IL-6 In Cancer Cells Research Articles

High-motility pro-tumorigenic monocytes drive macrophage enrichment in the tumor microenvironment.

Enrichment of tumor-associated macrophages (TAMΦs) in the tumor microenvironment correlates with worse clinical outcomes in triple-negative breast cancer (TNBC) patients, prompting the development of therapies to inhibit TAMΦ infiltration. However, the lackluster efficacy of CCL2-based chemotaxis blockade in clinical trials suggests that a new understanding of monocyte/macrophage infiltration may be necessary. Here we demonstrate that random migration, and not only chemotaxis, drives macrophage tumor infiltration. We identified tumor- associated monocytes (TAMos) that display a dramatically enhanced migration capability, induced rapidly by the tumor microenvironment, that drives effective tumor infiltration, in contrast to low-motility differentiated macrophages. TAMo, not TAMΦ, promotes cancer cell proliferation through activation of the MAPK pathway. IL-6 secreted both by cancer cells and TAMo themselves enhances TAMo migration by increasing dendritic protrusion dynamics and myosin- based contractility via the JAK2/STAT3 signaling pathway. Independent from CCL2 mediated chemotaxis, IL-6 driven enhanced migration and pro-proliferative effect of TAMo were validated in a syngeneic TNBC mouse model. Depletion of IL-6 in cancer cells significantly attenuated monocyte infiltration and reversed TAMo-induced cancer cell proliferation. This work reveals the critical role random migration plays in monocyte driven TAMΦ enrichment in a tumor and pinpoints IL-6 as a potential therapeutic target in combination with CCL2 to ameliorate current strategies against TAMΦ infiltration.

PB1967: ROLE OF CYTOKINES IN MULTIPLE MYELOMA: IL-1RN AND IL-4 VNTR POLYMORPHISMS

Background: Cytokines have important effects on immune regulation and oncogenesis. IL-1 is a cytokine with important physiological roles in cytokine regulation, vascular permeability and sepsis in autoimmune diseases. The IL-1 receptor antagonist (IL-1Ra or IL-1RN) is a member of the IL-1 superfamily that functions as a competitive antagonist of the cell surface IL-1 receptor, thereby regulating various immune and inflammatory responses related to IL-1. IL-1 induces tumor growth and metastasis, while IL-1RN inhibits the secretion of IL-1α and IL-6 in cancer cells. Interleukin-4 (IL-4) is a potent anti-inflammatory cytokine, and its gene is located on the long arm of chromosome 5 (q23-31) along with other cytokine genes. IL-4 can be secreted by many types of immune cells, including basophils, eosinophils, myeloid lineage cells, mast cells, and activated T cells. Aims: In this study, it was aimed to reveal the effects of IL-1RN and IL-4 VNTR polymorphisms on disease development and survival in patients with MM. Methods: In this study, 244 patients diagnosed with MM in hematology clinic between January 2010 and January 2021, and 179 healthy individuals were included. The control group did not have any kind of cancers and consisted of a unrelative population permanently residing in Turkey. ASCT was performed for 73% of the patients after 4 courses of VCD (bortezomib, cyclophosphamide, and dexamethasone) with at least a partial remission and then LD (lenalidomide and dexamethasone) was used as a maintenance therapy for the following follow-up period. The 1/1, 1/2, 1/3, 1/4, 2/2, 2/3 and 2/4 genotypes of the IL-1RN VNTR polymorphism were statistically compared before treatment between patients having undergone ASCT and healthy controls, as were the 1/1, 1/2 and 2/2 genotypes of IL-4 VNTR polymorphism. Additionally, the statistically significant effects of these genotypes on survival were examined. Results: The median age of 244 patients included in the study was 58 old years (range: 29-81). The 5-year and 10-year OS were 76% and 53%. The 5-year and 10-year PFS were 42% and 21%, respectively. The median PFS was 42,3 months. The median follow-up period was 27 months (4,4-155 months). In the statistical analysis of the distribution of IL-1RN VNTR gene variants, 1/3 and 1/4 genotypes were found to be significantly higher in patients with MM compared to the healthy controls (p=0,035). In the statistical analysis of the distribution of IL-4 VNTR gene variants, there was no significant difference between the MM patient group and the healthy controls in terms of genotype distribution (p>0.05, for all). IL-4 VNTR genotype distribution did not have a significant effect on PFS and OS. PFS of patients with IL-1RN VNTR non-2-allele carrier genotypes was significantly shorter, but no significant effect was found on OS (p=0,03, p=0,786, respectively. Patients with IL-1RN VNTR non-2-allele carrier genotypes had 1,718-fold increased risk of shorter PFS. Image:Summary/Conclusion: In conclusion, with this study, the effects of IL-1RN VNTR and IL-4 VNTR polymorphisms on MM were evaluated for the first time in the literature. The IL-1RN 1/3 and 1/4 genotypes were significantly more common in patients with MM compared to healthy controls. Patients with IL-1RN VNTR non-2-allele carrier genotypes had 1,718-fold increased risk of shorter PFS, but no significant effect on OS was demonstrated. IL-4 polymorphism, on the other hand, did not have a significant effect on MM development or survival. This study will shed light on ones on cytokine-MM relationship and epigenetic mechanisms.

Role of cytokines in multiple myeloma: IL-1RN and IL-4 VNTR polymorphisms

IntroductionThe IL-1 receptor antagonist (IL-1Ra or IL-1RN) is a member of the IL-1 superfamily that functions as a competitive antagonist of the cell surface IL-1 receptor, thereby regulating various immune and inflammatory responses related to IL-1. IL-1 induces tumor growth and metastasis, while IL-1RN inhibits the secretion of IL-1α and IL-6 in cancer cells. Interleukin-4 (IL-4) is a potent anti-inflammatory cytokine, can be secreted by many types of immune cells. In this study, it was aimed to reveal the effects of IL-1RN and IL-4 VNTR polymorphisms on disease development and survival in patients with multiple myeloma (MM). Material and methodsIn this study, 244 patients diagnosed with MM in hematology clinic between January 2010 and January 2021, and 179 healthy individuals were included. The genotypes of the IL-1RN VNTR polymorphism were statistically compared before treatment between patients having undergone stem cell transplantation and healthy controls, as were the genotypes of IL-4 VNTR polymorphism. Additionally, the statistically significant effects of these genotypes on survival were examined. ResultsIn the statistical analysis of the distribution of IL-1RN VNTR gene variants, 1/3 and 1/4 genotypes were found to be significantly higher in patients with MM compared to the healthy controls (p = 0.035). There was no significant difference between the MM patient group and the healthy controls in terms of IL-4 VNTR genotype distribution. PFS of patients with IL-1RN VNTR non-2-allele carrier genotypes was significantly shorter, but no significant effect was found on OS (p = 0.03, p = 0.786, respectively). Patients with IL-1RN VNTR non-2-allele carrier genotypes had 1.718-fold increased risk of shorter PFS. ConclusionsIn conclusion, with this study, the effects of IL-1RN VNTR and IL-4 VNTR polymorphisms on MM were evaluated for the first time in the literature. This study will shed light on ones on cytokine-MM relationship and epigenetic mechanisms.

Pharmacological Targeting of STING-Dependent IL-6 Production in Cancer Cells.

Activation of the STING pathway upon genotoxic treatment of cancer cells has been shown to lead to anti-tumoral effects, mediated through the acute production of interferon (IFN)-β. Conversely, the pathway also correlates with the expression of NF-κB-driven pro-tumorigenic genes, but these associations are only poorly defined in the context of genotoxic treatment, and are thought to correlate with a chronic engagement of the pathway. We demonstrate here that half of the STING-expressing cancer cells from the NCI60 panel rapidly increased expression of pro-tumorigenic IL-6 upon genotoxic DNA damage, often independent of type-I IFN responses. While preferentially dependent on canonical STING, we demonstrate that genotoxic DNA damage induced by camptothecin (CPT) also drove IL-6 production through non-canonical STING signaling in selected cancer cells. Consequently, pharmacological inhibition of canonical STING failed to broadly inhibit IL-6 production induced by CPT, although this could be achieved through downstream ERK1/2 inhibition. Finally, prolonged inhibition of canonical STING signaling was associated with increased colony formation of MG-63 cells, highlighting the duality of STING signaling in also restraining the growth of selected cancer cells. Collectively, our findings demonstrate that genotoxic-induced DNA damage frequently leads to the rapid production of pro-tumorigenic IL-6 in cancer cells, independent of an IFN signature, through canonical and non-canonical STING activation; this underlines the complexity of STING engagement in human cancer cells, with frequent acute pro-tumorigenic activities induced by DNA damage. We propose that inhibition of ERK1/2 may help curb such pro-tumorigenic responses to DNA-damage, while preserving the anti-proliferative effects of the STING-interferon axis.

Raloxifene inhibits IL-6/STAT3 signaling pathway and protects against high-fat-induced atherosclerosis in ApoE−/− mice

AimsThe signal transducer and activator of transcription 3 (STAT3) pathway plays an important role in inflammatory cascade process. Our previous studies found that Raloxifene targeted against IL-6/GP130 protein-protein interface and inhibited STAT3 phosphorylation induced by IL-6 in cancer cells. However, whether Raloxifene could suppress IL-6/STAT3 signaling pathway and attenuate atherosclerosis in high-fat diet (HFD)-induced mice remains unknown. The objective of this study was to explore the potential effect of Raloxifene on the prevention of atherosclerosis. Main methodsHFD-induced atherosclerosis was established in apoliprotein E-deficient (ApoE −/−) mice. Mice by daily intragastric gavage with Raloxifene or vehicle as controls were provided. The human umbilical vein endothelial cells (HUVEC), Rat VSMC and RAW264.7 cell lines were used to evaluate the effect of Raloxifene in vitro. Key findingsWe demonstrated that Raloxifene was effective in ameliorating HFD- induced atherosclerosis plaque burden and size. Histological analysis showed that the expression of IL-6, P-STAT3, ICAM-1, VCAM-1, CD68 and α-SMA were significantly decreased in the Raloxifene intervention group compared to HFD group. Moreover, we observed that IL-6 increased migration and cell viability of VSMCs and RAW264.7 cells, while Raloxifene treatment decreased migration and reduced cell viability of VSMCs and RAW264.7 cells stimulated by IL-6. Furthermore, this effect was related to blocking IL-6/STAT3 pathway. SignificanceRaloxifene has effects on inhibiting atherosclerosis development, the underlying mechanisms might involve in inhibiting inflammation-related IL-6/STAT3 signaling pathway.

IL-8 promotes HNSCC progression on CXCR1/2-meidated NOD1/RIP2 signaling pathway

NOD1 (nucleotide-binding oligomerization domain 1) is overexpressed in head and neck squamous cell carcinoma (HNSCC) cells, as is IL-8 in cancer cells. However, the mechanism of the IL-8-mediated overexpression of NOD in HNSCC not been identified. This study determines whether IL-8 promotes tumor progression via the NOD signaling pathway in HNSCC. Higher IL-8, NOD1 and receptor-interacting protein kinase (RIP2) expressions were observed in HNSCC tissue than in non-cancerous matched tissue (NCMT), whereas NOD2 was weakly expressed. Furthermore, IL-8 stimulated the proliferation of HNSCC cells (SCC4, SCC9 and SCC25) but not dysplastic oral mucosa DOK cells. Exposure to IL-8 increased the clonogenicity of HNSCC cells. IL-8 siRNA inhibited cell proliferation and cell colony formation, suggesting that IL-8 is involved in HNSCC cancer progression. The expressions of CXCR1 and CXCR2 were higher in HNSCC tissue than in NCMT. HNSCC cells that were exposed to IL-8 exhibited higher expression of CXCR1/2 than did controls. The blocking of IL-8 by siRNA reduced CXCR1/2 expression in HNSCC cells, suggesting that the cancer progression of HNSCC cells that is induced by IL-8 depends on CXCR1/2. Additionally, IL-8 is associated with increased NOD1 and RIP2 expression and reduced NOD2 expression in three types of HNSCC cells. The blocking of IL-8 by siRNA reduces IL-8, NOD1 and RIP2 expressions in HNSCC cells, but not the level of NOD2. These results suggest that IL-8 has an important role in HNSCC progression via a CXCR1/2-meidated NOD1/RIP2 signaling pathway.

AhR- and NF-κB-dependent induction of interleukin-6 by co-exposure to the environmental contaminant benzanthracene and the cytokine tumor necrosis factor-α in human mammary MCF-7 cells

Co-exposure to environmental polycyclic aromatic hydrocarbons (PAHs) and interleukin (IL)-1β induces expression of the tumor-promoting cytokine IL-6 in cancer cells. The present study was designed to determine whether such an IL-6 up-regulation also occurs in response to co-treatment by PAHs and tumor necrosis factor (TNF)-α, an inflammatory cytokine commonly found in tumor microenvironment. Co-exposure to the prototypical PAH benzanthracene (BZA) and TNF-α was found to markedly induce mRNA expression and secretion of IL-6 in human breast cancer cells MCF-7, whereas exposure to either BZA or TNF-α alone was without significant effect. Co-treatment by BZA and TNF-α-containing conditioned media from human inflammatory macrophages similarly up-regulated IL-6 expression in MCF-7 cells. BZA/TNF-α-mediated IL-6 induction in MCF-7 cells was counteracted by silencing aryl hydrocarbon receptor (AhR), known to mediates most of PAH effects. IL-6 up-regulation was moreover associated with NF-κB activation and was abolished by using chemical NF-κB inhibitors or knocking-down expression of the p65/RelA NF-κB subunit. Taken together, these data indicate that co-exposure to BZA/TNF-α induces IL-6 expression by AhR- and NF-κB-dependent pathways in MCF-7 cancer cells. This regulation of IL-6 by environmental PAHs, that is dependent of inflammatory cytokine microenvironment, may contribute to the well-known carcinogenic properties of these organic pollutants.

The role of interleukin-8 in cancer cells and microenvironment interaction

Abstract Interleukin (IL)-8, a cytokine of the CXC chemokine family that was originally classified as a neutrophil chemoattractant, is now reported to play an important role in tumor progression and metastasis in a variety of human cancers, including lung cancers. IL-8 biologic activity in tumors and the tumor microenvironment may contribute to tumor progression through its potential function in the regulation of angiogenesis, cancer cell growth and survival, tumor cell motion, leukocyte infiltration and modification of immune responses. Recently, infiltrating macrophages in tumor stroma have been considered to be able to stimulate cancer growth, enhance angiogenesis and promote metastasis, and has prognostic significance in several human cancers. Accumulating evidence also shows that cancer cells and stromal cell interaction can stimulate cancer cells, as well as stromal cells in the expression of IL-8 and other growth factors. Here, we summarize current information about IL-8 biology in human lung cancers and focus on its effect on tumor angiogenesis, regulation of IL-8 expression in tumors, its prognostic significances, the role of tumor infiltrating macrophages in the production of IL-8 in cancer cells and the tumor microenvironment, gene expression profiles after cancer cell-stromal cell interaction, and the effect of a variety anti- inflammatory drugs on the modification of IL-8 and other gene expressions in cancer cells and the tumor microenvironment in lung cancers.

Expression and up-regulation of interleukin-6 in oesophageal carcinoma cells by n-sodium butyrate.

Recently, the serum level of interleukin (IL)-6 has been shown to correlate with disease progression and prognosis of cancer patients. However, the available information about the source and the pathophysiological regulation of IL-6 in cancer cells is limited. Thus, in this study, we tried to identify the source and the clinical roles of serum IL-6 in patients with oesophageal squamous cell carcinoma (ESCC), and then further to characterize the biological regulation of IL-6 in ESCC cell lines. Sera and tissue specimens from 80 consecutive patients with ESCC were collected between 1993 and 1997. Additionally, three ESCC cell lines were used for in vitro study. The concentration of serum IL-6 was measured by enzyme-linked immunosorbent assay (ELISA), and correlated the survival time with measured IL-6 level. Expressions of IL-6, IL-6Rα (IL-6 receptor alpha) and gp130 in pathological sections and cell lines were characterized by immunological staining. Detection of IL-6 mRNA was determined by in situ hybridization (ISH) and reverse transcription-polymerase chain reaction (RT-PCR). Up-regulation of IL-6 by n-sodium butyrate (n-BT) was studied in ESCC cell lines. The levels of serum IL-6 in patients with ESCC were significantly higher than those in the healthy controls. Serum levels of IL-6 were also shown to correlate with disease progression and survival. However, sCD8 levels and lymphocyte counts in the peripheral blood were not parallel to the changed pattern of serum IL-6. In pathological sections and ESCC cell lines, message of IL-6 was identified by ISH in cancer cells. Expression of IL-6 mRNA was further confirmed with RT-PCR in ESCC cell lines. Although IL-6 was detected in some ESCC cell lines, IL-6 gene expression and protein production could be induced or enhanced by n-BT treatment in all three cell lines. The serum levels of IL-6 are frequently elevated at diagnosis of ESCC, and are associated with poor prognosis. IL-6 that could be produced by cancer cells is up-regulated by n-BT. © 1999 Cancer Research Campaign