Neu (HER2/ErbB2) is over-expressed in 25-30% of human breast cancer, correlating with a poor prognosis. Previous studies using the Neu transgenic mouse model (MMTV-Neu) demonstrated that the Neu-YB line had increased production of CXCL12 and increased metastasis, while the Neu-YD line had decreased metastasis. This study examines the role of increased production of CXCL12 in tumor cell invasion and malignancy.

We studied invasion in the tumor microenvironment using multiphoton intravital imaging, in vivo invasion, and intravasation assays. CXCL12 signaling was altered by using the CXCR4 inhibitor AMD3100 or increasing CXCL12 expression. The role of macrophage signaling in vivo was determined using a colony stimulating factor-1 (CSF-1) receptor blocking antibody.

The Neu-YD strain was reduced in invasion, intravasation, and metastasis compared to the Neu-YB and Neu-NDL strains. Remarkably, for the Neu-YB strain, in vivo invasion to epidermal growth factor was dependent on both CXCL12/CXCR4 and CSF1/CSF1R signaling. Neu-YB tumors had increased macrophage and microvessel density. Over-expression of CXCL12 in MTLn3 cells increased in vivo invasion, as well as microvessel and macrophage densities.

Expression of CXCL12 by tumor cells results in increased macrophage and microvessel density and in vivo invasiveness.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.