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19 pages, 1028 KiB

Open AccessArticle

TNFRSF1A Gene Polymorphism (−610 T > G, rs4149570) as a Predictor of Malnutrition and a Prognostic Factor in Patients Subjected to Intensity-Modulated Radiation Therapy Due to Head and Neck Cancer

by Iwona Homa-Mlak, Radosław Mlak, Marcin Mazurek, Anna Brzozowska, Tomasz Powrózek, Mansur Rahnama-Hezavah and Teresa Małecka-Massalska

Cancers 2022, 14(14), 3407; https://doi.org/10.3390/cancers14143407 - 13 Jul 2022

Cited by 4 | Viewed by 1410

Abstract

Background: Malnutrition is a nutritional disorder observed in 52% of patients with head and neck cancer (HNC). Malnutrition is frequently related to the increased level of proinflammatory cytokines. In turn, ongoing inflammation is associated with increased catabolism of skeletal muscle and lipolysis. [...] Read more.

Background: Malnutrition is a nutritional disorder observed in 52% of patients with head and neck cancer (HNC). Malnutrition is frequently related to the increased level of proinflammatory cytokines. In turn, ongoing inflammation is associated with increased catabolism of skeletal muscle and lipolysis. Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine that plays a pivotal role in the development of malnutrition and cachexia in cancer patients. The aim of the study was to assess the relationship between a functional single-nucleotide polymorphism (SNP) −610 T > G (rs4149570) of the TNFRSF1A gene and the occurrence of nutritional disorders in patients subjected to RT due to HNC. Methods: The study group consisted of 77 patients with HNC treated at the Oncology Department of the Medical University in Lublin. Genotyping of the TNFRSF1A gene was performed using capillary electrophoresis (Genetic Analyzer 3500). Results: Multivariable analysis revealed that the TT genotype of the TNFRSF1A gene (−610 T > G) was an independent predictor of severe malnutrition (odds ratio—OR = 5.05; p = 0.0350). Moreover, the TT genotype of this gene was independently related to a higher risk of critical weight loss (CWL) (OR = 24.85; p = 0.0009). Conclusions: SNP (−610 T > G) of the TNFRSF1A may be a useful marker in the assessment of the risk of nutritional deficiencies in HNC patients treated with intensity-modulated radiotherapy (IMRT). Full article

(This article belongs to the Special Issue Inflammatory Cytokines and Chemokines in Cancer: Regulation, Function and Translational Significance)

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12 pages, 584 KiB

Open AccessArticle

Lymphoma-Associated Biomarkers Are Increased in Current Smokers in Twin Pairs Discordant for Smoking

by Jun Wang, David V. Conti, Marta Epeldegui, Miina Ollikainen, Rachel F. Tyndale, Amie Eunah Hwang, Larry Magpantay, Thomas McCulloch Mack, Otoniel Martinez-Maza, Jaakko Kaprio and Wendy Cozen

Cancers 2021, 13(21), 5395; https://doi.org/10.3390/cancers13215395 - 27 Oct 2021

Cited by 2 | Viewed by 1960

Abstract

Smoking is associated with a moderate increased risk of Hodgkin and follicular lymphoma. To understand why, we examined lymphoma-related biomarker levels among 134 smoking and non-smoking twins (67 pairs) ascertained from the Finnish Twin Cohort. Previously collected frozen serum samples were tested for [...] Read more.

Smoking is associated with a moderate increased risk of Hodgkin and follicular lymphoma. To understand why, we examined lymphoma-related biomarker levels among 134 smoking and non-smoking twins (67 pairs) ascertained from the Finnish Twin Cohort. Previously collected frozen serum samples were tested for cotinine to validate self-reported smoking history. In total, 27 immune biomarkers were assayed using the Luminex Multiplex platform (R & D Systems). Current and non-current smokers were defined by a serum cotinine concentration of >3.08 ng/mL and ≤3.08 ng/mL, respectively. Associations between biomarkers and smoking were assessed using linear mixed models to estimate beta coefficients and standard errors, adjusting for age, sex and twin pair as a random effect. There were 55 never smokers, 43 current smokers and 36 former smokers. CCL17/TARC, sgp130, haptoglobin, B-cell activating factor (BAFF) and monocyte chemoattractant protein-1 (MCP1) were significantly (p < 0.05) associated with current smoking and correlated with increasing cotinine concentrations (P_trend < 0.05). The strongest association was observed for CCL17/TARC (P_trend = 0.0001). Immune biomarker levels were similar in former and never smokers. Current smoking is associated with increased levels of lymphoma-associated biomarkers, suggesting a possible mechanism for the link between smoking and risk of these two B-cell lymphomas. Full article

(This article belongs to the Special Issue Inflammatory Cytokines and Chemokines in Cancer: Regulation, Function and Translational Significance)

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15 pages, 3024 KiB

Open AccessArticle

Resistin Induces LIN28A-Mediated Let-7a Repression in Breast Cancer Cells Leading to IL-6 and STAT3 Upregulation

by Sachin Kumar Deshmukh, Sanjeev Kumar Srivastava, Haseeb Zubair, Mohammad Aslam Khan, Ajay Pratap Singh and Seema Singh

Cancers 2021, 13(18), 4498; https://doi.org/10.3390/cancers13184498 - 07 Sep 2021

Cited by 5 | Viewed by 2191

Abstract

Downregulation of the Let-7 family of microRNAs (miRNAs) has been reported in several cancers, including breast malignancy; however, underlying mechanisms are not completely understood. Resistin is an important component of the tumor microenvironment, having a functional impact on the tumor cell phenotypes. Here, [...] Read more.

Downregulation of the Let-7 family of microRNAs (miRNAs) has been reported in several cancers, including breast malignancy; however, underlying mechanisms are not completely understood. Resistin is an important component of the tumor microenvironment, having a functional impact on the tumor cell phenotypes. Here, we examined the role of resistin in the regulation of Let-7 miRNAs and studied its downstream consequences. We found that resistin treatment led to the reduced expression of Let-7 family miRNAs in breast cancer (BC) cells, with the highest downregulation reported for Let-7a. Furthermore, resistin induced the expression of LIN28A, and its silencing abrogated resistin-mediated Let-7a suppression. Let-7a restoration or LIN28A silencing abolished the resistin-induced growth, clonogenicity, and sphere-forming ability of BC cells. Restoration of Let-7a also suppressed the resistin-induced expression of genes associated with growth, survival, and stemness. Pathway analysis suggested STAT3 as a putative central node associated with Let-7a-mediated gene regulation. In silico analysis identified STAT3 and its upstream modifier, IL-6, as putative Let-7a gene targets, which were later confirmed by 3′UTR-reporter assays. Together, our findings demonstrate a novel resistin/LIN28A/Let-7a/IL-6/STAT3 signaling axis supporting the growth and stemness of BC cells. Full article

(This article belongs to the Special Issue Inflammatory Cytokines and Chemokines in Cancer: Regulation, Function and Translational Significance)

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12 pages, 3305 KiB

Open AccessArticle

CXCR6-CXCL16 Axis Promotes Breast Cancer by Inducing Oncogenic Signaling

by Hina Mir, Neeraj Kapur, Dominique N. Gales, Praveen K. Sharma, Gabriela Oprea-Ilies, Anita T. Johnson, Rajesh Singh and Shailesh Singh

Cancers 2021, 13(14), 3568; https://doi.org/10.3390/cancers13143568 - 16 Jul 2021

Cited by 6 | Viewed by 2720

Abstract

Precise mechanisms underlying breast cancer (BrCa) metastasis are undefined, which becomes a challenge for effective treatments. Chemokine signaling instigates the trafficking of cancer cells in addition to leukocytes. This study aimed to ascertain the clinical and biological significance of the CXCR6/CXCL16 signaling axis [...] Read more.

Precise mechanisms underlying breast cancer (BrCa) metastasis are undefined, which becomes a challenge for effective treatments. Chemokine signaling instigates the trafficking of cancer cells in addition to leukocytes. This study aimed to ascertain the clinical and biological significance of the CXCR6/CXCL16 signaling axis in the pathobiology of BrCa. Our data show a higher expression of CXCR6 in BrCa cell lines and tissues. Stage-III BrCa tissues express significantly higher CXCR6 compared to stage-II tissues. The ligand, CXCL16, could remain tethered to the cell surface, and, after proteolytic shedding of the ectodomain, the N-terminal fragment is released, converting it to its oncogenic, soluble form. Like CXCR6, N-terminal CXCL16 and ADAM-10 were significantly higher in stage-III than stage-II, but no significant difference was observed in the C-terminal fragment of CXCL16. Further, stimulation of the CXCR6/CXCL16 axis activated Src, FAK, ERK1/2, and PI3K signaling pathways, as per antibody microarray analysis, which also underlie CXCL16-induced F-actin polymerization. The CXCR6/CXCL16 axis induces cytoskeleton rearrangement facilitating migration and invasion and supports BrCa cell survival by activating the PI3K/Akt pathway. This study highlights the significance of the CXCR6/CXCL16 axis and ADAM10 as potential therapeutic targets for advanced-stage BrCa. Full article

(This article belongs to the Special Issue Inflammatory Cytokines and Chemokines in Cancer: Regulation, Function and Translational Significance)

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Review

Jump to: Research

18 pages, 360 KiB

Open AccessReview

The Role of Immune Modulatory Cytokines in the Tumor Microenvironments of Head and Neck Squamous Cell Carcinomas

by Nobuo Kondoh and Masako Mizuno-Kamiya

Cancers 2022, 14(12), 2884; https://doi.org/10.3390/cancers14122884 - 11 Jun 2022

Cited by 21 | Viewed by 2376

Abstract

HNSCCs are the major progressive malignancy of the upper digestive and respiratory organs. Malignant phenotypes of HNSCCs are regulated by the pro- and anti-tumoral activities of the immune modulatory cytokines associated with TMEs, i.e., a representative pro-inflammatory cytokine, interferon (IFN)-γ, plays a role [...] Read more.

HNSCCs are the major progressive malignancy of the upper digestive and respiratory organs. Malignant phenotypes of HNSCCs are regulated by the pro- and anti-tumoral activities of the immune modulatory cytokines associated with TMEs, i.e., a representative pro-inflammatory cytokine, interferon (IFN)-γ, plays a role as an anti-tumor regulator against HNSCCs; however, IFN-γ also drives programmed death-ligand (PD-L) 1 expression to promote cancer stem cells. Interleukin (IL)-2 promotes the cytotoxic activity of T cells and natural killer cells; however, endogenous IL-2 can promote regulatory T cells (Tregs), resulting in the protection of HNSCCs. In this report, we first classified and mentioned the immune modulatory aspects of pro-inflammatory cytokines, pro-/anti-inflammatory cytokines, and anti-inflammatory cytokines upon HNSCC phenotypes. In the TME of HNSCCs, pro-tumoral immune modulation is mediated by stromal cells, including CAFs, MDSCs, pDCs, and TAMs. Therefore, we evaluated the functions of cytokines and chemokines that mediate the crosstalk between tumor cells and stromal cells. In HNSCCs, the status of lymph node metastasis is an important hallmark of a worse prognosis. We therefore evaluated the possibility of chemokines mediating lymph node metastases in HNSCC patients. We also mention therapeutic approaches using anti-tumoral cytokines or immunotherapies that target cytokines, chemokines, or signal molecules essential for the immune evasion of HNSCCs. We finally discuss modulation by HPV infection upon HNSCC phenotypes, as well as the prognostic significance of serum cytokine levels in HNSCC patients. Full article

(This article belongs to the Special Issue Inflammatory Cytokines and Chemokines in Cancer: Regulation, Function and Translational Significance)

20 pages, 2934 KiB

Open AccessEditor’s ChoiceReview

Role of Cytokines and Chemokines in Angiogenesis in a Tumor Context

by Mannon GEINDREAU, Mélanie BRUCHARD and Frédérique VEGRAN

Cancers 2022, 14(10), 2446; https://doi.org/10.3390/cancers14102446 - 16 May 2022

Cited by 34 | Viewed by 3431

Abstract

During carcinogenesis, tumors set various mechanisms to help support their development. Angiogenesis is a crucial process for cancer development as it drives the creation of blood vessels within the tumor. These newly formed blood vessels insure the supply of oxygen and nutrients to [...] Read more.

During carcinogenesis, tumors set various mechanisms to help support their development. Angiogenesis is a crucial process for cancer development as it drives the creation of blood vessels within the tumor. These newly formed blood vessels insure the supply of oxygen and nutrients to the tumor, helping its growth. The main factors that regulate angiogenesis are the five members of the vascular endothelial growth factor (VEGF) family. Angiogenesis is a hallmark of cancer and has been the target of new therapies this past few years. However, angiogenesis is a complex phenomenon with many redundancy pathways that ensure its maintenance. In this review, we will first describe the consecutive steps forming angiogenesis, as well as its classical regulators. We will then discuss how the cytokines and chemokines present in the tumor microenvironment can induce or block angiogenesis. Finally, we will focus on the therapeutic arsenal targeting angiogenesis in cancer and the challenges they have to overcome. Full article

(This article belongs to the Special Issue Inflammatory Cytokines and Chemokines in Cancer: Regulation, Function and Translational Significance)

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17 pages, 1971 KiB

Open AccessReview

Cytokines: Can Cancer Get the Message?

by Rachel M. Morris, Toni O. Mortimer and Kim L. O’Neill

Cancers 2022, 14(9), 2178; https://doi.org/10.3390/cancers14092178 - 27 Apr 2022

Cited by 24 | Viewed by 4729

Abstract

Cytokines are small molecular messengers that have profound effects on cancer development. Increasing evidence shows that cytokines are heavily involved in regulating both pro- and antitumor activities, such as immune activation and suppression, inflammation, cell damage, angiogenesis, cancer stem-cell-like cell maintenance, invasion, and [...] Read more.

Cytokines are small molecular messengers that have profound effects on cancer development. Increasing evidence shows that cytokines are heavily involved in regulating both pro- and antitumor activities, such as immune activation and suppression, inflammation, cell damage, angiogenesis, cancer stem-cell-like cell maintenance, invasion, and metastasis. Cytokines are often required to drive these cancer-related processes and, therefore, represent an important research area for understanding cancer development and the potential identification of novel therapeutic targets. Interestingly, some cytokines are reported to be related to both pro- and anti-tumorigenicity, indicating that cytokines may play several complex roles relating to cancer pathogenesis. In this review, we discuss some major cancer-related processes and their relationship with several cytokines. Full article

(This article belongs to the Special Issue Inflammatory Cytokines and Chemokines in Cancer: Regulation, Function and Translational Significance)

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20 pages, 1003 KiB

Open AccessReview

Bone Metastatic Breast Cancer: Advances in Cell Signaling and Autophagy Related Mechanisms

by Ahmad Othman, Marcus Winogradzki, Linus Lee, Manish Tandon, Alan Blank and Jitesh Pratap

Cancers 2021, 13(17), 4310; https://doi.org/10.3390/cancers13174310 - 26 Aug 2021

Cited by 12 | Viewed by 3426

Abstract

Bone metastasis is a frequent complication of breast cancer with nearly 70% of metastatic breast cancer patients developing bone metastasis during the course of their disease. The bone represents a dynamic microenvironment which provides a fertile soil for disseminated tumor cells, however, the [...] Read more.

Bone metastasis is a frequent complication of breast cancer with nearly 70% of metastatic breast cancer patients developing bone metastasis during the course of their disease. The bone represents a dynamic microenvironment which provides a fertile soil for disseminated tumor cells, however, the mechanisms which regulate the interactions between a metastatic tumor and the bone microenvironment remain poorly understood. Recent studies indicate that during the metastatic process a bidirectional relationship between metastatic tumor cells and the bone microenvironment begins to develop. Metastatic cells display aberrant expression of genes typically reserved for skeletal development and alter the activity of resident cells within the bone microenvironment to promote tumor development, resulting in the severe bone loss. While transcriptional regulation of the metastatic process has been well established, recent findings from our and other research groups highlight the role of the autophagy and secretory pathways in interactions between resident and tumor cells during bone metastatic tumor growth. These reports show high levels of autophagy-related markers, regulatory factors of the autophagy pathway, and autophagy-mediated secretion of matrix metalloproteinases (MMP’s), receptor activator of nuclear factor kappa B ligand (RANKL), parathyroid hormone related protein (PTHrP), as well as WNT5A in bone metastatic breast cancer cells. In this review, we discuss the recently elucidated mechanisms and their crosstalk with signaling pathways, and potential therapeutic targets for bone metastatic disease. Full article

(This article belongs to the Special Issue Inflammatory Cytokines and Chemokines in Cancer: Regulation, Function and Translational Significance)

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