RESUMEN
Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.
Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Humanos , Femenino , Receptor Toll-Like 4/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Interleucina-6/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Neoplasias de la Mama/genética , Encéfalo/patología , Neoplasias Encefálicas/tratamiento farmacológico , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Microambiente TumoralRESUMEN
Ascorbic acid (AA), the reduced form of vitamin C, acts as a neuroprotector by eliminating free radicals in the brain. Sodium/vitamin C co-transporter isoform 2 (SVCT2) mediates uptake of AA by neurons. It has been reported that SVCT2 mRNA is induced in astrocytes under ischemic damage, suggesting that its expression is enhanced in pathological conditions. However, it remains to be established if SVCT expression is altered in the presence of reactive astrogliosis generated by different brain pathologies. In the present work, we demonstrate that SVCT2 expression is increased in astrocytes present at sites of neuroinflammation induced by intracerebroventricular injection of a GFP-adenovirus or the microbial enzyme, neuraminidase. A similar result was observed at 5 and 10 days after damage in a model of traumatic injury and in the hippocampus and cerebral cortex in the in vivo kindling model of epilepsy. Furthermore, we defined that cortical astrocytes maintained in culture for long periods acquire markers of reactive gliosis and express SVCT2, in a similar way as previously observed in situ. Finally, by means of second harmonic generation and 2-photon fluorescence imaging, we analyzed brain necropsied material from patients with Alzheimer's disease (AD), which presented with an accumulation of amyloid plaques. Strikingly, although AD is characterized by focalized astrogliosis surrounding amyloid plaques, SVCT2 expression at the astroglial level was not detected. We conclude that SVCT2 is heterogeneously induced in reactive astrogliosis generated in different pathologies affecting the central nervous system (CNS).