Relevance of CCL3/CCR5 axis in oral carcinogenesis

Abstract

The chemokine CCL3 is a chemotactic cytokine crucial for inflammatory cell recruitment in homeostatic and pathological conditions. CCL3 might stimulate cancer progression by promoting leukocyte accumulation, angiogenesis and tumour growth. The expression of CCL3 and its receptors CCR1 and CCR5 was demonstrated in oral squamous cell carcinoma (OSCC), but their role was not defined. Here, the functions of CCL3 were assessed using a model of chemically induced tongue carcinogenesis with 4-nitroquinoline-1-oxide (4NQO). Lineages of OSCC were used to analyse the effects of CCL3 in vitro. The 4NQO-induced lesions exhibited increased expression of CCL3, CCR1 and CCR5. CCL3-/- and CCR5-/- mice presented reduced incidence of tongue tumours compared to wild-type (WT) and CCR1-/- mice. Consistently, attenuated cytomorphological atypia and reduced cell proliferation were observed in lesions of CCL3-/- and CCR5-/- mice. OSCC from CCL3-/- mice exhibited lower infiltration of eosinophils and reduced expression of Egf, Fgf1, Tgf-β1, Vegfa, Vegfb, Itga-4, Vtn, Mmp-1a, Mmp-2 and Mmp-9 than WT mice. In vitro, CCL3 induced invasion and production of CCL5, IL-6, MMP -2, -8, -9. Blockage of CCL3 in vitro using α-CCL3 or Evasin-1 (a CCL3-binding protein) impaired tumour cell invasion. In conclusion, CCL3/CCR5 axis has pro-tumourigenic effects in oral carcinogenesis. The induction of inflammatory and angiogenic pathways and eosinophils recruitment appear to be the underlying mechanism explaining these effects. These data reveal potential protective effects of CCL3 blockade in oral cancer.

Clinicopathological significance of chemokine receptor (CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4) expression in head and neck squamous cell carcinomas

“…18 The CCL3/CCR5 axis also promotes pro-tumorigenic effects in oral cancer. 19 Furthermore, CCR5 expression is associated with the recruitment of myeloid-derived suppressor cells in melanoma, promoting the tumour progression, 20 but this association was not being studied in HNSCCs. Additionally, polymorphisms in CCR5…”

“…However, it was reported that the CCL5/CCR5 axis promotes the motility of oral cancer cells via upregulation of MMP‐9 production, suggesting its role in metastasis . The CCL3/CCR5 axis also promotes pro‐tumorigenic effects in oral cancer . Furthermore, CCR5 expression is associated with the recruitment of myeloid‐derived suppressor cells in melanoma, promoting the tumour progression, but this association was not being studied in HNSCCs.…”

Mouse Tumor-Bearing Models as Preclinical Study Platforms for Oral Squamous Cell Carcinoma

“…In the combined model, in contrast to simple 4NQO induction, specific gene deletion or overexpression can be studied; compared with simple GEMMs, more specific OSCC can be induced, and genetic changes that are not directly carcinogenic can be investigated. This model can be used to study the role of miRNA (199,200), proteins (82, 184,203), and pathways (201,202) involved in the carcinogenesis of OSCC. Furthermore, the knock-in of green fluorescent protein can be used to label cells with specific gene changes (158,199).…”

Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function

“…In the gene ontology (GO) analysis using these 233 genes, migrationrelated GO terms were dominant (Additional file 1: Figure S8), which is consistent with the role of EICD in cell motility. Notably, several chemokine ligands (CCL3, CCL20, and CXCL2), widely studied as mediators of epithelialmesenchymal transition, tumorigenesis, and metastasis [31][32][33][34][35], were increased ( Fig. 5a) and top-ranked in terms of the fold increase (Additional file 2: Table S1).…”