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In vivo imaging reveals that extravasation of cancer cells is a dynamic process regulated by metastatic genes targeting adhesion, intravascular migration, and endothelial remodelling.
Comparison of membrane protrusion dynamics of MDAtwist (red) and MDAwt (blue) cells. Middle panel, red and blue channels showing individual tumour cell shapes. Right panel shows schematic outlines of the blood vessel and MDAtwist tumour cell.
From J. Cell Sci. 123, 2332–2341 (2010). doi: 10.1242/jcs.069443 Reproduced with permission from Journal of Cell Science.
Analysis of tumour cell extravasation during metastasis often involves interpreting 'static' histological data from human xenograft assays in mouse or chick. Reporting in the Journal of Cell Science, Stoletov et al., however, have exploited the optical transparency and highly patterned vasculature of zebrafish to perform real-time in vivo imaging.
The researchers initially demonstrated, using stable fluorescent cell lines in transgenic zebrafish expressing green fluorescent protein throughout their vasculature, the differing extravasation potentials of different metastatic human tumour cells. Overexpressing the metastatic genes Twist and VEGFA increased the metastatic potential, whereas silencing ITGB1, which encodes β1 integrin, reduced the potential. Following their arrest in small blood vessels, the tumour cells actively migrated along the luminal surface, often against blood flow.
Expression of Twist caused the cells, through Rho kinase (ROCK), to rapidly change their shape and become more protrusive, and increased this intravascular migration. Interestingly, silencing of ITGB1 in Twist-overexpressing tumour cells failed to inhibit extravasation, whereas wild-type tumour cells that lacked ITGB1 were not protrusive, did not adhere to the vessel surface and remained immotile. By contrast, silencing of ITGB1 in VEGF-overexpressing tumour cells reduced VEGF-induced extravasation, indicating that extravasation can be β1 integrin-dependent or -independent, according to the metastatic gene signature.
Finally, imaging studies showed that the arrested tumour cells induced endothelial cells to cluster around them and to remodel their cell–cell junctions, possibly to create new sites through which to penetrate into the surrounding tissue; vessel damage or vascular leak was not detected.
Original Research Paper
- Stoletov K. et al. Visualizing extravasation dynamics of metastatic tumor cells. J. Cell Sci. 123, 2332–2341 (2010).
doi: 10.1242/jcs.069443 | Article
