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Galectin-9 Mediates the Functions of Microglia in the Hypoxic Brain Tumor Microenvironment
Cancer Research ( IF 12.5 ) Pub Date : 2024-08-29 , DOI: 10.1158/0008-5472.can-23-3878
Chanju Lee 1 , Dahee Yu 1 , Hyung-Seok Kim 1 , Ki Sun Kim 1 , Chi Young Chang 1 , Hee Jung Yoon 1 , Su Bin Won 1 , Dae Yeon Kim 1 , Eun Ah Goh 1 , Yong Sun Lee 1 , Jong Bae Park 1 , Sang Soo Kim 2 , Eun Jung Park 1
Affiliation  

Galectin-9 is a multifaceted regulator of various pathophysiological processes that exerts positive or negative effects in a context-dependent manner. Here, we elucidated the distinctive functional properties of galectin-9 on myeloid cells within the brain tumor microenvironment. Galectin-9-expressing cells were abundant at the hypoxic tumor edge in the tumor-bearing ipsilateral hemisphere compared to the contralateral hemisphere in an intracranial mouse brain tumor model. Galectin-9 was highly expressed in microglia and macrophages in tumor-infiltrating cells. In primary glia, both the expression and secretion of galectin-9 were influenced by tumors. Analysis of a human glioblastoma bulk RNA-sequencing dataset and a single-cell RNA-sequencing dataset from a murine glioma model revealed a correlation between galectin-9 expression and glial cell activation. Notably, the galectin-9high microglial subset was functionally distinct from the galectin-9neg/low subset in the brain tumor microenvironment. Galectin-9high microglia exhibited properties of inflammatory activation and higher rates of cell death, whereas galectin-9neg/low microglia displayed a superior phagocytic ability against brain tumor cells. Blockade of galectin-9 suppressed tumor growth and altered the activity of glial and T cells in a mouse glioma model. Additionally, glial galectin-9 expression was regulated by Hif-2α in the hypoxic brain tumor microenvironment. Myeloid-specific Hif-2α deficiency led to attenuated tumor progression. Together, these findings reveal that galectin-9 on myeloid cells is an immunoregulator and putative therapeutic target in brain tumors.

中文翻译:


半乳糖凝集素-9 介导低氧脑肿瘤微环境中小胶质细胞的功能



半乳糖凝集素 9 是各种病理生理过程的多方面调节因子,以环境依赖性方式发挥积极或消极影响。在这里,我们阐明了半乳糖凝集素-9 在脑肿瘤微环境中骨髓细胞上的独特功能特性。在颅内小鼠脑肿瘤模型中,与对侧半球相比,表达半乳糖凝集素 9 的细胞在荷瘤同侧半球的缺氧肿瘤边缘丰富。半乳糖凝集素-9 在肿瘤浸润细胞的小胶质细胞和巨噬细胞中高表达。在原代神经胶质细胞中,半乳糖凝集素-9 的表达和分泌都受肿瘤影响。对人类胶质母细胞瘤大量 RNA 测序数据集和来自小鼠胶质瘤模型的单细胞 RNA 测序数据集的分析揭示了半乳糖凝集素-9 表达与神经胶质细胞活化之间的相关性。值得注意的是,半乳糖凝集素-9 高小胶质细胞亚群在功能上与脑肿瘤微环境中的半乳糖凝集素-9neg/低亚群不同。半乳糖凝集素-9 高小胶质细胞表现出炎症激活的特性和较高的细胞死亡率,而半乳糖凝集素-9 neg/低小胶质细胞表现出对脑肿瘤细胞的优越吞噬能力。在小鼠神经胶质瘤模型中,半乳糖凝集素-9 的阻断抑制了肿瘤生长并改变了神经胶质细胞和 T 细胞的活性。此外,在缺氧性脑肿瘤微环境中,神经胶质半乳糖凝集素-9 的表达受 Hif-2α 的调节。髓系特异性 Hif-2α 缺陷导致肿瘤进展减轻。总之,这些发现揭示了髓系细胞上的半乳糖凝集素-9 是脑肿瘤中的免疫调节剂和推定的治疗靶点。
更新日期:2024-08-29
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