神经周围侵犯（PNI）是唾液腺腺样囊性癌（SACC）和其他神经性肿瘤的一个臭名昭著的特征。 PNI 的发病机制涉及肿瘤与受影响神经之间的分子通讯，目前尚不清楚。 SACC细胞与背根神经节（DRG）或神经细胞的体外共培养实验表明，神经源性CCL2激活SACC细胞中CCR2的表达，通过ERK1/促进SACC细胞的增殖、粘附、迁移和侵袭。 2/ITGβ5 途径。同时，SACC 衍生的外泌体递送 ITGβ5 以促进神经细胞或 DRG 的神经突生长。在体外模型中，通过 DRG 与 SACC 细胞的 3D 共培养，以及在体内通过将 SACC 细胞异种移植到小鼠坐骨神经上，CCL2/CCR2 轴或 ITGβ5 的阻断抑制了 SACC 细胞的 PNI。组织或血浆外泌体中高水平的ITGβ5与组织中CCL2和CCR2的表达显着相关，并与PNI和SACC病例的不良预后相关。我们的研究结果揭示了 SACC PNI 期间由 CCL2/CCR2 轴和外泌体 ITGβ5 驱动的神经细胞和肿瘤细胞之间的一种新的相互循环。本研究可能通过针对神经-肿瘤相互作用为 SACC 患者提供前瞻性诊断和抗 PNI 治疗策略。版权所有 © 2024。由 Elsevier B.V. 出版。

Perineural invasion (PNI) is a notorious feature of salivary adenoid cystic carcinoma (SACC) and other neurotropic tumors. The pathogenesis of PNI that involves the molecular communication between the tumor and the suffered nerve is elusive. The in vitro co-culture assays of SACC cells with dorsal root ganglia (DRG) or neural cells showed that nerve-derived CCL2 activated CCR2 expression in SACC cells, promoting the proliferation, adhesion, migration, and invasion of SACC cells via the ERK1/2/ITGβ5 pathway. Meanwhile, SACC-derived exosomes delivered ITGβ5 to promote the neurite outgrowth of neural cells or DRG. Blocking of CCL2/CCR2 axis or ITGβ5 inhibited the PNI of SACC cells in models in vitro by 3D co-culture of DRG with SACC cells and in vivo by xenografting SACC cells onto the murine sciatic nerve. High levels of ITGβ5 in tissues or plasma exosomes were significantly correlated with CCL2 and CCR2 expression in the tissues and associated with PNI and poor prognosis of SACC cases. Our findings revealed a novel reciprocal loop between neural and tumor cells driven by the CCL2/CCR2 axis and exosomal ITGβ5 during PNI of SACC. The present study may provide a prospective diagnostic and anti-PNI treatment strategy for SACC patients via targeting the nerve-tumor interactions.Copyright © 2024. Published by Elsevier B.V.