1. Department of Immunology, DNAX Research Institute, 901 California Avenue, Palo Alto, California 94304, USA
2. Departments of Radiation Oncology and Dermatology, Heinrich-Heine University, Moorenstrasse 5, D-40225 Düsseldorf, Germany
3. Department of Dermatology, University of Essen, Hufelandstrasse 55, D-45147 Essen, Germany
4. Instituto Nacional de Cancerología, Av. San Fernando 22, Tlalpan 14000 D.F., México
5. Instituto de Investigaciones Biomédicas, Ciudad Universitaria, 04510 D.F., México
6. These authors contributed equally to this work

Correspondence to: Albert Zlotnik¹ Correspondence and requests for materials should be addressed to A.Z. (e-mail: Email: azlotnik@eosbiotech.com).

Abstract

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