Dataset Information

Actinomyosin contraction, phosphorylation of VE-cadherin, and actin remodeling enable melanoma-induced endothelial cell-cell junction disassembly.

ABSTRACT: During melanoma cell extravasation through the vascular endothelium, melanoma cells interact with endothelial cells through secretion of cytokines and by adhesion between proteins displayed on opposing cell surfaces. How these tumor cell associated signals together regulate the dynamics of intracellular signaling pathways within endothelial cells leading to endothelial cell-cell junction disruption is not well understood. Here, we used a combination of experimental and computational approaches to examine the individual and combined effects of activation of the vascular cell adhesion molecule (VCAM)-1, interleukin (IL)-8, and IL-1? signaling pathways on the integrity of vascular junctions. Our simulations predict a multifaceted interplay of signaling resulting from individual activation of VCAM-1, IL-8 and IL-1? pathways that is neither synergistic nor additive compared to all inputs turned on simultaneously. Furthermore, we show that the levels of phosphorylated proteins associated with actinomyosin contractility and junction disassembly peak prior to those related to actin remodeling. The results of this work provide insight into the dynamics of tumor-mediated endothelial junction disassembly and suggest that targeting proteins downstream of several interaction pathways may be the most effective therapeutic approach to reduce melanoma extravasation.

SUBMITTER: Weidert E

PROVIDER: S-EPMC4167543 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Actinomyosin contraction, phosphorylation of VE-cadherin, and actin remodeling enable melanoma-induced endothelial cell-cell junction disassembly.

Weidert Eric E Pohler Steven E SE Gomez Esther W EW Dong Cheng C

PloS one 20140916 9

During melanoma cell extravasation through the vascular endothelium, melanoma cells interact with endothelial cells through secretion of cytokines and by adhesion between proteins displayed on opposing cell surfaces. How these tumor cell associated signals together regulate the dynamics of intracellular signaling pathways within endothelial cells leading to endothelial cell-cell junction disruption is not well understood. Here, we used a combination of experimental and computational approaches t ...[more]

PMID: 25225982

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Project description:BACKGROUND: VE-cadherin is an endothelial specific, transmembrane protein, that clusters at adherens junctions where it promotes homotypic cell-cell adhesion. VE-cadherin null mutation in the mouse results in early fetal lethality due to altered vascular development. However, the mechanism of action of VE-cadherin is complex and, in the mouse embryo, it is difficult to define the specific steps of vascular development in which this protein is involved. METHODOLOGY AND PRINCIPAL FINDINGS: In order to study the role VE-cadherin in the development of the vascular system in a more suitable model, we knocked down the expression of the coding gene in zebrafish. The novel findings reported here are: 1) partial reduction of VE-cadherin expression using low doses of morpholinos causes vascular fragility, head hemorrhages and increase in permeability; this has not been described before and suggests that the total amount of the protein expressed is an important determinant of vascular stability; 2) concentrations of morpholinos which abrogate VE-cadherin expression prevent vessels to establish successful reciprocal contacts and, as a consequence, vascular sprouting activity is not inhibited. This likely explains the observed vascular hyper-sprouting and the presence of several small, collapsing vessels; 3) the common cardinal vein lacks a correct connection with the endocardium leaving the heart separated from the rest of the circulatory system. The lack of closure of the circulatory loop has never been described before and may explain some downstream defects of the phenotype such as the lack of a correct vascular remodeling. CONCLUSIONS AND SIGNIFICANCE: Our observations identify several steps of vascular development in which VE-cadherin plays an essential role. While it does not appear to regulate vascular patterning it is implicated in vascular connection and inhibition of sprouting activity. These processes require stable cell-cell junctions which are defective in absence of VE-cadherin. Notably, also partial modifications in VE-cadherin expression prevent the formation of a stable vasculature. This suggests that partial internalization or change of function of this protein may strongly affect vascular stability and organization.

Dataset Information

Actinomyosin contraction, phosphorylation of VE-cadherin, and actin remodeling enable melanoma-induced endothelial cell-cell junction disassembly.

Publications

Actinomyosin contraction, phosphorylation of VE-cadherin, and actin remodeling enable melanoma-induced endothelial cell-cell junction disassembly.

Similar Datasets

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