The CCL5/CCR5 Chemotactic Pathway Promotes Perineural Invasion in Salivary Adenoid Cystic Carcinoma

Abstract

Perineural invasion (PNI) is a hallmark of salivary adenoid cystic carcinoma (SACC) and represents an important risk factor for local recurrence and poor survival. However, the mechanism of PNI has yet to be explored. We sought to examine the CCL5-CCR5 ligand-receptor interaction between nerves and SACC cells. CCL5/CCR5 expression was determined by immunohistochemistry in SACC tissue specimens. The correlations between CCL5/CCR5 expression and clinicopathologic features were investigated. Dorsal root ganglia (DRG) and SACC cells cocultured invitro were used to evaluate the effects of CCL5/CCR5 on PNI progression and pathogenesis. CCR5 expression was significantly elevated in SACC tissues and associated with distant metastasis, PNI, and TNM grade (P<.05). DRG and SACC cells cocultured invitro showed that the activation of the CCL5/CCR5 axis significantly increased SACC cell invasion and promoted the outgrowth of the DRG. SACC cell lines expressing CCR5 migrated in response to CCL5 derived from DRG, eventually leading toPNI. More importantly, further study showed that blocking of CCL5 or CCR5 effectively inhibited the invasive capacity and PNI activity of SACC cells (P<.05). Our results suggest a pivotal role of CCL5/CCR5 axis in tumor-nerve interactions during PNI of SACC. The CCL5/CCR5 pathway might prove to be an attractive new target for the treatment of SACC with PNI.