Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone.

TLDR

Neoplasms frequently metastasize to bone, a process analogous to embryonic hematopoietic cell homing that relies on the SDF‑1/CXCL12–CXCR4 chemokine axis expressed by osteoblasts and endothelial cells. The study hypothesizes that metastatic prostate cancers exploit the SDF‑1/CXCR4 pathway to home to bone. The authors assessed CXCR4 expression in prostate cancer cell lines via RT‑PCR and Western blot, then performed in vitro adhesion and invasion assays showing that SDF‑1 enhances adhesion to osteosarcoma and endothelial cells and promotes basement‑membrane invasion, effects blocked by CXCR4 antibody. The data demonstrate that bone‑metastasizing prostate cancer lines express CXCR4, migrate toward SDF‑1, and exhibit SDF‑1‑stimulated adhesion and invasion that are CXCR4‑dependent, supporting the hypothesis that the SDF‑1/CXCR4 axis mediates bone metastasis.

Abstract

Neoplasms have a striking tendency to metastasize or "home" to bone. Hematopoietic cells also home to bone during embryonic development, where evidence points to the chemokine stromal cell-derived factor-1 (SDF-1 or CXCL12; expressed by osteoblasts and endothelial cells) and its receptor (CXCR4) as key elements in these processes. We hypothesized that metastatic prostate carcinomas also use the SDF-1/CXCR4 pathway to localize to the bone. To test this, levels of CXCR4 expression were determined for several human prostate cancer cell lines by reverse transcription-PCR and Western blotting. Positive results were obtained for cell lines derived from malignancies that had spread to bone and marrow. Prostate cancer cells were also observed migrating across bone marrow endothelial cell monolayers in response to SDF-1. In in vitro adhesion assays, pretreatment of the prostate cancer cells with SDF-1 significantly increased their adhesion to osteosarcomas and endothelial cell lines in a dose-dependent manner. Invasion of the cancer cell lines through basement membranes was also supported by SDF-1 and inhibited by antibody to CXCR4. Collectively, these results suggest that prostate cancers and perhaps other neoplasms may use the SDF-1/CXCR4 pathway to spread to bone.