RESUMO
Control of breast-to-brain metastasis remains an urgent unmet clinical need. While chemotherapies are essential in reducing systemic tumor burden, they have been shown to promote non-brain metastatic invasiveness and drug-driven neurocognitive deficits through the formation of neurofibrillary tangles (NFT), independently. Now, in this study, we investigated the effect of chemotherapy on brain metastatic progression and promoting tumor-mediated NFT. Results show chemotherapies increase brain-barrier permeability and facilitate enhanced tumor infiltration, particularly through the blood-cerebrospinal fluid barrier (BCSFB). This is attributed to increased expression of matrix metalloproteinase 9 (MMP9) which, in turn, mediates loss of Claudin-6 within the choroid plexus cells of the BCSFB. Importantly, increased MMP9 activity in the choroid epithelium following chemotherapy results in cleavage and release of Tau from breast cancer cells. This cleaved Tau forms tumor-derived NFT that further destabilize the BCSFB. Our results underline for the first time the importance of the BCSFB as a vulnerable point of entry for brain-seeking tumor cells post-chemotherapy and indicate that tumor cells themselves contribute to Alzheimer's-like tauopathy.
Assuntos
Doença de Alzheimer , Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Feminino , Metaloproteinase 9 da Matriz/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismoRESUMO
Macrophages have recently gained attention in systemic lupus erythematosus (SLE) pathogenesis for their role in the anti-inflammatory clearance of apoptotic cells. The M1/M2 polarization of macrophages improves efferocytic capability. Peroxisome proliferator-activated receptor γ is proposed to function in the expansion of the M2 subpopulation. Pioglitazone is a peroxisome proliferator-activated receptor γ agonist with a variety of anti-inflammatory effects. In this paper, we investigated the ex vivo alterations of monocyte-derived macrophages of 15 newly diagnosed SLE patients and 10 normal subjects triggered by apoptotic cells among SLE patients following pioglitazone treatment. The phagocytosis capacity of macrophages and M1/M2 polarization (CD86/CD163) was evaluated. The supernatants were also analyzed for the expression of interleukin (IL)-10, IL-12, transforming growth factor ß1 and TNF-α. The mRNA expression of IL-1ß and mannose receptor C-type 1 were also quantified among treated and non-treated monocyte-derived macrophages. We found that efferocytosis is defective among monocyte-derived macrophages of SLE patients and might be a major underlying mechanism involved in the sustained inflammation. Pioglitazone could enhance alternative activation of monocyte-derived macrophages and consequently immunomodulation in these patients.