Nature子刊综述:肿瘤相关成纤维细胞的临床和治疗关联

2021-09-19 外泌体资讯网 外泌体资讯网

肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤微环境中最主要的成分之一,在肿瘤的发生发展中发挥着必不可少的作用。骨髓和脂肪的局部组织固有成纤维细胞及间

肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤微环境中最主要的成分之一,在肿瘤的发生发展中发挥着必不可少的作用。骨髓和脂肪的局部组织固有成纤维细胞及间充质干细胞是CAFs来源的主要前体细胞。大量研究表明,CAFs并不作为单独细胞在肿瘤周围存在,而是和肿瘤细胞相互作用,促进肿瘤的生长与存活并维持其恶性倾向。肿瘤细胞可以影响CAFs前体的招募,并诱导正常成纤维细胞活化为CAFs;同时,CAFs可以分泌多种细胞因子、生长因子和细胞外基质蛋白质,促进肿瘤细胞的增殖、耐药及侵袭转移,从而影响肿瘤的预后。CAFs还参与血管淋巴管的生成、细胞外基质重塑、免疫抑制以及肿瘤细胞上皮间质转化等有利于肿瘤发生发展的外源性途径,为肿瘤细胞提供了一个良好的微环境。大量研究显示,研发靶向CAFs的药物可以中断其与肿瘤细胞之间的联系,从而抑制肿瘤的生长和转移。

近日,外泌体领域大牛、MD安德森癌症中心的RaghuKalluri教授在Nature Reviews Clinical Oncology杂志上发表综述,总结了肿瘤相关成纤维细胞 (CAF)的临床相关性,并强调了它们作为预后因素和治疗靶点的价值。其中包含外泌体相关内容,如成纤维细胞中金属蛋白酶组织抑制蛋白 (TIMP) 表达的基因缺失与ECM沉积增加和肿瘤生长以及含有去整合素和金属蛋白酶结构域蛋白10 (ADAM10) 的促迁移外泌体的分泌有关;来自CAFs的外泌体也被证明含有各种表面蛋白(如WNT)和代谢物(如TCA循环中间体),可以影响TME中的其他细胞群,从而影响癌症进展、基质重塑和耐药性。

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在原发性和转移性肿瘤中发现的癌症相关成纤维细胞 (CAF) 是高度多功能的、可塑的和有弹性的细胞,它们通过与肿瘤微环境中其他细胞类型的复杂相互作用积极参与癌症进展。除了产生有助于肿瘤基质结构和功能的细胞外基质成分外,CAF还会发生表观遗传变化,产生影响肿瘤血管生成、免疫学和代谢的分泌因子、外泌体和代谢物。由于其推定的促癌功能,CAF长期以来一直被认为是有吸引力的治疗靶点。然而,针对CAF的治疗策略的临床试验大多以失败告终,并且在某些情况下加速了癌症进展并导致较差的生存结果。重要的是,CAF是异质细胞,它们的特征和与其他细胞类型的相互作用可能会随着癌症的发展而动态变化。涉及单细胞RNA 测序和新型小鼠模型的研究增加了我们对CAF多样性的理解,尽管不同CAF种群的相关作用及其可互换的可塑性在很大程度上仍然未知。CAF亚型的促肿瘤和抑制肿瘤活性的综合表征,包括这些复杂的双重功能如何在癌症进展过程中演变和被肿瘤细胞抑制,可能有助于开发新的诊断和治疗方法。在这篇综述中,总结了CAF的临床相关性,并强调了它们作为预后因素和治疗靶点的价值。

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CAFs的激活

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具有抑制肿瘤和促进肿瘤功能的CAFs的异质性和可塑性

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解释CAFs在癌症中的不同功能和表型的建议模型

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CAFs与肿瘤微环境中其他细胞类型之间的相互作用

来自University of Southampton的科研人员发现:在包括头颈部肿瘤、直肠肿瘤在内的多种肿瘤组织中,CAF细胞分布越多,肿瘤患者生存率越低。成纤维细胞向CAF细胞的转变需要依赖NOX4酶(属于NADPH氧化酶家族),研究发现,在多种肿瘤细胞中均观察到NOX4酶表达水平的显著升高,这与肿瘤组织中的CAF细胞量呈强相关性。基因水平上或用小分子化合物抑制NOX4的表达均可以改变CAF细胞的表型,包括细胞表面α-平滑肌肌动蛋白(α-SMA)表达的减少,另外,在多种肿瘤类型的荷瘤小鼠体内实验表明:抑制NOX4的表达可以阻止CAF细胞在肿瘤组织中的聚集,抑制肿瘤的生长,使肿瘤缩小30.6%-64.0%。以CAF细胞上的NOX4酶作为靶点,开发出能抑制NOX4的化合药物,未来将可能在临床上广泛应用于多种肿瘤的治疗。目前这种药物正处于研发中。

参考文献:

ChenY, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol.2021 Sep 6. doi: 10.1038/s41571-021-00546-5. PMID: 34489603.

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    2021-09-19 医者仁者

    太高深了

    0

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    2021-09-19 病毒猎手

    #肿瘤相关成纤维细胞#虽然是热点,它的主要治疗靶点为#NOX4#,但是真正成药还是有相当难度的,也许NOX4的特异性仍然不够。此前有研究显示,研究人员对20例人类恶性实体肿瘤的组织芯片分析显示,与正常组织相比,#膀胱癌#、食道癌、头颈部癌、卵巢癌、前列腺癌和黑色素瘤中IHC差异的NOX4表达较高,表明在具体的人类肿瘤标本中,NOX4表达是增加的。除此之外,对卵巢癌细胞株COV362的免疫荧光实验显示,NOX4表达位于核周区域,表明#卵巢癌#细胞中高水平的内源性NOX4表达仅与核周膜相关。https://www.medsci.cn/article/show_article.do?id=63ff1014107e 但是,NOX4特异性仍然存疑!另外,这是核内蛋白,也许#PROTAC#技术有助于成药。

    0

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