Systemic Analysis of Tumor Cell-Induced Endothelial Calcium Signaling and Junction Disassembly.

It has been shown in our previous study that melanoma cells induce junction disassembly in the manner related to phospholipase C-calcium activation. In light of this observation, we have developed a mathematical model of the signaling pathway and adapted multi-parametric sensitivity analysis (MPSA) to identify important parameters in the model, which examines tumor cell-induced calcium mobilization in endothelial cells. The objective functions, with respect to individual parameters, were generated for the calcium mobilization model and MPSA was performed according to the function. The results showed that sarco/endoplasmic reticulum calcium ATPase was one of the putative key factors in regulating calcium mobilization. The model is a proof of concept of systemic analysis of a signaling network, and the results may have practical applications in describing how endothelial cells respond to tumor cells. Taken together, we have devised numerical means to macroscopically study roles of calcium signaling in endothelial cells in contact with metastatic tumor cells.