Special Issue "Cytokines in Cancers"

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

Deadline for manuscript submissions: closed (31 December 2020).

Special Issue Editors

Dr. Venkataswarup Tiriveedhi
E-Mail Website
Guest Editor
1. Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA
2. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
Interests: breast cancer; medicine; Healthcare; immunology; cancer; transplant; role of cytokines in the development of inflammatory injury mediated carcinogenesis
Special Issues and Collections in MDPI journals
Dr. Dayanidhi Raman
E-Mail Website
Co-Guest Editor
1. Department of Cancer Biology, College of Medicine and Life Sciences, Health Science Campus, University of Toledo, Toledo, OH 43614, USA
2. Department of Pharmacology, Vanderbilt University, Nashville, TN, USA
Interests: chemokine receptors; chemotaxis; LASP1; cap-dependent protein translation in cancer; metastasis; breast cancer; pancreatic cancer; targeted therapy; small molecule inhibitors
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

Cytokines play a critical role in various aspects and stages of cancer development and progression. Cytokines, through their interaction with specific receptors, trigger a plethora of signaling pathways within cancer cells and the tumor microenvironment. Several new therapies and clinical trials have been developed and/or designed to target cytokine-based anti-cancer therapies. Advances in the understanding of T-cells and macrophages have resulted in the development of specific cell-phenotype-modulating therapies to enhance cancer cell cytotoxicity. In this Special Issue, "Cytokines and Cancer", authors are invited to contribute original research papers or review articles that will provide critical and in-depth insights into the specific impact of cytokines on cancer cells, the signaling mechanism and molecular events leading to and mediated by cytokines in the tumor microenvironment, and the clinical application of cytokine-based therapies in the treatment of cancers.

Dr. Venkataswarup Tiriveedhi
Dr. Dayanidhi Raman
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 papers will be 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 2200 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

  • cytokines
  • chemokines
  • interleukins
  • interferons
  • cancer
  • innate immunity
  • adaptive immunity
  • immune-check point inhibitors
  • tumor microenvironment
  • transcription factors
  • cell signaling

Published Papers (6 papers)

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Research

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Article
Ex Vivo High Salt Activated Tumor-Primed CD4+T Lymphocytes Exert a Potent Anti-Cancer Response
Cancers 2021, 13(7), 1690; https://doi.org/10.3390/cancers13071690 - 02 Apr 2021
Cited by 1 | Viewed by 469
Abstract
Cell based immunotherapy is rapidly emerging as a promising cancer treatment. A modest increase in salt (sodium chloride) concentration in immune cell cultures is known to induce inflammatory phenotypic differentiation. In our current study, we analyzed the ability of salt treatment to induce [...] Read more.
Cell based immunotherapy is rapidly emerging as a promising cancer treatment. A modest increase in salt (sodium chloride) concentration in immune cell cultures is known to induce inflammatory phenotypic differentiation. In our current study, we analyzed the ability of salt treatment to induce ex vivo expansion of tumor-primed CD4 (cluster of differentiation 4)+T cells to an effector phenotype. CD4+T cells were isolated using immunomagnetic beads from draining lymph nodes and spleens from tumor bearing C57Bl/6 mice, 28 days post-injection of Py230 syngeneic breast cancer cells. CD4+T cells from non-tumor bearing mice were isolated from splenocytes of 12-week-old C57Bl/6 mice. These CD4+T cells were expanded ex vivo with five stimulation cycles, and each cycle comprised of treatment with high salt (Δ0.035 M NaCl) or equimolar mannitol controls along with anti-CD3/CD28 monoclonal antibodies for the first 3 days, followed by the addition of interleukin (IL)-2/IL-7 cytokines and heat killed Py230 for 4 days. Ex vivo high salt treatment induced a two-fold higher Th1 (T helper type 1) expansion and four-fold higher Th17 expansion compared to equimolar mannitol treatment. Importantly, the high salt expanded CD4+T cells retained tumor-specificity, as demonstrated by higher in vitro cytotoxicity against Py230 breast cancer cells and reduced in vivo syngeneic tumor growth. Metabolic studies revealed that high salt treatment enhanced the glycolytic reserve and basal mitochondrial oxidation of CD4+T cells, suggesting a role of high salt in enhanced pro-growth anabolic metabolism needed for inflammatory differentiation. Mechanistic studies demonstrated that the high salt induced switch to the effector phenotype was mediated by tonicity-dependent transcription factor, TonEBP/NFAT5. Using a transgenic murine model, we demonstrated that CD4 specific TonEBP/NFAT5 knock out (CD4cre/creNFAT5flox/flox) abrogated the induction of the effector phenotype and anti-tumor efficiency of CD4+T cells following high salt treatment. Taken together, our data suggest that high salt-mediated ex vivo expansion of tumor-primed CD4+T cells could induce effective tumor specific anti-cancer responses, which may have a novel cell-based cancer immunotherapeutic application. Full article
(This article belongs to the Special Issue Cytokines in Cancers)
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Article
Lung Cancer Cell-Derived Secretome Mediates Paraneoplastic Inflammation and Fibrosis in Kidney in Mice
Cancers 2020, 12(12), 3561; https://doi.org/10.3390/cancers12123561 - 28 Nov 2020
Viewed by 560
Abstract
Kidney failure is a possible but rare complication in lung cancer patients that may be caused by massive tumor lysis or a paraneoplastic effect. Clinical case reports have documented pathological characteristics of paraneoplastic syndrome in glomeruli, but are short of molecular details. When [...] Read more.
Kidney failure is a possible but rare complication in lung cancer patients that may be caused by massive tumor lysis or a paraneoplastic effect. Clinical case reports have documented pathological characteristics of paraneoplastic syndrome in glomeruli, but are short of molecular details. When Lewis lung carcinoma 1 (LLC1) cells were implanted in mice lungs to establish lung cancer, renal failure was frequently observed two weeks post orthotopic xenograft. The high urinary albumin-to-creatinine ratio (ACR) was diagnosed as paraneoplastic nephrotic syndrome in those lung cancer mice. Profiling the secretome of the lung cancer cells revealed that the secretory proteins were potentially nephrotoxic. The nephrotoxicity of lung cancer-derived secretory proteins was tested by examining the pathogenic effects of 1 × 106, 2 × 106, and 5 × 106 LLC1 cell xenografts on the pathogenic progression in kidneys. Severe albuminuria was present in the mice that received 5 × 106 LLC1 cells implantation, whereas 106 cell and 2 × 106 cell-implanted mice have slightly increased albuminuria. Pathological examinations revealed that the glomeruli had capillary loop collapse, tumor antigen deposition in glomeruli, and renal intratubular casts. Since IL-6 and MCP-1 are pathologic markers of glomerulopathy, their distributions were examined in the kidneys of the lung cancer mice. Moderate to severe inflammation in the kidneys was correlated with increases in the number of cells implanted in the mice, which was reflected by renal IL-6 and MCP-1 levels, and urine ACR. TGF-β signaling-engaged renal fibrosis was validated in the lung cancer mice. These results indicated that lung cancer cells could provoke inflammation and activate renal fibrosis. Full article
(This article belongs to the Special Issue Cytokines in Cancers)
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Article
Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer
Cancers 2020, 12(9), 2372; https://doi.org/10.3390/cancers12092372 - 21 Aug 2020
Cited by 3 | Viewed by 1037
Abstract
The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). [...] Read more.
The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3β, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3β, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1. Full article
(This article belongs to the Special Issue Cytokines in Cancers)
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Article
The Composition of Surgical Wound Fluids from Breast Cancer Patients is Affected by Intraoperative Radiotherapy Treatment and Depends on the Molecular Subtype of Breast Cancer
Cancers 2020, 12(1), 11; https://doi.org/10.3390/cancers12010011 - 18 Dec 2019
Cited by 2 | Viewed by 944
Abstract
Invasive oncological procedures affect the remaining tumor cells by increasing their survival, proliferation, and migration through the induction of wound healing response. The phenomena of local relapse after breast-conserving surgery (BCS) has resulted in a series of research and clinical trials with the [...] Read more.
Invasive oncological procedures affect the remaining tumor cells by increasing their survival, proliferation, and migration through the induction of wound healing response. The phenomena of local relapse after breast-conserving surgery (BCS) has resulted in a series of research and clinical trials with the aim of assessing whether localized intraoperative radiotherapy (IORT), may be beneficial in inhibiting local recurrences. Therefore, it is essential to assess the impact of intraoperative radiotherapy in modulating the immunological response and wound healing process. Thus, we decided to perform a quantitative analysis of the composition of surgical wound fluids (SWF) in two groups of breast cancer (BC) patients: those treated with BCS followed by IORT, and those who underwent BCS alone. We found that several cytokines, which are believed to have anti-tumor properties, were highly expressed in the luminal A breast cancer subtype in the IORT treatment group. Interestingly, we also found significant differences between IORT patients with tumors of different molecular subtypes. Based on these findings, we hypothesized that IORT treatment might be beneficial in changing the tumor bed microenvironment, making it less favorable for tumor recurrence due to decreased concentration of tumor-facilitating cytokines, especially in the luminal A subtype of BC. Full article
(This article belongs to the Special Issue Cytokines in Cancers)
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Review

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Review
Eotaxins and Their Receptor in Colorectal Cancer—A Literature Review
Cancers 2020, 12(6), 1383; https://doi.org/10.3390/cancers12061383 - 28 May 2020
Cited by 3 | Viewed by 729
Abstract
Colorectal cancer (CRC) is one of the most common malignancies in the world, with a global incidence of almost 2 million new cases every year. Despite the availability of many diagnostic tests, including laboratory tests and molecular diagnostics, an increasing number of new [...] Read more.
Colorectal cancer (CRC) is one of the most common malignancies in the world, with a global incidence of almost 2 million new cases every year. Despite the availability of many diagnostic tests, including laboratory tests and molecular diagnostics, an increasing number of new cases is observed. Thus, it is very important to search new markers that would show high diagnostic sensitivity and specificity in the detection of colorectal cancer in early stages of the disease. Eotaxins are proteins that belong to the cytokine group—small molecules with a variety of applications. Their main role is the activation of basophils and eosinophils involved in inflammatory processes. Therefore, we performed an extensive search of the literature pertaining to our investigation via the MEDLINE/PubMed database. On the basis of available literature, we can assume that eotaxins accumulate in cancer cells in the course of CRC. This leads to a decrease in the chemotaxis of eosinophils, which are effector immune cells with anti-tumor activity. This may explain a decrease in their number as a defense mechanism of cancer cells against their destruction and may be useful when attempting anti-tumor therapy with the use of chemokines. Full article
(This article belongs to the Special Issue Cytokines in Cancers)
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Other

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Perspective
Type I Interferons and Cancer: An Evolving Story Demanding Novel Clinical Applications
Cancers 2019, 11(12), 1943; https://doi.org/10.3390/cancers11121943 - 04 Dec 2019
Cited by 14 | Viewed by 1239
Abstract
The first report on the antitumor effects of interferon α/β (IFN-I) in mice was published 50 years ago. IFN-α were the first immunotherapeutic drugs approved by the FDA for clinical use in cancer. However, their clinical use occurred at a time when most [...] Read more.
The first report on the antitumor effects of interferon α/β (IFN-I) in mice was published 50 years ago. IFN-α were the first immunotherapeutic drugs approved by the FDA for clinical use in cancer. However, their clinical use occurred at a time when most of their mechanisms of action were still unknown. These cytokines were being used as either conventional cytostatic drugs or non-specific biological response modifiers. Specific biological activities subsequently ascribed to IFN-I were poorly considered for their clinical use. Notably, a lot of the data in humans and mice underlines the importance of endogenous IFN-I, produced by both immune and tumor cells, in the control of tumor growth and in the response to antitumor therapies. While many oncologists consider IFN-I as “dead drugs”, recent studies reveal new mechanisms of action with potential implications in cancer control and immunotherapy response or resistance, suggesting novel rationales for their usage in target and personalized anti-cancer treatments. In this Perspectives Article, we focus on the following aspects: (1) the added value of IFN-I for enhancing the antitumor impact of standard anticancer treatments (chemotherapy and radiotherapy) and new therapeutic approaches, such as check point inhibitors and epigenetic drugs; (2) the role of IFN-I in the control of cancer stem cells growth and its possible implications for the development of novel antitumor therapies; and (3) the role of IFN-I in the development of cancer vaccines and the intriguing therapeutic possibilities offered by in situ delivery of ex vivo IFN-stimulated dendritic cells. Full article
(This article belongs to the Special Issue Cytokines in Cancers)
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