Involvement of chemokine receptors in breast cancer metastasis

Breast cancer is characterized by a distinct metastatic pattern involving t he regional lymph nodes, bone marrow, lung and liver. Tumour cell migration and metastasis share many similarities with leukocyte trafficking, which i s critically regulated by chemokines and their receptors. Here we report th at the chemokine receptors CXCR4 and CCR7 are highly expressed in human bre ast cancer cells, malignant breast tumours and metastases. Their respective ligands CXCL12/SDF-1 alpha and CCL21/6Ckine exhibit peak levels of express ion in organs representing the first destinations of breast cancer metastas is. In breast cancer cells, signalling through CXCR4 or CCR7 mediates actin polymerization and pseudopodia formation, and subsequently induces chemota ctic and invasive responses. In vivo, neutralizing the interactions of CXCL 12/CXCR4 significantly impairs metastasis of breast cancer cells to regiona l lymph nodes and lung. Malignant melanoma, which has a similar metastatic pattern as breast cancer but also a high incidence of skin metastases, show s high expression levels of CCR10 in addition to CXCR4 and CCR7. Our findin gs indicate that chemokines and their receptors have a critical role in det ermining the metastatic destination of tumour cells.