IL-6 Receptor Is a Possible Target against Growth of Metastasized Lung Tumor Cells in the Brain

Нода, Мами; Yamakawa, Yuki; Matsumoto, Naoya; Naoe, Satoko; Jodoi, Taishi; Yamafuji, Megumi; Akimoto, Nozomi; Teramoto, Norihiro; Fujita, Kyota; Ohdo, Shigehiro; Iguchi, Haruo

doi:10.3390/ijms14010515

Cited by 10 publications

(10 citation statements)

References 41 publications

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“…Each of these cytokines would be expected to produce complex phenotypes in addition to BBB/BTB permeability, including myeloid, dendritic cell and lymphocyte recruitment 55 , 57 – 59 , neuronal and neural stem cell function 60 – 62 , and cognition 63 . A beneficial drug permeability effect of CCL2 or IL-6 must outweigh potential tumor stimulatory pathways 64 , 65 . Lung cancer lines including a brain-derived variant were insensitive to IL-6, but the extent of this resistance profile is unknown 66 .…”

Section: Discussionmentioning

confidence: 99%

Reactive astrocytic S1P3 signaling modulates the blood–tumor barrier in brain metastases

Gril¹,

Paranjape

Woditschka

et al. 2018

Nat Commun

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Brain metastases are devastating complications of cancer. The blood–brain barrier (BBB), which protects the normal brain, morphs into an inadequately characterized blood–tumor barrier (BTB) when brain metastases form, and is surrounded by a neuroinflammatory response. These structures contribute to poor therapeutic efficacy by limiting drug uptake. Here, we report that experimental breast cancer brain metastases of low- and high permeability to a dextran dye exhibit distinct microenvironmental gene expression patterns. Astrocytic sphingosine-1 phosphate receptor 3 (S1P3) is upregulated in the neuroinflammatory response of the highly permeable lesions, and is expressed in patients’ brain metastases. S1P3 inhibition functionally tightens the BTB in vitro and in vivo. S1P3 mediates its effects on BTB permeability through astrocytic secretion of IL-6 and CCL2, which relaxes endothelial cell adhesion. Tumor cell overexpression of S1P3 mimics this pathway, enhancing IL-6 and CCL-2 production and elevating BTB permeability. In conclusion, neuroinflammatory astrocytic S1P3 modulates BTB permeability.

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Section: Discussionmentioning

confidence: 99%

Reactive astrocytic S1P3 signaling modulates the blood–tumor barrier in brain metastases

Gril¹,

Paranjape

Woditschka

et al. 2018

Nat Commun

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“…Cytokines expressed by glioma cells, like IL‐6, IL‐8, and VEGF, determine a wide variety of effects like promotion of tumor cell invasion, proliferation, migration, neo‐ angiogenesis and immune cell infiltration. Specifically, IL‐6 is a pleiotropic cytokine that contributes to malignant progression and apoptosis resistance of different tumors (Noda et al, ). Il‐6 act by forming a complex with IL‐6R alpha and a transmembrane glycoprotein called gp130 lead to the activation of the signal transducer and activator of transcription (STATs) able to induce cellular transformation of fibroblasts and tumor growth in GBM cells (Heinrich, Behrmann, Müller‐Newen, Schaper, & Graeve, ).…”

Section: Discussionmentioning

confidence: 99%

Novel nanohydrogel of hyaluronic acid loaded with quercetin alone and in combination with temozolomide as new therapeutic tool, CD44 targeted based, of glioblastoma multiforme

Barbarisi

Iaffaioli

Armenia

et al. 2018

Journal Cellular Physiology

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Glioblastoma multiforme is the most common and aggressive primary brain cancer with only ∼3% of patients surviving more than 3 years from diagnosis. Several mechanisms are involved in drug and radiation resistance to anticancer treatments and among them one of the most important factors is the tumor microenvironment status, characterized by cancer cell hypersecretion of interleukins and cytokines. The aim of our research was the synthesis of a nanocarrier of quercetin combined with temozolomide, to enhance the specificity and efficacy of this anticancer drug commonly used in glioblastoma treatment. The nanohydrogel increased the internalization and cytotoxicity of quercetin in human glioblastoma cells and, when co-delivered with temozolomide, contribute to an improved anticancer effect. The nanohydrogel loaded with quercetin had the ability to recognize CD44 receptor, a brain cancer cell marker, through an energy and caveolae dependent mechanism of internalization. Moreover, nanohydrogel of quercetin was able to reduce significantly IL-8, IL-6, and VEGF production in pro-inflammatory conditions with interesting implications on the mechanism of glioblastoma cells drug resistance. In summary, novel CD44 targeted polymeric based nanocarriers appear to be proficient in mediating site-specific delivery of quercetin via CD44 receptor in glioblastoma cells. This targeted therapy lead to an improved therapeutic efficacy of temozolomide by modulating the brain tumor microenvironment.

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“…Several studies have revealed the role of IL-6 in NSCLC and suggested that it promotes tumor growth and survival ( 10 – 12 ). Increased expression of IL-6R in human LUSC-derived cells (HARA-B) has been shown in vitro ( 13 ) and in a murine model of brain metastasis ( 14 ). Tocilizumab is an anti-IL-6R antibody, upon application, the stimulated growth of HARA-B cells was significantly inhibited and when it was injected to the animal model, the volume of metastatic focus was significantly smaller ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma

Yue

et al. 2018

Oncol Lett

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Previous studies have demonstrated that the interleukin (IL)-6/ IL-6 receptor (IL-6R) signaling pathway contributes to the pathogenesis of lung cancer. Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the two major pathological subtypes of non-small cell lung cancer (NSCLC). The present study aimed to elucidate the potential clinical prognosis and biological function of IL-6R mRNA expression in LUAD and LUSC. The search term ‘lung cancer’ was used to search through the Gene Expression Omnibus database. Including LUAD and LUSC datasets in The Cancer Genome Atlas database, a total of 8 LUAD and 6 LUSC datasets were included in the present analysis. It was observed that a higher expression level of IL-6R mRNA in tumor tissues was a significant positive prognostic factor for overall survival in LUAD [pooled hazard ratio (HR), 0.48 and P<0.001 for univariate analysis; pooled HR, 0.50 and P<0.001 for multivariate analysis] while there was no similar association in LUSC (pooled HR, 1.59 and P=0.062 for univariate analysis; pooled HR, 1.58 and P=0.079 for multivariate analysis). Correlation analysis revealed that IL-6 and IL-6R were negatively correlated in LUAD and positively correlated in LUSC. IL-6R and its most correlated genes were primarily involved in cell cycle progression in LUAD and primarily involved in tumor angiogenesis, invasion and metastasis in LUSC. These results suggest a possible role of tumoral expression for IL-6R in LUAD, which means it may have potential as a prognostic marker for this type of cancer.

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IL-6 Receptor Is a Possible Target against Growth of Metastasized Lung Tumor Cells in the Brain

Cited by 10 publications

References 41 publications

Reactive astrocytic S1P3 signaling modulates the blood–tumor barrier in brain metastases

Reactive astrocytic S1P3 signaling modulates the blood–tumor barrier in brain metastases

Novel nanohydrogel of hyaluronic acid loaded with quercetin alone and in combination with temozolomide as new therapeutic tool, CD44 targeted based, of glioblastoma multiforme

Prognostic value of IL‑6R mRNA in lung adenocarcinoma and squamous cell carcinoma

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