BREAST CANCER BRAIN METASTASIZATION: COMPARISON OF HIPPOCAMPAL AND CEREBELLAR PATTERNS

Abstract

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Aim. To decipher key aspects of breast cancer (BC) brain metastasization related with blood-brain barrier (BBB) transposition by malignant cells, their phenotype, and migratory and proliferative features, as well as to establish the regional pattern of the brain metastatic process. Material and Methods. Hippocampal and cerebellar sections of mice inoculated with BC cells (BCCs) were studied along metastasization (5 hours, 3, 7, and 10 days) by histologic/immunohistochemical/immunofluorescence analysis. Results and Discussion. Brain metastases were detected from 7 days onwards, with greater tumour area observed in the hippocampus. Accordingly, a higher number of cells expressing the proliferation marker Ki-67 and platelet-derived growth factor-B was observed in the hippocampus. Malignant cells entering in the parenchyma expressed the mesenchymal marker vimentin, whereas in metastasis the epithelial marker pan Cytokeratin was observed as well, particularly in the hippocampus. Moreover, an earlier expression of Rac 1 was observed in the hippocampus, compatible with mesenchymal-like migration. The brain metastatic process was accompanied by BBB alterations, depicted by impairment of tight and adherens junctions’ proteins claudin-5 and β-catenin, and enhanced caveolae protein’s expression, together with an earlier activation of myosin light chain kinase in pericytes, in the hippocampus. Conclusions. These results reveal the alterations occurring in BBB endothelial and mural cells along brain metastasization, and the ability of BCC to express growth factors and migration-associated proteins, essential for their survival and invasiveness. Moreover, they reveal that brain metastasization of BC occurs earlier and more severely in hippocampus than in cerebellum. Supported by FCT (Portugal) and NKFIH/OTKA (Hungary).