The majority of cancer-related deaths occur due to the development of metastatic tumours. Solid evidence implicates the protein family of chemokines and their cognate receptors in several aspects of neoplastic development and progression, and chemokine receptors CXCR4 and CCR7 have been assigned major roles in advancing metastatic dissemination of various tumours. A multitude of data from clinical and laboratory studies supports a critical function for these G-protein coupled receptors (GPCRs) in the pathobiology of malignant breast tumours, however the fundamental biochemical and cellular mechanisms that underpin the critical role of these chemokine receptors in metastasis are as yet unknown.
The latest paradigm suggests that chemokine receptors exist as homo- and/or heterodimers. We have found that native chemokine receptors CXCR4 and CCR7 physically and functionally interact in breast and colon cancer cells. Moreover we have demonstrated that their interaction on the cell surface is a prerequisite for cell metastatic behaviour. Thus, using a variety of methods, we have documented the presence of heterodimeric CXCR4/CCR7 chemokine receptors in cancer cell lines as well as mouse and human primary tumours. Importantly, we have also correlated the formation of this novel receptor dimer with the activation of both CXCR4 and CCR7 and metastatic phenotype. Specifically, we have established that dimeric receptors are only detected on metastatic cells and tumours where activation of both CXCR4 and CCR7 can be induced by their respective ligands. However, in benign or non-invasive cancer cells, while individual CXCR4 and CCR7 receptors are still expressed on the cell surface, they do not heterodimerise and both receptors are silent.
Most importantly, we have discovered a highly significant correlation between levels of the CXCR4/CCR7 heterodimeric receptor and stage/grade of human primary mammary tumours. These novel findings may potentially have far-reaching implications for fundamental chemokine receptor biology, cancer research and cancer therapeutics.