1. Academic Validation
  2. CCL2/CCR2 axis promotes perineural invasion of salivary adenoid cystic carcinoma via ITGβ5-mediated nerve-tumor interaction

CCL2/CCR2 axis promotes perineural invasion of salivary adenoid cystic carcinoma via ITGβ5-mediated nerve-tumor interaction

  • Biochim Biophys Acta Mol Basis Dis. 2024 Aug 31;1871(1):167484. doi: 10.1016/j.bbadis.2024.167484.
Zihui Yang 1 Huan Li 1 Jun Wang 1 Wanpeng Gao 1 Qi Zhao 1 Qingzhe Meng 1 Junhong Huang 1 Qi Xi 1 Jianhua Wei 2 Xinjie Yang 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an 710032, China.
  • 2 State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: weiyoyo@fmmu.edu.cn.
  • 3 State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an 710032, China. Electronic address: yangxinjie@fmmu.edu.cn.
Abstract

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.

Keywords

CCL2; CCR2; Exosomes; ITGβ5; Perineural invasion; Salivary adenoid cystic carcinoma.

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