意外发现!免疫疗法治疗胃癌的新思路 | Immunity
2018/04/26
胃癌是常见癌症之一,早期诊断率和生存率都较低。许多胃癌的发生与长期不受控制的炎症有关。近期,科学家们在一个驱动癌症发生的蛋白家族中找到一个“异类”——它的低表达甚至于缺失会促进胃癌发生。


Researchers have made the surprise discovery that the 'odd one out' in a family of proteins known to drive cancer development is instead critical for preventing stomach cancers.The research team from the Walter and Eliza Hall Institute in Melbourne, Australia, showed switching off a gene called NF-κB1 caused spontaneous development of stomach cancers, driven by chronic inflammation. Credit: Walter and Eliza Hall Institute

这一最新研究发表于Cell子刊《Immunity》上,由墨尔本Walter and Eliza Hall 研究所的Andreas Strasser教授、莫纳什大学的Steve Gerondakis教授带领团队完成。

他们发现,抑制NF-κB1蛋白表达会导致慢性炎症朝着胃癌的方向发展。这意味着,NF-κB1蛋白是防治胃癌的关键。


doi.org/10.1016/j.immuni.2018.03.003

有悖于已有研究

文章一作Lorraine O'Reilly博士表示,这一发现让他们很意外,因为已有研究表明,NF-κB家族成员的高表达是造成胃癌及其他癌症的诱因。

然而,最新研究揭示,NF-kB1是家族里的“异类”——在诱导胃癌发生过程中,NF-kB1的表达量异常低。“我们发现,低水平的NF-kB1会导致胃部发生不受控制的严重炎症反应。长期下去,这会诱导侵袭性胃癌的发生。”O'Reilly博士说道。

免疫疗法治疗胃癌

最新研究第一次构建了胃癌的临床前模型,还原了人类胃癌发展的过程,从慢性胃炎到完全侵袭性胃癌的发生。结果显示,NF-kB1缺失会导致JAK-STAT信号紊乱,进而导致炎症、抗原呈递和免疫检查点表达异常。

这提醒我们,免疫疗法有望成为治疗胃癌的重要方案,例如免疫检查点抑制剂。总而言之,这项研究不仅为进一步研究胃癌的免疫疗法提供了让人信服的证据,而且还为该治疗策略的临床前检测提供了首个模型。

责编:悠然

参考资料:

Odd one out: Protein goes against the family to prevent cancer

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  • Loss of NF-κB1 Causes Gastric Cancer with Aberrant Inflammation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner

    Polymorphisms in NFKB1 that diminish its expression have been linked to human inflammatory diseases and increased risk for epithelial cancers. The underlying mechanisms are unknown, and the link is perplexing given that NF-κB signaling reportedly typically exerts pro-tumorigenic activity. Here we have shown that NF-κB1 deficiency, even loss of a single allele, resulted in spontaneous invasive gastric cancer (GC) in mice that mirrored the histopathological progression of human intestinal-type gastric adenocarcinoma. Bone marrow chimeras revealed that NF-κB1 exerted tumor suppressive functions in both epithelial and hematopoietic cells. RNA-seq analysis showed that NF-κB1 deficiency resulted in aberrant JAK-STAT signaling, which dysregulated expression of effectors of inflammation, antigen presentation, and immune checkpoints. Concomitant loss of STAT1 prevented these immune abnormalities and GC development. These findings provide mechanistic insight into how polymorphisms that attenuate NFKB1 expression predispose humans to epithelial cancers, highlighting the pro-tumorigenic activity of STAT1 and identifying targetable vulnerabilities in GC.

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