{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T06:59:07Z","timestamp":1785135547935,"version":"3.55.0"},"reference-count":72,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Brain metastases have traditionally been investigated primarily with regard to interactions between tumor cells, the surrounding brain microenvironment, and associated inflammatory responses. By contrast, the presence of a true intratumoral stromal compartment in brain metastases has received much less attention, partly because the normal brain parenchyma lacks classical interstitial fibroblasts. However, recent histological, transcriptomic, and spatial studies suggest that at least a subset of carcinoma brain metastases contains fibroblast-like or cancer-associated fibroblast-like cells associated with collagen-rich extracellular matrix deposition. This raises a fundamental biological question: where do these cells come from? In this review, we discuss seven non-mutually exclusive hypotheses for the origin of cancer-associated fibroblast (CAF)-like cells in brain metastases, including pseudostromal mimics, meningeal or perivascular fibroblast-related cells, vascular mural cells, glial cells, cancer stem cell plasticity, tumor\u2013stroma clusters, and circulating mesenchymal precursors. We compare the current findings for each hypothesis and highlight their major limitations. Overall, the available data support a heterogeneous and context-dependent model rather than a single universal origin. A better understanding of these stromal cell states may help refine the biological classification of brain metastases and support the future development of more targeted stromal therapies.<\/jats:p>","DOI":"10.3390\/cancers18152397","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:49:27Z","timestamp":1785131367000},"page":"2397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Origin of Cancer-Associated Fibroblasts (CAFs) in Brain Metastases: Seven Hypotheses and Current Evidence"],"prefix":"10.3390","volume":"18","author":[{"given":"Dave","family":"Bandke","sequence":"first","affiliation":[{"name":"Department of Pathology and Molecular Pathology, Johannes Kepler University Linz, Kepler University Hospital GmbH, Wagner-Jauregg-Weg 15, 4020 Linz, Austria"},{"name":"Clinical Research Institute for Neurosciences, Johannes Kepler University, Neuromed Campus, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rupert","family":"Langer","sequence":"additional","affiliation":[{"name":"Department of Pathology and Molecular Pathology, Johannes Kepler University Linz, Kepler University Hospital GmbH, Wagner-Jauregg-Weg 15, 4020 Linz, Austria"},{"name":"Clinical Research Institute for Neurosciences, Johannes Kepler University, Neuromed Campus, 4020 Linz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1016\/j.celrep.2019.03.085","article-title":"Transcriptomic Hallmarks of Tumor Plasticity and Stromal Interactions in Brain Metastasis","volume":"27","author":"Wingrove","year":"2019","journal-title":"Cell Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.semcancer.2019.10.012","article-title":"The macro-metastasis\/organ parenchyma interface (MMPI)\u2014A hitherto unnoticed area","volume":"60","author":"Blazquez","year":"2020","journal-title":"Semin. 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