Tumor cell-specific blockade of CXCR4/SDF-1 interactions in prostate cancer cells by hTERT promoter induced CXCR4 knockdown: A possible metastasis preventing and minimizing approach

Abstract

Stromal cell-derived factor-1 (SDF-1)/CXCR4 pathway has been shown to play an important role in prostate cancer (PCa) metastasis and siRNA expression using cell-specific promoters has been demonstrated to be a potential tool for targeted gene therapy. Here, we illustrate that human telomerase reverse transcriptase (hTERT) promoter-induced CXCR4 knockdown inhibits PCa bone metastasis. We first investigated CXCR4 expressions and interactions of CXCR4/SDF-1 in PCa cells, developed a retrovirus system that could stably express CXCR4 small hairpin RNA driven by hTERT promoter and then determined the inhibitory effects of cell-specific blockade of CXCR4/SDF-1 pathway on PCa metastasis. It was shown that both PCa tissues and cell lines expressed CXCR4 and the expression in PCa tissue had a positive correlation to clinical stages while not to Gleason scores or serum PSA level. PCa metastases most presenting human tissues expressed high levels of SDF-1. Exogenous SDF-1 enhanced in vitro adhesion, migration and invasion of PCa cells and these bioeffects were repressed by hTERT promoter-induced CXCR4-shRNA expression. This CXCR4 knockdown was also found to significantly inhibit bone metastasis in vivo. We conclude that CXCR4/SDF-1 pathway plays an important role in PCa bone metastasis. hTERT promoter-induced tumor cell-specific CXCR4 gene silencing may prevent in vitro invasiveness and in vivo bone metastasis of PCa. These findings may enable new avenues of prevention and treatment for PCa metastasis.

Human aging and CD31+T-cell number, migration, apoptotic susceptibility, and telomere length

“…Diminished receptor expression would limit chemotactic responses to VEGF and SDF-1␣, thus impairing migratory capacity. Moreover, several investigations (32,39) have shown that telomerase activity is positively linked to CXCR4/SDF-1␣ expression. Therefore, it is possible that the blunted migratory capacity observed in CD31 ϩ T cells from middle-aged and older men is due, at least in part, to reduced telomerase activity.…”

Mesenchymal stem cells in prostate cancer have higher expressions of SDF-1, CXCR4 and VEGF

“…Recent studies have confirmed that the SDF-1/CXCR4 system plays an important role in tumor invasion. Xing et al find that CXCR4 has positive expression in several human prostate cancer cell lines with bone metastasis (Xing et al 2008). At the same time, they have observed that prostate cancer cells can invade through the single layer of endothelial cells in bone marrow through SDF-l/CXCR4, which can be inhibited by CXCR4 antibody.…”

“…Some studies have shown that the SDF-1/CXCR4 has close relationship with proliferation of tumor cells (Kang et al 2005). Vaday et al (2004) and Xing et al (2008) have found the high expression of CXCR4 mRNA in clinical PCa specimens and a variety of PCa cell lines. Recent studies have confirmed that the SDF-1/CXCR4 system plays an important role in tumor invasion.…”

Chemokines and Bone

“…The expression of CXCR4 is positively regulated by androgen receptor (AR), a critical player in the survival and proliferation of prostate cells. Using a retrovirus system to stably express CXCR4 small hairpin RNA, Xing et al [150] found knockdown of CXCR4 decreased overall bone metastasis in vivo. Furthermore, transplanted hematopoietic stem cells and PC cells localize to the same (endosteal) region of BM [151].…”