Relevance of Thymic Stromal Lymphopoietin on the Pathogenesis of Glioblastoma: Role of the Neutrophil.

IF 3.6 4区 医学 Q3 CELL BIOLOGY Cellular and Molecular Neurobiology Pub Date : 2024-04-01 DOI:10.1007/s10571-024-01462-9
Alejandra Infante Cruz, Juan Valentin Coronel, Paula Saibene Vélez, Federico Remes Lenicov, Juan Iturrizaga, Martín Abelleyro, Micaela Rosato, Carolina Maiumi Shiromizu, Marianela Candolfi, Mónica Vermeulen, Carolina Jancic, Ezequiel Yasuda, Silvia Berner, Marcela Solange Villaverde, Gabriela Verónica Salamone
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Abstract

Glioblastoma multiforme (GBM) is the most predominant and malignant primary brain tumor in adults. Thymic stromal lymphopoietin (TSLP), a cytokine primarily generated by activated epithelial cells, has recently garnered attention in cancer research. This study was aimed to elucidate the significance of TSLP in GBM cells and its interplay with the immune system, particularly focused on granulocyte neutrophils. Our results demonstrate that the tumor produces TSLP when stimulated with epidermal growth factor (EGF) in both the U251 cell line and the GBM biopsy (GBM-b). The relevance of the TSLP function was evaluated using a 3D spheroid model. Spheroids exhibited increased diameter, volume, and proliferation. In addition, TSLP promoted the generation of satellites surrounding the main spheroids and inhibited apoptosis in U251 treated with temozolomide (TMZ). Additionally, the co-culture of polymorphonuclear (PMN) cells from healthy donors with the U251 cell line in the presence of TSLP showed a reduction in apoptosis and an increase in IL-8 production. TSLP directly inhibited apoptosis in PMN from GBM patients (PMN-p). Interestingly, the vascular endothelial growth factor (VEGF) production was elevated in PMN-p compared with PMN from healthy donors. Under these conditions, TSLP also increased VEGF production, in PMN from healthy donors. Moreover, TSLP upregulated programed death-ligand 1 (PDL-1) expression in PMN cultured with U251. On the other hand, according to our results, the analysis of RNA-seq datasets from Illumina HiSeq 2000 sequencing platform performed with TIMER2.0 webserver demonstrated that the combination of TSLP with neutrophils decreases the survival of the patient. In conclusion, our results position TSLP as a possible new growth factor in GBM and indicate its modulation of the tumor microenvironment, particularly through its interaction with PMN.

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胸腺基质淋巴细胞生成素与胶质母细胞瘤发病机制的相关性:中性粒细胞的作用
多形性胶质母细胞瘤(GBM)是成人中最主要的恶性原发性脑肿瘤。胸腺基质淋巴细胞生成素(TSLP)是一种主要由活化的上皮细胞产生的细胞因子,最近在癌症研究中备受关注。本研究旨在阐明 TSLP 在 GBM 细胞中的意义及其与免疫系统的相互作用,特别是与粒细胞中性粒细胞的相互作用。我们的研究结果表明,在表皮生长因子(EGF)的刺激下,U251 细胞系和 GBM 活检组织(GBM-b)中的肿瘤都会产生 TSLP。我们使用三维球体模型评估了 TSLP 功能的相关性。球形细胞的直径、体积和增殖都有所增加。此外,在使用替莫唑胺(TMZ)治疗 U251 的过程中,TSLP 还能促进围绕主球体的卫星球的生成并抑制细胞凋亡。此外,健康供体的多形核(PMN)细胞与 U251 细胞系在 TSLP 存在下进行共培养,结果表明细胞凋亡减少,IL-8 的产生增加。TSLP 可直接抑制 GBM 患者 PMN(PMN-p)的细胞凋亡。有趣的是,与健康供体的 PMN 相比,PMN-p 中血管内皮生长因子(VEGF)的产生量升高。在这些条件下,TSLP 也增加了健康供体 PMN 中血管内皮生长因子的生成。此外,在用 U251 培养的 PMN 中,TSLP 上调了程序性死亡配体 1(PDL-1)的表达。另一方面,根据我们的研究结果,利用 TIMER2.0 网络服务器对来自 Illumina HiSeq 2000 测序平台的 RNA-seq 数据集进行的分析表明,TSLP 与中性粒细胞结合会降低患者的存活率。总之,我们的研究结果将 TSLP 定位为一种可能的 GBM 新生长因子,并表明它能调节肿瘤微环境,特别是通过与 PMN 的相互作用。
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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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