Ionizing radiation increases the endothelial permeability and the transendothelial migration of tumor cells through ADAM10-activation and subsequent degradation of VE-cadherin.

Abstract

BACKGROUND:

We analyzed the changes in permeability of endothelial cell layers after photon irradiation, with a focus on the metalloproteases ADAM10 and ADAM17, and on VE-cadherin, components crucial for the integrity of endothelial intercellular junctions, and their roles in the transmigration of cancer cells through endothelial cell monolayers.

METHODS:

Primary HUVEC were irradiated with 2 or 4 Gy photons at a dose rate of 5 Gy/min. The permeability of an irradiated endothelial monolayer for macromolecules and tumor cells was analyzed in the presence or absence of the ADAM10/17 inhibitors GI254023X and GW280264X. Expression of ADAM10, ADAM17 and VE-Cadherin in endothelial cells was quantified by immunoblotting and qRT. VE-Cadherin was additionally analyzed by immunofluorescence microscopy and ELISA.

RESULTS:

Ionizing radiation increased the permeability of endothelial monolayers and the transendothelial migration of tumor cells. This was effectively blocked by a selective inhibition (GI254023X) of ADAM10. Irradiation increased both, the expression and activity of ADAM10, which led to increased degradation of VE-cadherin, but also led to higher rates of VE-cadherin internalization. Increased degradation of VE-cadherin was also observed when endothelial monolayers were exposed to tumor-cell conditioned medium, similar to when exposed to recombinant VEGF.

CONCLUSIONS:

Our results suggest a mechanism of irradiation-induced increased permeability and transendothelial migration of tumor cells based on the activation of ADAM10 and the subsequent change of endothelial permeability through the degradation and internalization of VE-cadherin.

• Authors: Pascaline Nguemgo Kouam, Günther A Rezniczek, Irenäus A Adamietz, Helmut Bühler
• Journal: BMC cancer (BMC Cancer) Vol. 19 Issue 1 Pg. 958 (Oct 16 2019) ISSN: 1471-2407 [Electronic] England
• PMID: 31619190 (Publication Type: Journal Article)

Chemical References

• 3-(formylhydroxyamino)-2-(3-phenyl-1-propyl)butanoic acid (2,2-dimethyl-1-methylcarbamoyl-1-propyl)amide
• Antigens, CD
• Cadherins
• Dipeptides
• GW280264X
• Hydroxamic Acids
• Membrane Proteins
• Tumor Necrosis Factor-alpha
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• cadherin 5
• Amyloid Precursor Protein Secretases
• ADAM10 Protein
• ADAM10 protein, human
• ADAM17 Protein
• ADAM17 protein, human

Topics

• ADAM10 Protein (antagonists & inhibitors, genetics, metabolism)
• ADAM17 Protein (antagonists & inhibitors, genetics, metabolism)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors, genetics, metabolism)
• Antigens, CD (metabolism)
• Cadherins (metabolism)
• Cell Line, Tumor
• Dipeptides (pharmacology)
• Endothelial Cells (metabolism, radiation effects)
• Human Umbilical Vein Endothelial Cells (radiation effects)
• Humans
• Hydroxamic Acids (pharmacology)
• Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
• Permeability (radiation effects)
• Proteolysis (radiation effects)
• Radiation, Ionizing
• Radiotherapy (adverse effects)
• Signal Transduction (radiation effects)
• Transendothelial and Transepithelial Migration (drug effects, radiation effects)
• Tumor Necrosis Factor-alpha (pharmacology)
• Vascular Endothelial Growth Factor A (metabolism, pharmacology)