten whether TGF-β and such other players could be potential targets for therapy. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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Other

37 pages, 851 KiB  
Systematic Review
The Role of Cytokines in Epithelial–Mesenchymal Transition in Gynaecological Cancers: A Systematic Review
by Irene Ray, Agnieszka Michael, Lisiane B. Meira and Patricia E. Ellis
Cells 2023, 12(3), 416; https://doi.org/10.3390/cells12030416 - 26 Jan 2023
Cited by 18 | Viewed by 3559
Abstract
Chronic inflammation has been closely linked to the development and progression of various cancers. The epithelial–mesenchymal transition (EMT) is a process involving the acquisition of mesenchymal features by carcinoma cells and is an important link between inflammation and cancer development. Inflammatory mediators in [...] Read more.
Chronic inflammation has been closely linked to the development and progression of various cancers. The epithelial–mesenchymal transition (EMT) is a process involving the acquisition of mesenchymal features by carcinoma cells and is an important link between inflammation and cancer development. Inflammatory mediators in the tumour micro-environment, such as cytokines and chemokines, can promote EMT changes in cancer cells. The aim of this systematic review is to analyse the effect of cytokines on EMT in gynaecological cancers and discuss their possible therapeutic implications. A search of the databases CINAHL, Cochrane, Embase, Medline, PubMed, TRIP, and Web of Science was performed using the keywords: “cytokines” AND “epithelial mesenchymal transition OR transformation” AND “gynaecological cancer”. Seventy-one articles reported that various cytokines, such as TGF-β, TNF-α, IL-6, etc., promoted EMT changes in ovarian, cervical, and endometrial cancers. The EMT changes included from epithelial to mesenchymal morphological change, downregulation of the epithelial markers E-cadherin/β-catenin, upregulation of the mesenchymal markers N-cadherin/vimentin/fibronectin, and upregulation of the EMT-transformation factors (EMT-TF) SNAI1/SNAI2/TWIST/ZEB. Cytokine-induced EMT can lead to gynaecological cancer development and metastasis and hence novel therapies targeting the cytokines or their EMT signalling pathways could possibly prevent cancer progression, reduce cancer recurrence, and prevent drug-resistance. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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