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

Abstract

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.

CCL3–CCR5 axis contributes to progression of esophageal squamous cell carcinoma by promoting cell migration and invasion via Akt and ERK pathways

“…Herein, we detected immunoreactivities for both CCL3 and CCR5 in the tumor nests of human ESCC tissues. These observations are consistent with those of immunohistochemical and immunofluorescent examinations of CCL3 and CCR5 in human or murine cancer tissues [ 17 , 20 , 21 , 23 , 26 , 27 , 32 , 34 – 36 ]. Our examination of double IF showed that CCL3 was expressed in both neoplastic cells and TAMs in the tumor nest of human ESCC tissue.…”

“…A high plasma level of CCL3 was associated with poor survival rate in chronic lymphocytic leukemia [ 66 ] and diffuse-large B-cell lymphoma [ 67 ]. CCR5 was reported to be associated with poor overall survival in breast cancer [ 34 ], poor relapse-free survival in prostate cancer [ 68 ], high histological grade in pancreatic cancer [ 35 ], and perineural invasion in salivary adenoid cystic carcinoma [ 36 ]. The present study is the first report which revealed that the expression of both CCL3 and CCR5 in human cancer tissue is associated with poor patient prognosis.…”

“…CCR5 is not only a receptor for CCL3 but also a receptor for the following members of the CC chemokine family: CCL4, CCL5, CCL8, and CCL3 like-1 (CCL3L1) [ 29 , 30 ]. CCR5 is expressed in various neoplastic cells including oral squamous cell carcinoma [ 27 ], murine renal cell carcinoma [ 20 ], chondrosarcoma [ 21 ], osteosarcoma [ 23 ], breast cancer [ 31 – 34 ], pancreatic cancer [ 35 ], salivary adenoid cystic carcinoma [ 36 ], and Hodgkin lymphoma [ 37 ]. CCR5 expressed in neoplastic cells contributes to cell migration, invasion and tumor progression not only via the CCL3–CCR5 axis [ 20 , 21 , 23 , 27 ], but also via the CCL5–CCR5 axis in breast cancer, pancreatic cancer, salivary adenoid cystic carcinoma, Hodgkin lymphoma, and ESCC [ 31 – 38 ].…”

<p>Sympathetic innervation contributes to perineural invasion of salivary adenoid cystic carcinoma via the &beta;2-adrenergic receptor</p>

“…PNI was defined as described previously 6. The IHC assay was performed using the streptavidin–biotin–peroxidase method, as we have previously described 13. Briefly, 5-μm-thick sections were cut from formalin-fixed, paraffin-embedded tissue specimens.…”

“…Recently, with the development of tumor microenvironment theory, an increasing number of studies have focused on reciprocal interactions between tumor cells and nerves 11. For example, we have investigated the effects of nerve growth factor and chemokine (C-C motif) ligand 5/C-C chemokine receptor type 5 signaling on PNI in SACC 13. In addition, data from several recent studies indicated that the sympathetic nervous system may play a key role in tumor progression 14,15.…”