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Data from Aging and CNS Myeloid Cell Depletion Attenuate Breast Cancer Brain Metastasis

Authors :
Patricia S. Steeg
Lalage M. Wakefield
Dorian B. McGavern
Quentin R. Smith
Imran Khan
Maxwell P. Lee
Simone Difilippantonio
Christina Robinson
Emma L. Dolan
Yuan Yang
Kristine Isanogle
Esra Taner
Debbie Wei
Andy D. Tran
Helen R. Thorsheim
Howard H. Yang
Brunilde Gril
Monika A. Chung
Ramakrishna Samala
Selamawit Gossa
Alex Man Lai Wu
Publication Year :
2023
Publisher :
American Association for Cancer Research (AACR), 2023.

Abstract

Purpose:Breast cancer diagnosed in young patients is often aggressive. Because primary breast tumors from young and older patients have similar mutational patterns, we hypothesized that the young host microenvironment promotes more aggressive metastatic disease.Experimental Design:Triple-negative or luminal B breast cancer cell lines were injected into young and older mice side-by-side to quantify lung, liver, and brain metastases. Young and older mouse brains, metastatic and naïve, were analyzed by flow cytometry. Immune populations were depleted using antibodies or a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, and brain metastasis assays were conducted. Effects on myeloid populations, astrogliosis, and the neuroinflammatory response were determined.Results:Brain metastases were 2- to 4-fold higher in young as compared with older mouse hosts in four models of triple-negative or luminal B breast cancer; no age effect was observed on liver or lung metastases. Aged brains, naïve or metastatic, contained fewer resident CNS myeloid cells. Use of a CSF-1R inhibitor to deplete myeloid cells, including both microglia and infiltrating macrophages, preferentially reduced brain metastasis burden in young mice. Downstream effects of CSF-1R inhibition in young mice resembled that of an aged brain in terms of myeloid numbers, induction of astrogliosis, and Semaphorin 3A secretion within the neuroinflammatory response.Conclusions:Host microenvironmental factors contribute to the aggressiveness of triple-negative and luminal B breast cancer brain metastasis. CSF-1R inhibitors may hold promise for young brain metastasis patients.

Details

Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....243cf2f37e92b609abf3ddbfee1b1f80
Full Text :
https://doi.org/10.1158/1078-0432.c.6530715.v1