Breast-to-brain metastasis is exacerbated with chemotherapy through blood–cerebrospinal fluid barrier and induces Alzheimer's-like pathology Journal Article

   

Authors:	Saatian, B.; Deshpande, K.; Herrera, R.; Sedighi, S.; Eisenbarth, R.; Iyer, M.; Das, D.; Julian, A.; Martirosian, V.; Lowman, A.; LaViolette, P.; Remsik, J.; Boire, A.; Sankey, E.; Fecci, P. E.; Shiroishi, M. S.; Chow, F.; Hurth, K.; Neman, J.
Article Title:	Breast-to-brain metastasis is exacerbated with chemotherapy through blood–cerebrospinal fluid barrier and induces Alzheimer's-like pathology
Abstract:	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. © 2023 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.
Keywords:	adult; cancer chemotherapy; controlled study; human tissue; protein expression; human cell; microscopy; fluorouracil; nonhuman; paclitaxel; chemotherapy; nuclear magnetic resonance imaging; brain tumor; brain neoplasms; mouse; metabolism; breast cancer; gelatinase b; animal experiment; animal model; immunofluorescence; in vitro study; breast neoplasms; enzyme linked immunosorbent assay; brain; messenger rna; immunocytochemistry; breast tumor; brain metastasis; protein secretion; upregulation; choroid; autopsy; fluorescence activated cell sorting; dynamic contrast-enhanced magnetic resonance imaging; lapatinib; short hairpin rna; oligomerization; alzheimer disease; protein cleavage; tau protein; cell vacuole; rna isolation; matrix metalloproteinase 9; choroid plexus; heart left ventricle; blood cerebrospinal fluid barrier; tau; csf; humans; human; female; article; mda-mb-231 cell line; claudin 6; blood–cerebrospinal fluid barrier
Journal Title:	Journal of Neuroscience Research
Volume:	101
Issue:	12
ISSN:	0360-4012
Publisher:	Wiley Liss
Date Published:	2023-12-01
Start Page:	1900
End Page:	1913
Language:	English
DOI:	10.1002/jnr.25249
PUBMED:	37787045
PROVIDER:	scopus
PMCID:	PMC10769085
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85173455824&doi=10.1002%2fjnr.25249&partnerID=40&md5=a1add8c6877d6b627811801cc44c1f9f
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/210554