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Endothelial-mesenchymal transition of brain endothelial cells: possible role during metastatic extravasation

Krizbai, István A ; Gasparics, Ákos ; Nagyőszi, Péter ; Fazakas, Csilla ; Molnár, Judit ; Wilhelm, Imola ; Bencs, Rita ; Rosivall, László ; Sebe, Attila Languino, Lucia R.

PloS one, 2015-03, Vol.10 (3), p.e0119655 [Periódico revisado por pares]

United States: Public Library of Science

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Título:
Endothelial-mesenchymal transition of brain endothelial cells: possible role during metastatic extravasation
Autor: Krizbai, István A ; Gasparics, Ákos ; Nagyőszi, Péter ; Fazakas, Csilla ; Molnár, Judit ; Wilhelm, Imola ; Bencs, Rita ; Rosivall, László ; Sebe, Attila
Languino, Lucia R.
Assuntos: Actin ; Animals ; Benzamides - pharmacology ; Brain ; Brain - cytology ; Brain - drug effects ; Breast cancer ; Calponin ; Cancer ; Cancer metastasis ; Cell Line, Tumor ; Cell migration ; Cells, Cultured ; Conditioning ; Culture Media, Conditioned - pharmacology ; Cytoskeleton ; Development and progression ; Dioxoles - pharmacology ; Electric contacts ; Endothelial cells ; Endothelial Cells - drug effects ; Endothelial Cells - physiology ; Epithelial-Mesenchymal Transition ; Extravasation ; Fibronectin ; Gene Expression Regulation - drug effects ; Health aspects ; Human Umbilical Vein Endothelial Cells ; Humans ; Kinases ; MCF-7 Cells ; Melanoma ; Mesenchyme ; Metastases ; Metastasis ; Mice ; Muscle contraction ; Muscles ; Neoplasm Metastasis ; Phosphorylation ; Proteins ; Rats ; Rodents ; Signaling ; Skin cancer ; Smad2 protein ; Smad3 protein ; Smooth muscle ; Stimulation ; Transdifferentiation ; Transforming Growth Factor beta1 - antagonists & inhibitors ; Transforming Growth Factor beta1 - pharmacology ; Transforming growth factor-b1 ; Tumor cells ; Vascular endothelium
É parte de: PloS one, 2015-03, Vol.10 (3), p.e0119655
Notas: Conceived and designed the experiments: IAK ÁG IW AS. Performed the experiments: ÁG PN CF JM IW RB. Analyzed the data: IAK ÁG IW AS. Contributed reagents/materials/analysis tools: IAK LR. Wrote the paper: AS.
Competing Interests: The authors have declared that no competing interests exist.
These authors are shared first co-authors on this work.
Descrição: Cancer progression towards metastasis follows a defined sequence of events described as the metastatic cascade. For extravasation and transendothelial migration metastatic cells interact first with endothelial cells. Yet the role of endothelial cells during the process of metastasis formation and extravasation is still unclear, and the interaction between metastatic and endothelial cells during transendothelial migration is poorly understood. Since tumor cells are well known to express TGF-β, and the compact endothelial layer undergoes a series of changes during metastatic extravasation (cell contact disruption, cytoskeletal reorganization, enhanced contractility), we hypothesized that an EndMT may be necessary for metastatic extravasation. We demonstrate that primary cultured rat brain endothelial cells (BEC) undergo EndMT upon TGF-β1 treatment, characterized by the loss of tight and adherens junction proteins, expression of fibronectin, β1-integrin, calponin and α-smooth muscle actin (SMA). B16/F10 cell line conditioned and activated medium (ACM) had similar effects: claudin-5 down-regulation, fibronectin and SMA expression. Inhibition of TGF-β signaling during B16/F10 ACM stimulation using SB-431542 maintained claudin-5 levels and mitigated fibronectin and SMA expression. B16/F10 ACM stimulation of BECs led to phosphorylation of Smad2 and Smad3. SB-431542 prevented SMA up-regulation upon stimulation of BECs with A2058, MCF-7 and MDA-MB231 ACM as well. Moreover, B16/F10 ACM caused a reduction in transendothelial electrical resistance, enhanced the number of melanoma cells adhering to and transmigrating through the endothelial layer, in a TGF-β-dependent manner. These effects were not confined to BECs: HUVECs showed TGF-β-dependent SMA expression when stimulated with breast cancer cell line ACM. Our results indicate that an EndMT may be necessary for metastatic transendothelial migration, and this transition may be one of the potential mechanisms occurring during the complex phenomenon known as metastatic extravasation.
Editor: United States: Public Library of Science
Idioma: Inglês

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Endothelial-mesenchymal transition of brain endothelial cells: possible role during metastatic extravasation

Krizbai, István A ; Gasparics, Ákos ; Nagyőszi, Péter ; Fazakas, Csilla ; Molnár, Judit ; Wilhelm, Imola ; Bencs, Rita ; Rosivall, László ; Sebe, Attila Languino, Lucia R.

United States: Public Library of Science

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