Head and neck cancer exosomes drive microRNA-mediated reprogramming of local neurons.
Head and neck cancer exosomes drive microRNA-mediated reprogramming of local neurons.
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头颈癌外泌体驱动局部神经元的microRNA介导的重编程。
DOI：
10.20517/evcna.2020.04
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Amit M
中科院分区：
文献类型：
--
作者：
Hunt PJ;Amit M
实体瘤是由良性组织包围的复杂细胞集合，良性组织影响肿瘤并受肿瘤影响。这些周围的细胞包括脉管系统、免疫细胞、神经元和其他细胞类型，统称为肿瘤微环境。肿瘤为了肿瘤的利益而操纵它们的微环境。自主神经元支配并驱动多种实体瘤的恶性生长。然而，神经元-肿瘤关系的潜在机制还不清楚。最近，Amit等人描述了口腔鳞状细胞癌（OCSCC）和附近自主神经元之间的营养关系是通过肿瘤和局部神经元之间的直接信号传导产生的。将4 NQO引入Trp 53敲除小鼠的饮用水中的可诱导肿瘤模型用于模拟OCSCC-微环境相互作用。使用这个模型，这个小组发现在OCSCC肿瘤中p53表达的缺失导致这些肿瘤中神经密度的增加。这种轴突发生是由肿瘤来源的microRNA负载的细胞外囊泡（EV）控制的。具体而言，EV递送的miR-34 a抑制了轴突发生，而EV递送的miR-21和miR-324增加了轴突发生。支配p53缺陷型OCSCC肿瘤的神经元主要是肾上腺素能的，并且通过三叉神经感觉神经纤维向肾上腺素能神经纤维的转分化而产生。这种转分化与神经元重编程转录因子的表达增加相对应，包括POU 5 F1，KLF 4和ASCL 1，这些转录因子在p53缺陷样本中过表达，并且是miR-34 a介导的调控的目标。富含肾上腺素能神经元标志物的人OCSCC样本与不良结局密切相关，从而证明这些发现与癌症患者的相关性。
Solid tumors are complex collections of cells surrounded by benign tissues that influence and are influenced by the tumor. These surrounding cells include vasculature, immune cells, neurons, and other cell types, and are collectively known as the tumor microenvironment. Tumors manipulate their microenvironment for the benefit of the tumor. Autonomic neurons innervate and drive malignant growth in a variety of solid tumors. However, the mechanisms underlying neuron-tumor relationships are not well understood. Recently, Amit et al. described that trophic relationships between oral cavity squamous cell carcinomas (OCSCCs) and nearby autonomic neurons arise through direct signaling between tumors and local neurons. An inducible tumor model in which 4NQO was introduced into the drinking water of Trp53 knockout mice was used to model OCSCC-microenvironment interactions. Using this model, this group discovered that loss of p53 expression in OCSCC tumors resulted in increased nerve density within these tumors. This neuritogenesis was controlled by tumor-derived microRNA-laden extracellular vesicles (EVs). Specifically, EV-delivered miR-34a inhibited neuritogenesis, whereas EV-delivered miR-21 and miR-324 increased neuritogenesis. The neurons innervating p53-deficient OCSCC tumors were predominantly adrenergic and arose through the transdifferentiation of trigeminal sensory nerve fibers to adrenergic nerve fibers. This transdifferentiation corresponded with increased expression of neuron-reprogramming transcription factors, including POU5F1, KLF4, and ASCL1, which were overexpressed in the p53-deficient samples, and are proposed targets of miR-34a-mediated regulation. Human OCSCC samples enriched in adrenergic neuron markers are associated strongly with poor outcomes, thus demonstrating the relevance of these findings to cancer patients.
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影响因子：
7.3
作者：
Lynch C;Panagopoulou M;Gregory CD
通讯作者：
Gregory CD
影响因子：
9.7
作者：
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64.5
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通讯作者：
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影响因子：
64.8
作者：
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影响因子：
64.5
作者：
Murillo, Oscar D.;Thistlethwaite, William;Milosavljevic, Aleksandar
通讯作者：
Milosavljevic, Aleksandar