Reactive glia are recruited by highly proliferative brain metastases of breast cancer and promote tumor cell colonization
Open accessAbstract
Interactions between tumor cells and the microenvironment are crucial to tumor formation and metastasis. The central nervous system serves as a "sanctuary" site for metastasis, resulting in poor prognosis in diagnosed patients. The incidence of brain metastasis is increasing; however, little is known about interactions between the brain and metastatic cells. Brain pathology was examined in an experimental model system of brain metastasis, using a subline of MDA-MB-231 human breast cancer cells. The results were compared with an analysis of sixteen resected human brain metastases of breast cancer. Experimental metastases formed preferentially in specific brain regions, with a distribution similar to clinical cases. In both the 231-BR model, and in human specimens, Ki67 expression indicated that metastases were highly proliferative (approximately 50%). Little apoptosis was observed in either set of tumors. In the model system, metastases elicited a brain inflammatory response, with extensive reactive gliosis surrounding metastases. Similarly, large numbers of glial cells were found within the inner tumor mass of human brain metastases. In vitro co-cultures demonstrated that glia induced a approximately 5-fold increase in metastatic cell proliferation (P<0.001), suggesting that brain tissue secretes factors conducive to tumor cell growth. Molecules used to signal between tumor cells and the surrounding glia could provide a new avenue of therapeutic targets for brain metastases.
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Cancer cells communicate with their microenvironment, specifically with organ-specific cells, resulting in organ-selectivity in metastasis.
“This is particularly important as there is growing evidence that cancer cells communicate with their microenvironment[29], specifically with organ-specific cells[30], resulting in organ-selectivity in metastasis[31].”
From Microfluidics: A New Tool for Modeling Cancer–Immune Interactions (2016) · cites this paper as [30]
The Introduction (page unavailable) invokes the seed-and-soil hypothesis to explain why tumors metastasize to particular organs. The Discussion (page unavailable) supports a narrower finding: breast cancer cells alter the brain microenvironment, which contributes to metastatic progression. The paper does not establish that communication with organ-specific cells causes organ selectivity across metastases. (LLM, conf=0.84)
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“This is particularly important as there is growing evidence that cancer cells communicate with their microenvironment[29], specifically with organ-specific cells[30], resulting in organ-selectivity in metastasis[31].”
Background
- Authors
- Fitzgerald, D. P., Palmieri, D., Hua, E., Hargrave, E., Herring, J. M., Qian, Y., Vega-Valle, E., Weil, R. J., Stark, A. M., Vortmeyer, A. O., & Steeg, P. S.
- Affiliations
- National Institutes of Health (US)
- Cleveland Clinic (US)
- University Hospital Schleswig-Holstein (DE)
- Corresponding author
- Fitzgerald, Daniel P.
- Venue
- Clinical & Experimental Metastasis
- Published
- 2008-07-23
- Volume
- 25
- Issue
- 7
- Pages
- 799-810
- ISSN
- 0262-0898 (ISSN-L)
- 1573-7276
- PMC
- PMC2679391
- OpenAlex
- W2008508879
- Cited by
- 218
- References
- 54
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 11 · 2023: 14 · 2022: 9 · 2021: 15 · 2020: 9 · 2019: 10 · 2018: 5 · 2017: 11 · 2016: 22 · 2015: 19 · 2014: 12 · 2013: 20 · 2012: 13
- FWCI
- 9.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Clinical & Experimental Metastasis (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (Z01BC010538)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- brain metastases, breast cancer, reactive gliosis, tumor microenvironment, MDA-MB-231 cells, Ki-67 proliferation index, neuroinflammation, tumor cell proliferation, co-culture, tumor colonization, therapeutic target
- MeSH terms
- Adult, Aged, Animals, Brain Neoplasms, Breast Neoplasms, Cell Movement, Female, Humans, Mice, Inbred BALB C, Middle Aged, Neuroglia, Apoptosis, Leukocyte Common Antigens, CD11b Antigen, Cell Proliferation, Mice
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