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-1β 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-1β 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.
Highlights
The spread of cancer cells from a primary tumor site to distant organs, metastasis, is one of the most devastating aspects of cancer accounting for 90% of cancer-related deaths
Cellcell junctions were monitored by examining vascular endothelial (VE)-cadherin localization and it was observed that co-culture of melanoma cells with Human umbilical vein endothelial cells (HUVECs) resulted in dissolution of VE-cadherin junctions local to the tumor cells (Figure 1A)
These results are consistent with previous results that demonstrate a role for melanoma signals including soluble factors such as IL-8 and IL-1b and receptor-ligand interactions between proteins displayed on the surfaces of tumor and endothelial cells such as very late antigen (VLA)-4/vascular cell adhesion molecule (VCAM)-1 as mediators of gap formation [26,34]
Summary
The spread of cancer cells from a primary tumor site to distant organs, metastasis, is one of the most devastating aspects of cancer accounting for 90% of cancer-related deaths. A key event during tumor metastasis is the extravasation of a cancer cell through the blood vessel wall [1,2], which is mediated by both chemical and physical signals from the cellular microenvironment [3]. Breakdown of endothelial cell-cell junctions during extravasation is mediated by the complex interplay of cytokines secreted by the tumor cells and by adhesion between tumor cells and endothelial cells. The maintenance and stability of endothelial cell-cell junctions is thought to be regulated by the balance between cell-cell adhesion and cellular contractility [4,5]. Adhesion between neighboring endothelial cells is mediated by a variety of transmembrane cell-cell adhesion molecules including vascular endothelial (VE)-cadherin, an adherens junction protein that has been implicated in controlling vascular permeability and leukocyte extravasation [6,7,8,9]. Recent studies suggest that phosphorylation of VE-cadherin is necessary but not sufficient to induce dissolution of endothelial junctions [10]; the coordinated induction of multiple signaling cascades is likely key to the opening of endothelial junctions
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