The expression of chemokine receptor CCR7 has been associated with various neoplasms, including breast cancer; however the exact role of CCR7 remains unknown. Many studies have shown a correlation of CCR7 with increased metastatic potential and poor prognosis, however there was no proof for the direct role of CCR7 in an in vivo model. Using a PyMT transgenic mouse model for breast cancer together with a CCR7 null mutant, we have provided the first evidence for the critical role of CCR7 in mammary tumourigenesis. As this process is governed by the activity of cancer stem cells, it was hypothesised that CCR7 plays a role in regulating cancer stem cells in breast disease.
CCR7 is expressed on the surface of breast cancer stem cells of both mouse and human origin. Furthermore, CCR7 is functional in these populations, as the receptor responds to ligand stimulation in mammosphere culture, and the presence of CCR7 is vital for the maintenance of stem cell content and self-renewal. Moreover, CCR7 sustains the tumour-initiating cell frequency and self-renewal capacity of stem cells in the epithelium. This provides for the first time direct evidence for the important role of CCR7 in breast tissue stem cell pathobiology. In order to then define a clinical role for targeting CCR7 we used a truncated ligand antagonist, CCL19(8-83), to block the function of CCR7. Most importantly, treatment with this antagonist significantly reduces the cancer stem cell-enriched population in vivo.
Our data demonstrate that CCR7 plays a major role in maintenance of stem cell populations. This finding may have important implications for the delineation of breast cancer initiation and progression. Targeting CCR7 in the context of breast cancer stem cells could potentially supplement conventional chemotherapy protocols that target the rapidly-proliferating bulk tumour mass but fail to eliminate the quiescent tumour-propagating cancer stem cells.