Real-time imaging reveals the single steps of brain metastasis formation.
Abstract
Brain metastasis frequently occurs in individuals with cancer and is often fatal. We used multiphoton laser scanning microscopy to image the single steps of metastasis formation in real time. Thus, it was possible to track the fate of individual metastasizing cancer cells in vivo in relation to blood vessels deep in the mouse brain over minutes to months. The essential steps in this model were arrest at vascular branch points, early extravasation, persistent close contacts to microvessels and perivascular growth by vessel cooption (melanoma) or early angiogenesis (lung cancer). Inefficient steps differed between the tumor types. Long-term dormancy was only observed for single perivascular cancer cells, some of which moved continuously. Vascular endothelial growth factor-A (VEGF-A) inhibition induced long-term dormancy of lung cancer micrometastases by preventing angiogenic growth to macrometastases. The ability to image the establishment of brain metastases in vivo provides new insights into their evolution and response to therapies.
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Proteolytic enzymes such as heparanase and seprase are important for the capacity of metastatic cells to traverse the BBB and occupy the brain, and micrometastases give rise to macrometastases through proliferation along brain microvessels.
“proteolytic enzymes such as heparanase and seprase are important for the capacity of metastatic cells to traverse the BBB and occupy the brain”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Kienast et al., 2010
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- Authors
- Kienast, Y., von Baumgarten, L., Fuhrmann, M., Klinkert, W. E. F., Goldbrunner, R., Herms, J., & Winkler, F.
- Affiliations
- Ludwig-Maximilians-Universität München (DE)
- Max Planck Institute of Neurobiology (DE)
- Corresponding author
- Winkler, Frank
- Venue
- Nature Medicine
- Published
- 2009-12-20
- Volume
- 16
- Issue
- 1
- Pages
- 116-122
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2043166238
- Cited by
- 1,138
- References
- 39
- Citations by year
- 2026: 43 · 2025: 57 · 2024: 68 · 2023: 78 · 2022: 64 · 2021: 93 · 2020: 91 · 2019: 91 · 2018: 74 · 2017: 78 · 2016: 75 · 2015: 76 · 2014: 56 · 2013: 65 · 2012: 56
- FWCI
- 36.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Brain Metastases and Treatment
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- brain metastases, metastasis, in vivo imaging, multiphoton laser scanning microscopy, single-cell tracking, extravasation, micrometastases, metastatic dormancy, VEGF-A inhibition, angiogenesis, melanoma, lung cancer, tumor cell migration
- MeSH terms
- Animals, Brain Neoplasms, Disease Models, Animal, Humans, Lung Neoplasms, Melanoma, Mice, Nude, Neoplasm Metastasis, Neovascularization, Pathologic, Microscopy, Confocal, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Mice
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