Eph/Ephrin Signaling in the Tumor Microenvironment

Ieguchi, Katsuaki; Maru, Yoshiro

doi:10.1007/978-3-030-47189-7_3

Cited by 6 publications

(6 citation statements)

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“…Since some previous resarches have indicated that Ephs is related to angiogenesis in tumor microenvironment and oxidative stress induced by inflammation during solid tissue tumorigenesis, [13][14][15] the design concept of this study was derived. That is, we speculated that EphA1 may enhance the expression of VEGF and IL-6 in tumor microenvironment, thus promoting the tumorigenesis and progression of malignant tumors.…”

Section: Discussionmentioning

confidence: 99%

“…11,12 Coincidentally, increasing data show that Ephs has been involed to the angiogenesis in tumor microenvironment and oxidative stress due to inflammation during occurrence of solid tumoures. [13][14][15] In addition, studies have found positive relationship among the expression of EphA1 and tumor microenvironment marker proteins VEGF, IL-6 in clinical specimens of malignant tumors, but no further mechanism has been explored. 16 Taken together, We hypothesized that EphA1 may involved in the regulation of tumor microenvironment, and consequently facilitates tumorigenesis and progression through drives the expression of IL-6 and VEGF in tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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Erythropoietin-producing hepatocyte kinase receptor A1 facilitating the prgression of SGC-7901 cells and its transplanted tumor by increasing the expression of interleukin-6 and vascular endothelial growth factor in tumor microenvironment

Wang

Zheng

et al. 2022

Eur J Inflamm

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Objectives Many researches showed that Erythropoietin-producing hepatocyte kinase receptor A1 (EphA1) can promote the occurrence and development of malignant tumors and may be related to tumor microenvironment. But most of them are phenomenon studies, and there are few in-depth and complete mechanism studies. This study aims to understand how EphA1 promotes the progression of malignant tumors by regulating tumor microenvironment (focusing on Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF)) from two experimental dimensions of in vitro and in vivo by using genetic engineering technology. Material and Methods We used genetic engineering technology to enhance and knock down EphA1 gene expression in SGC-7901 cells, respectively, and analyzed its influence on cell function and the expression levels of VEGF and IL-6 in cells. Subsequently, we constructed human EphA1 gene overexpression, EphA1 gene silencing, and normal expression of human EphA1 gene subcutaneous transplanted tumor models of SGC-7901 cells nude mice, and analyzed the differences in tumor development and the changes in the expression levels of VEGF and ILl-6 in tumor tissues. Results After EphA1 gene expression was enhanced, the proliferation, invasion and migration of SGC-7901 cells were enhanced, and apoptosis was weakened, and the expression levels of VEGF and IL-6 were increased. While the opposite results were found when EphA1 gene expression were knocked down. Meanwhile, tumor formation time and growth rate of subcutaneous transplantation in nude mice were advanced and the expression levels of VEGF and IL-6 in tumor tissues were increased when EphA1 gene expression were overexpressed by genetic engineering technology. Similarly, the opposite effect occurred in transplanted tumor model when EphA1 gene was silenced. Conclusion Our study showed that EphA1 can up-regulating VEGF and IL-6 expression, thereby enhancing the inflammatory environment and angiogenesis in the tumor microenvironment, and this helps to promote the progression of SGC-7901 cells and its transplanted tumor.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Erythropoietin-producing hepatocyte kinase receptor A1 facilitating the prgression of SGC-7901 cells and its transplanted tumor by increasing the expression of interleukin-6 and vascular endothelial growth factor in tumor microenvironment

Wang

Zheng

et al. 2022

Eur J Inflamm

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“…According to studies, EphB4/ephrinB2 signaling pathways are involved in the migration of ECs and the formation of veins and arteries [ 242 ]. EphB4 and ephrinB2 are transmembrane receptor and ligand respectively which their connection brings on forward signaling in the cell that contains EphB4 and on the opposite side, reverse signaling occurs [ 243 ].…”

Section: Induced Tumor Angiogenesis By Stimulated Signaling Pathwaysmentioning

confidence: 99%

The roles of metabolic profiles and intracellular signaling pathways of tumor microenvironment cells in angiogenesis of solid tumors

Zalpoor

Aziziyan²,

Liaghat³

et al. 2022

Cell Commun Signal

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Innate and adaptive immune cells patrol and survey throughout the human body and sometimes reside in the tumor microenvironment (TME) with a variety of cell types and nutrients that may differ from those in which they developed. The metabolic pathways and metabolites of immune cells are rooted in cell physiology, and not only provide nutrients and energy for cell growth and survival but also influencing cell differentiation and effector functions. Nowadays, there is a growing awareness that metabolic processes occurring in cancer cells can affect immune cell function and lead to tumor immune evasion and angiogenesis. In order to safely treat cancer patients and prevent immune checkpoint blockade-induced toxicities and autoimmunity, we suggest using anti-angiogenic drugs solely or combined with Immune checkpoint blockers (ICBs) to boost the safety and effectiveness of cancer therapy. As a consequence, there is significant and escalating attention to discovering techniques that target metabolism as a new method of cancer therapy. In this review, a summary of immune-metabolic processes and their potential role in the stimulation of intracellular signaling in TME cells that lead to tumor angiogenesis, and therapeutic applications is provided.

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“…These receptors bind to glycosylphosphatidylinositol-anchored ligands Ephrin-A (A1-A5) and transmembrane Ephrin-B (B1-B3) with short cytoplasmic regions containing PDZ binding motifs ( Uchiyama et al, 2015 ). In recent years, members of this family have been investigated for their role in regulating tumorigenesis, aggressiveness, tumor-related angiogenesis, metastasis, and prognosis ( Leite et al, 2020 ; Ieguchi and Maru, 2021 ). Furthermore, EFNA2 has been found to play an important role in angiogenesis and promoting epithelial-mesenchymal transformation in prostate cancer through in vitro and in vivo migration—and therefore a potential therapeutic target for prostate cancer ( Zhao et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

The Pan-Cancer Crosstalk Between the EFNA Family and Tumor Microenvironment for Prognosis and Immunotherapy of Gastric Cancer

Xie

Yuan

Jiang

2022

Front. Cell Dev. Biol.

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Background:EFNA1–5 have important physiological functions in regulating tumorigenesis and metastasis. However, correlating EFNA genes in the tumor immune microenvironment (TIME), and the prognosis of patients with gastric cancer remains to be determined.Methods: Using public databases, the expression of EFNA1-5 in pan-cancer and gastric cancer was comprehensively analyzed using UCSC Xena, the Oncomine dataset and UALCAN. We further completed survival analysis by Kaplan-Meier plotter to evaluate the prognosis of the high and low expression groups of the EFNAs gene in patients with gastric cancer. The TIMER tool was used to reveal the correlation between immune cell infiltration and genes of interest. Spearman correlation was used to find an association between the EFNA genes and tumor stem cells, TIME, microsatellite instability (MSI) or tumor mutational burden (TMB). We also used cBioportal, GeneMANIA and STRINGS to explore the types of changes in these genes and the protein interactions. Finally, we described the TIME based on QUANTISEQ algorithm, predicted the relationship between the EFNA genes and half-maximal inhibitory concentration (IC50), and analyzed the relationship between the EFNA family genes and immune checkpoints.Results: The expression of EFNA1, EFNA3, EFNA4, and EFNA5 was elevated in pan-cancer. Compared with normal adjacent tissues, EFNA1, EFNA3, and EFNA4 were up-regulated in gastric cancer. In terms of the influence on the survival of patients, the expression of EFNA3 and EFNA4 were related to overall survival (OS) and disease-free survival (DFS) for patients with gastric cancer. High expression of EFNA5 often predicted poor OS and DFS. In gastric cancer, the expression of EFNA3 and EFNA4 showed a significant negative correlation with B cells. The higher the expression of EFNA5, the higher the abundance of B cells, CD4+T cells and macrophages. CD8+T cells, dendritic cells infiltration and EFNA1-4 expression were negatively correlated. The infiltration of CD4+T cells, macrophages and neutrophils was negatively correlated with the expression of EFNA1, EFNA3, and EFNA4. TMB and MSI were positively correlated with EFNA3/EFNA4 expression. In the tumor microenvironment and drug sensitivity, EFNA3/4/5 also showed a significant correlation. In addition, we explored the relationship between the EFNA family genes and the immune microenvironment (B cells, M2 macrophages, monocytes, CD8+ T cells, regulatory T cells, myeloid dendritic cells, natural killer cells, non-regulatory CD4+ T cells), immune checkpoint (PDCD1, PDCD1LG2, CD274, CTLA4), and IC50 of common chemotherapeutic drugs for gastric cancer (5-fluorouracil, cisplatin, docetaxel and gemcitabine).Conclusions: Our study provides new ideas for tumor treatment and prognosis from the perspective of TIME, and nominates EFNA1–5 to become potential therapeutic targets for gastric cancer.

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Eph/Ephrin Signaling in the Tumor Microenvironment

Cited by 6 publications

References 64 publications

Erythropoietin-producing hepatocyte kinase receptor A1 facilitating the prgression of SGC-7901 cells and its transplanted tumor by increasing the expression of interleukin-6 and vascular endothelial growth factor in tumor microenvironment

Erythropoietin-producing hepatocyte kinase receptor A1 facilitating the prgression of SGC-7901 cells and its transplanted tumor by increasing the expression of interleukin-6 and vascular endothelial growth factor in tumor microenvironment

The roles of metabolic profiles and intracellular signaling pathways of tumor microenvironment cells in angiogenesis of solid tumors

The Pan-Cancer Crosstalk Between the EFNA Family and Tumor Microenvironment for Prognosis and Immunotherapy of Gastric Cancer

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