Astrocyte-breast cancer interactions facilitate brain metastasis

Diagnosis and treatment of breast cancer patients have been considerably improved, including those at the metastatic stage. However, brain metastasis still presents a major clinical challenge, and it is a leading cause of death. Unfortunately, there are no targeted therapies specific for this secondary tumor formation, and the current treatment modalities present limited clinical outcomes. Thus, better understanding of the pathways involved in the metastatic cascade, which lead to brain metastases colonization and progression, is essential. To that end, the mutual effects of astrocytes and breast cancer cells have been investigated, using the traditional 2-dimensional cell-culture and a 3-dimensional model of multicellular breast cancer brain metastases spheroids. We found that astrocytes enhance the proliferation, migration and invasion of breast cancer cells, suggesting a supportive role for astrocytes in the metastatic process of breast cancer in the brain. Using a protein array, we identified several cytokines to be elevated following the co-culturing of breast cancer cells with astrocytes, suggesting them as potential key candidates involved in breast cancer-brain stroma interactions. One of these cytokines was CCL2, which is a chemokine that is associated with poor prognosis in breast cancer patients. When it was functionally neutralized, breast cancer cell proliferation, migration and invasion were reduced. Similar results were obtained by applying Amphiphilic poly (α) glutamate polymeric micelles¹ carrying a small molecular-weight inhibitor of the CCL2-CCR2/4 axis. Considering these results, CCL2 is suggested as one of the key factors promoting breast cancer brain metastasis. Although further validation using in vivo models is still required, this study deepens our understanding of the contribution of the metastatic breast cancer cells-brain microenvironment crosstalk to brain colonization. Taken together, our findings may be utilized to provide a novel therapeutic approach for the prevention of breast cancer brain metastasis following resection of the primary lesion.

1. Krivitsky, Adva, et al. "Amphiphilic poly (α) glutamate polymeric micelles for systemic administration of siRNA to tumors." Nanomedicine: Nanotechnology, Biology and Medicine 14.2 (2018): 303-315.