CXC chemokine receptor CXCR4 expression enhances tumorigenesis and angiogenesis of basal cell carcinoma

Abstract

Chemokines and their receptors, well known for their ability to attract leucocytes, also play important roles for tumour progression. To investigate the possible involvement of chemokine receptors in the pathogenesis of cutaneous basal cell carcinoma (BCC). We performed an expression analysis of chemokine receptors using a well-characterized human BCC cell line. Upon the finding of CXCR4 expression by BCC, retroviral transduction of BCC cells with the CXCR4 gene was employed to address its functional significance for BCC in vitro and in vivo. We found expression of the CXC chemokine receptor CXCR4 by a human cell line and a subset of tissue samples from BCC, especially in noduloulcerative and sclerosing types. Following treatment with CXCL12, the ligand for CXCR4, CXCR4-transduced BCC cells (CXCR4-BCC) showed increased proliferation under low serum concentration and resistance to apoptosis induced by ultraviolet B irradiation in vitro. Conditioned media from CXCR4-BCC preincubated with CXCL12 enhanced tubule formation of human endothelial cells in vitro. These responses of CXCR4-BCC were negated by cotreatment with either neutralizing antibodies or specific blocking peptides for CXCR4 in vitro. Moreover, xenograft tumour transplants produced by injection of CXCR4-BCC yielded significant tumour progression in nude mice, whereas additional serial injections of CXCR4-blocking peptides resulted in tumour regression. CXCR4 expression may play a critical role in tumour progression and angiogenesis of certain subtypes of BCC with more aggressive nature, and functional blockade of CXCR4 could be a potential therapeutic strategy for these tumours.