Endothelial barrier disruption by VEGF-mediated Src activity potentiates tumor cell extravasation and metastasis

Abstract

VEGF is unique among angiogenic growth factors because it disrupts endothelial barrier function. Therefore, we considered whether this property of VEGF might contribute to tumor cell extravasation and metastasis. To test this, mice lacking the Src family kinases Src or Yes, which maintain endothelial barrier function in the presence of VEGF, were injected intravenously with VEGF-expressing tumor cells. We found a dramatic reduction in tumor cell extravasation in lungs or livers of mice lacking Src or Yes. At the molecular level, VEGF compromises the endothelial barrier by disrupting a VE-cadherin–β-catenin complex in lung endothelium from wild-type, but not Yes-deficient, mice. Disrupting the endothelial barrier directly with anti–VE-cadherin both amplifies metastasis in normal mice and overcomes the genetic resistance in Yes-deficient mice. Pharmacological blockade of VEGF, VEGFR-2, or Src stabilizes endothelial barrier function and suppresses tumor cell extravasation in vivo. Therefore, disrupting Src signaling preserves host endothelial barrier function providing a novel host-targeted approach to control metastatic disease.

Vascular Endothelial Growth Factor C Disrupts the Endothelial Lymphatic Barrier to Promote Colorectal Cancer Invasion

“…Consistent with other findings, in the tumoral context we do not observe any effects on blood vessel density and enlargement upon VEGFC treatment 29,30 or VEGFR3 inhibition 7 . It is worthy of note that these experiments do not It is still unclear whether tumor cell intravasation/extravasation requires the transmigration of cancer cells through the cytoplasm of endothelial cells, as occurs for leukocytes, or whether they transmigrate between two adjacent endothelial cells after the disruption of cell-cell connections 19 . The endothelial barrier integrity is maintained by a complex balance between cell-to-cell adherens junctions.…”

“…In this scenario, VEGFA facilitates cancer cell intravasation by disrupting the VE-Cad-β-catenin complex and inducing adherens junction weakness and formation of transcellular holes 34 . Weis et al, provided evidence that VEGFA-mediated breakdown in blood endothelial integrity through VE-Cad disruption hastens metastases 19 . Moreover, they demonstrated that VE-Cad inhibition compromises endothelial barrier function and promotes tumor cell extravasation 19 .…”

“…6 intravasation and extravasation, thus increasing the metastatic spread of several tumors, including CRC 19 . VE-Cad expression on the microvascular endothelial cell membrane depends on its internalization and degradation, and one of the mechanisms mediating these two events is the activation of VEGFR2 by its ligand VEGFA 12 .…”

“…In greater detail, the VE-Cad intracellular region forms a complex with an intracellular protein network, including α-, β-and γ-catenin and p120 17 , thus contributing to the strength of intracellular adhesion 18 . Phosphorylation of VE-Cad on Tyr residues disrupts endothelial cell adherens junctions by causing the dissociation of catenins from VE-Cad, facilitating the diapedesis of leukocytes and metastatic cancer cells 19 . It has been reported that an aberrant localization of VE-Cad on blood vessels is responsible for cancer cell M A N U S C R I P T…”

La VE-cadhérine prend des chemins de traverse

“…Même si des progrès ont été réalisés dans la compréhension de la signalisation intracellulaire par laquelle le VEGF promeut la croissance, la survie et la migration endothéliale, comment le VEGF contrôle l'étanchéité vasculaire reste encore mal connu, plus de 20 ans après sa découverte [2]. Des étu-des in vivo et in vitro avaient montré l'implication des tyrosine kinases de la famille Src dans l'augmentation de la perméabilité vasculaire par le VEGF, via la régulation des jonctions intercellulaires [4][5][6]. Parallèlement, l'ablation génétique de la VE-cadhérine ou l'inhibition de sa fonction adhésive augmente la perméabilité…”