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13 pages, 656 KiB

Open AccessArticle

Vitamin D3 (Calcitriol) Monotherapy Decreases Tumor Growth, Increases Survival, and Correlates with Low Neutrophil-to-Lymphocyte Ratio in a Murine HPV-16-Related Cancer Model

by Alejandra E. Hernández-Rangel, Gustavo A. Hernandez-Fuentes, Daniel A. Montes-Galindo, Carmen A. Sanchez-Ramirez, Ariana Cabrera-Licona, Margarita L. Martinez-Fierro, Iram P. Rodriguez-Sanchez, Idalia Garza-Veloz, Janet Diaz-Martinez, Juan C. Casarez-Price, Jorge E. Plata-Florenzano, Hector Ochoa-Díaz-Lopez, Angel Lugo-Trampe and Iván Delgado-Enciso

Biomedicines 2024, 12(6), 1357; https://doi.org/10.3390/biomedicines12061357 - 18 Jun 2024

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Abstract

Vitamin D3 or calcitriol (VitD3) has been shown to have anticancer and anti-inflammatory activity in in vitro models and clinical studies. However, its effect on HPV-16-related cancer has been sparsely explored. In this study, we aimed to determine whether monotherapy or combination therapy [...] Read more.

Vitamin D3 or calcitriol (VitD3) has been shown to have anticancer and anti-inflammatory activity in in vitro models and clinical studies. However, its effect on HPV-16-related cancer has been sparsely explored. In this study, we aimed to determine whether monotherapy or combination therapy with cisplatin (CP) reduces tumor growth and affects survival and systemic inflammation. Treatments were administered to C57BL/6 mice with HPV-16-related tumors (TC-1 cells) as follows: (1) placebo (100 µL vehicle, olive oil, orally administered daily); (2) VitD3 (3.75 µg/kg calcitriol orally administered daily); (3) CP (5 mg/kg intraperitoneally, every 7 days); and (4) VitD3+CP. Tumor growth was monitored for 25 days, survival for 60 days, and the neutrophil-to-lymphocyte ratio (NLR) was evaluated on days 1 (baseline), 7, and 14. VitD3+CP showed greater success in reducing tumor volume compared to CP monotherapy (p = 0.041), while no differences were observed between CP and VitD3 monotherapy (p = 0.671). Furthermore, VitD3+CP prolonged survival compared to CP (p = 0.036) and VitD3 (p = 0.007). Additionally, at day 14 the VitD3 and VitD3+CP groups showed significantly lower NLR values than the CP group (p < 0.05, for both comparisons). Vitamin D3 could be a promising adjuvant in the treatment of cervical cancer or solid tumors and deserves further investigation. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)

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18 pages, 3334 KiB

Open AccessArticle

The Role of Salivary Vascular Endothelial Growth Factor A, Cytokines, and Amino Acids in Immunomodulation and Angiogenesis in Breast Cancer

by Elena A. Sarf, Elena I. Dyachenko and Lyudmila V. Bel’skaya

Biomedicines 2024, 12(6), 1329; https://doi.org/10.3390/biomedicines12061329 - 14 Jun 2024

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Abstract

In this work, we focused on the analysis of VEGF content in saliva and its relationship with pro-inflammatory cytokines and amino acids involved in immunomodulation and angiogenesis in breast cancer. The study included 230 breast cancer patients, 92 patients with benign breast disease, [...] Read more.

In this work, we focused on the analysis of VEGF content in saliva and its relationship with pro-inflammatory cytokines and amino acids involved in immunomodulation and angiogenesis in breast cancer. The study included 230 breast cancer patients, 92 patients with benign breast disease, and 59 healthy controls. Before treatment, saliva samples were obtained from all participants, and the content of VEGF and cytokines in saliva was determined by an enzyme-linked immunosorbent assay, as well as the content of amino acids by high-performance liquid chromatography. It was found that VEGF was positively correlated with the level of pro-inflammatory cytokines IL-1β (r = 0.6367), IL-6 (r = 0.3813), IL-8 (r = 0.4370), and IL-18 (r = 0.4184). Weak correlations were shown for MCP-1 (r = 0.2663) and TNF-α (r = 0.2817). For the first time, we demonstrated changes in the concentration of VEGF and related cytokines in saliva in different molecular biological subtypes of breast cancer depending on the stage of the disease, differentiation, proliferation, and metastasis to the lymph nodes. A correlation was established between the expression of VEGF and the content of aspartic acid (r = −0.3050), citrulline (r = −0.2914), and tryptophan (r = 0.3382) in saliva. It has been suggested that aspartic acid and citrulline influence the expression of VEGF via the synthesis of the signaling molecule NO, and then tryptophan ensures tolerance of the immune system to tumor cells. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)

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13 pages, 6490 KiB

Open AccessArticle

YAP1 Regulates the YAP1/AR/PSA Axis through Autophagy in Castration-Resistant Prostate Cancer and Mediates T-Cell Immune and Inflammatory Cytokine Infiltration

by Youzhi Wang, Ning Wu, Junbo Li, Diansheng Zhou, Jiaming Liang, Qian Cao, Zhaokai Guan, Yangyang Xu and Ning Jiang

Biomedicines 2024, 12(3), 661; https://doi.org/10.3390/biomedicines12030661 - 15 Mar 2024

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Abstract

The emergence of castration-resistant prostate cancer (CRPC) following androgen deprivation therapy (ADT) is associated with increased malignancy and limited treatment options. This study aims to investigate potential connections between immune cell infiltration and inflammatory cytokines with the YAP1/AR/PSA axis by exploring their interactions [...] Read more.

The emergence of castration-resistant prostate cancer (CRPC) following androgen deprivation therapy (ADT) is associated with increased malignancy and limited treatment options. This study aims to investigate potential connections between immune cell infiltration and inflammatory cytokines with the YAP1/AR/PSA axis by exploring their interactions with autophagy. Our research reveals heightened levels of Yes-associated protein 1 (YAP1) expression in CRPC tissues compared with tissues from androgen-dependent prostate cancer (ADPC) and benign prostate hyperplasia (BPH). Additionally, a correlation was observed between YAP1 and PSA expressions in CRPC tissues, suggesting that YAP1 may exert a regulatory influence on PSA expression within CRPC. Enhanced YAP1 expression in C4-2 cells resulted in the upregulation of androgen receptor (AR) nuclear translocation and intracellular prostate-specific antigen (PSA) levels. Conversely, the suppression of YAP1 led to a decrease in PSA expression, suggesting that YAP1 may positively regulate the PSA in castration-resistant prostate cancer (CRPC) by facilitating AR nuclear import. The modulation of the autophagy activity exerts a significant impact on the expression levels of YAP1, the AR, and the PSA. Moreover, recent advancements in immunity and inflammation studies present promising avenues for potential therapies targeting prostate cancer (PC). Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)

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17 pages, 5268 KiB

Open AccessArticle

Cold-Inducible RNA Binding Protein Impedes Breast Tumor Growth in the PyMT Murine Model for Breast Cancer

by Daniel A. Lujan, Joey L. Ochoa, Ellen J. Beswick, Tamara A. Howard, Helen J. Hathaway, Nora I. Perrone-Bizzozero and Rebecca S. Hartley

Biomedicines 2024, 12(2), 340; https://doi.org/10.3390/biomedicines12020340 - 1 Feb 2024

Cited by 1 | Viewed by 1429

Abstract

RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by associating with regulatory sequences in the untranslated regions of mRNAs. Cold-inducible RBP (CIRP) is a stress-induced RBP that was recently shown to modulate inflammation in response to cellular stress, where it increases or decreases [...] Read more.

RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by associating with regulatory sequences in the untranslated regions of mRNAs. Cold-inducible RBP (CIRP) is a stress-induced RBP that was recently shown to modulate inflammation in response to cellular stress, where it increases or decreases pro-tumorigenic (proinflammatory) cytokines in different contexts. CIRP expression is altered in several cancers, including breast cancer, but the effects of CIRP on inflammation in breast cancer is not known. Here, we investigate if CIRP alters growth and the inflammatory profile of breast tumors. Transgenic mice overexpressing CIRP in the mammary epithelium were crossed with the PyMT mouse model of breast cancer, and the effects on both early and late tumorigenesis and inflammation were assessed. The effects of CIRP knockdown were also assessed in Py2T cell grafts. Overexpression of CIRP led to decreased tumorigenesis in the PyMT mouse model. Conversely, the knockdown of CIRP in Py2T cell grafts led to increased tumor growth. Luminex cytokine assays assessed the effects on the inflammatory environment. CIRP/PyMT mammary glands/mammary tumors and serum had decreased cytokines that promote inflammation, angiogenesis, and metastasis compared to PyMT mammary glands and serum, documenting a shift towards an environment less supportive of tumorigenesis. CIRP overexpression also decreased CD4⁺ helper T cells and increased CD8⁺ cytotoxic T cells in mammary tumors. Overall, these data support a role for CIRP as a potent antitumor molecule that suppresses both local and systemic pro-tumorigenic inflammation. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)

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19 pages, 2406 KiB

Open AccessArticle

Association of Four Interleukin-8 Polymorphisms (−251 A>T, +781 C>T, +1633 C>T, +2767 A>T) with Ovarian Cancer Risk: Focus on Menopausal Status and Endometriosis-Related Subtypes

by Rafał Watrowski, Eva Schuster, Gerda Hofstetter, Michael B. Fischer, Sven Mahner, Toon Van Gorp, Stefan Polterauer, Robert Zeillinger and Eva Obermayr

Biomedicines 2024, 12(2), 321; https://doi.org/10.3390/biomedicines12020321 - 30 Jan 2024

Cited by 2 | Viewed by 1553

Abstract

Interleukin-8 (IL-8) is involved in the regulation of inflammatory processes and carcinogenesis. Single-nucleotide polymorphisms (SNPs) within the IL-8 gene have been shown to alter the risks of lung, gastric, or hepatocellular carcinomas. To date, only one study examined the role of IL-8 SNPs [...] Read more.

Interleukin-8 (IL-8) is involved in the regulation of inflammatory processes and carcinogenesis. Single-nucleotide polymorphisms (SNPs) within the IL-8 gene have been shown to alter the risks of lung, gastric, or hepatocellular carcinomas. To date, only one study examined the role of IL-8 SNPs in ovarian cancer (OC), suggesting an association between two IL-8 SNPs and OC risk. In this study, we investigated four common IL-8 SNPs, rs4073 (−251 A>T), rs2227306 (+781 C>T), rs2227543 (+1633 C>T), and rs1126647 (+2767 A>T), using the restriction fragment length polymorphism (PCR-RFLP) technique. Our study included a cohort of 413 women of Central European descent, consisting of 200 OC patients and 213 healthy controls. The most common (73.5%) histological type was high-grade serous OC (HGSOC), whereas 28/200 (14%) patients had endometriosis-related (clear cell or endometrioid) OC subtypes (EROC). In postmenopausal women, three of the four investigated SNPs, rs4073 (−251 A>T), rs2227306 (+781 C>T), and rs2227543 (+1633 C>T), were associated with OC risk. Furthermore, we are the first to report a significant relationship between the T allele or TT genotype of SNP rs1126647 (+2767 A>T) and the EROC subtype (p = 0.02 in the co-dominant model). The TT homozygotes were found more than twice as often in EROC compared to other OC subtypes (39% vs. 19%, p = 0.015). None of the examined SNPs appeared to influence OC risk in premenopausal women, nor were they associated with the aggressive HGSOC subtype or the stage of disease at the initial diagnosis. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)

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Review

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11 pages, 934 KiB

Open AccessReview

Expanding the Perspective on PARP1 and Its Inhibitors in Cancer Therapy: From DNA Damage Repair to Immunomodulation

by Flurina Böhi and Michael O. Hottiger

Biomedicines 2024, 12(7), 1617; https://doi.org/10.3390/biomedicines12071617 - 20 Jul 2024

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Abstract

The emergence of PARP inhibitors as a therapeutic strategy for tumors with high genomic instability, particularly those harboring BRCA mutations, has advanced cancer treatment. However, recent advances have illuminated a multifaceted role of PARP1 beyond its canonical function in DNA damage repair. This [...] Read more.

The emergence of PARP inhibitors as a therapeutic strategy for tumors with high genomic instability, particularly those harboring BRCA mutations, has advanced cancer treatment. However, recent advances have illuminated a multifaceted role of PARP1 beyond its canonical function in DNA damage repair. This review explores the expanding roles of PARP1, highlighting its crucial interplay with the immune system during tumorigenesis. We discuss PARP1’s immunomodulatory effects in macrophages and T cells, with a particular focus on cytokine expression. Understanding these immunomodulatory roles of PARP1 not only holds promise for enhancing the efficacy of PARP inhibitors in cancer therapy but also paves the way for novel treatment regimens targeting immune-mediated inflammatory diseases. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)

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14 pages, 298 KiB

Open AccessReview

How General and Inflammatory Status Impacts on the Prognosis of Patients Affected by Lung Cancer: State of the Art

by Antonio Mazzella, Riccardo Orlandi, Sebastiano Maiorca, Clarissa Uslenghi, Matteo Chiari, Luca Bertolaccini, Monica Casiraghi, Giorgio Lo Iacono, Lara Girelli and Lorenzo Spaggiari

Biomedicines 2024, 12(7), 1554; https://doi.org/10.3390/biomedicines12071554 - 12 Jul 2024

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Abstract

Pulmonary cancer is often associated with systemic inflammation and poor nutritional status and these two aspects are strongly correlated and related to the scarce infiltration of a tumor by immune cells. We reviewed all English literature reviews from 2000 to 2024 from PubMed, [...] Read more.

Pulmonary cancer is often associated with systemic inflammation and poor nutritional status and these two aspects are strongly correlated and related to the scarce infiltration of a tumor by immune cells. We reviewed all English literature reviews from 2000 to 2024 from PubMed, Scopus and Google Scholar, including original articles, review articles, and metanalyses. We excluded non-English language articles and case reports/case series. Generally speaking, nutritional and inflammatory status largely affect medium and long-term prognosis in lung cancer patients. A correct stratification of patients could improve their preoperative general functional nutritional and inflammatory status, minimizing, therefore, possible treatment complications and improving long-term prognosis. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)

14 pages, 2413 KiB

Open AccessReview

Signal Transducer and Activator of Transcription Proteins at the Nexus of Immunodeficiency, Autoimmunity and Cancer

by Clifford Liongue, Mohamed Luban Sobah and Alister C. Ward

Biomedicines 2024, 12(1), 45; https://doi.org/10.3390/biomedicines12010045 - 23 Dec 2023

Cited by 2 | Viewed by 1535

Abstract

The signal transducer and activator of transcription (STAT) family of proteins has been demonstrated to perform pivotal roles downstream of a myriad of cytokines, particularly those that control immune cell production and function. This is highlighted by both gain-of-function (GOF) and loss-of-function (LOF) [...] Read more.

The signal transducer and activator of transcription (STAT) family of proteins has been demonstrated to perform pivotal roles downstream of a myriad of cytokines, particularly those that control immune cell production and function. This is highlighted by both gain-of-function (GOF) and loss-of-function (LOF) mutations being implicated in various diseases impacting cells of the immune system. These mutations are typically inherited, although somatic GOF mutations are commonly observed in certain immune cell malignancies. This review details the growing appreciation of STAT proteins as a key node linking immunodeficiency, autoimmunity and cancer. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)

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28 pages, 1103 KiB

Open AccessReview

The RELT Family of Proteins: An Increasing Awareness of Their Importance for Cancer, the Immune System, and Development

by John K. Cusick, Jessa Alcaide and Yihui Shi

Biomedicines 2023, 11(10), 2695; https://doi.org/10.3390/biomedicines11102695 - 2 Oct 2023

Cited by 2 | Viewed by 1874

Abstract

This review highlights Receptor Expressed in Lymphoid Tissues (RELT), a Tumor Necrosis Factor Superfamily member, and its two paralogs, RELL1 and RELL2. Collectively, these three proteins are referred to as RELTfms and have gained much interest in recent years due to their association [...] Read more.

This review highlights Receptor Expressed in Lymphoid Tissues (RELT), a Tumor Necrosis Factor Superfamily member, and its two paralogs, RELL1 and RELL2. Collectively, these three proteins are referred to as RELTfms and have gained much interest in recent years due to their association with cancer and other human diseases. A thorough knowledge of their physiological functions, including the ligand for RELT, is lacking, yet emerging evidence implicates RELTfms in a variety of processes including cytokine signaling and pathways that either promote cell death or survival. T cells from mice lacking RELT exhibit increased responses against tumors and increased inflammatory cytokine production, and multiple lines of evidence indicate that RELT may promote an immunosuppressive environment for tumors. The relationship of individual RELTfms in different cancers is not universal however, as evidence indicates that individual RELTfms may be risk factors in certain cancers yet appear to be protective in other cancers. RELTfms are important for a variety of additional processes related to human health including microbial pathogenesis, inflammation, behavior, reproduction, and development. All three proteins have been strongly conserved in all vertebrates, and this review aims to provide a clearer understanding of the current knowledge regarding these interesting proteins. Full article

(This article belongs to the Special Issue The Role of Inflammatory Cytokines in Cancer Progression 2.0)

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