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

B. Saatian; K. Deshpande; R. Herrera; S. Sedighi; R. Eisenbarth; M. Iyer; D. Das; A. Julian; V. Martirosian; A. Lowman; P. LaViolette; J. Remsik; A. Boire; E. Sankey; P. E. Fecci; M. S. Shiroishi; F. Chow; K. Hurth; Josh Neman

doi:10.1002/jnr.25249

journal article Open Access Oct 03, 2023

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

B. Saatian K. Deshpande R. Herrera S. Sedighi R. Eisenbarth M. Iyer D. Das

A. Julian V. Martirosian

A. Lowman P. LaViolette J. Remsik A. Boire E. Sankey P. E. Fecci M. S. Shiroishi F. Chow K. Hurth Josh Neman

Journal of Neuroscience Research Vol. 101 No. 12 pp. 1900-1913 · Wiley

View at Publisher Save 10.1002/jnr.25249

Abstract

AbstractControl 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.

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Metrics

13

Citations

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References

Details

Published: Oct 03, 2023
Vol/Issue: 101(12)
Pages: 1900-1913
License: View

Authors

B

B. Saatian

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA; Brain Tumor Center University of Southern California Los Angeles California USA

K

K. Deshpande

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA; Brain Tumor Center University of Southern California Los Angeles California USA

R

R. Herrera

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA; Brain Tumor Center University of Southern California Los Angeles California USA

S

S. Sedighi

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA; Brain Tumor Center University of Southern California Los Angeles California USA

R

R. Eisenbarth

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA; Brain Tumor Center University of Southern California Los Angeles California USA

M

M. Iyer

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA

D

D. Das

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA

A

A. Julian

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA; Brain Tumor Center University of Southern California Los Angeles California USA

V

V. Martirosian

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA; Brain Tumor Center University of Southern California Los Angeles California USA

A

A. Lowman

Department of Radiology and Biomedical Engineering Medical College of Wisconsin Milwaukee Wisconsin USA

P

P. LaViolette

Department of Radiology and Biomedical Engineering Medical College of Wisconsin Milwaukee Wisconsin USA

J

J. Remsik

Department of Neurology Memorial Sloan Kettering Cancer Center New York New York USA

A

A. Boire

Department of Neurology Memorial Sloan Kettering Cancer Center New York New York USA

E

E. Sankey

Department of Neurosurgery Duke University School of Medicine Durham North Carolina USA

P

P. E. Fecci

Department of Neurosurgery Duke University School of Medicine Durham North Carolina USA

M

M. S. Shiroishi

Brain Tumor Center University of Southern California Los Angeles California USA; Department of Pathology, Keck School of Medicine University of Southern California Los Angeles California USA

F

F. Chow

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA; Brain Tumor Center University of Southern California Los Angeles California USA; Norris Comprehensive Cancer Center University of Southern California Los Angeles California USA

K

K. Hurth

Brain Tumor Center University of Southern California Los Angeles California USA; Norris Comprehensive Cancer Center University of Southern California Los Angeles California USA; Department of Neuroscience and Physiology, Keck School of Medicine University of Southern California Los Angeles California USA

J

Josh Neman

Department of Neurological Surgery, Keck School of Medicine University of Southern California Los Angeles California USA; Brain Tumor Center University of Southern California Los Angeles California USA; Norris Comprehensive Cancer Center University of Southern California Los Angeles California USA; Department of Neuroscience and Physiology, Keck School of Medicine University of Southern California Los Angeles California USA; Department of Radiology, Keck School of Medicine University of Southern California Los Angeles California USA

Funding

National Institutes of Health

U.S. Department of Defense

Susan G. Komen

METAvivor

Cite This Article

B. Saatian, K. Deshpande, R. Herrera, et al. (2023). Breast‐to‐brain metastasis is exacerbated with chemotherapy through blood–cerebrospinal fluid barrier and induces Alzheimer's‐like pathology. Journal of Neuroscience Research, 101(12), 1900-1913. https://doi.org/10.1002/jnr.25249

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

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