Figure 4

Downstream target network for the predicted upstream regulators of the mouse genes IL15 (dashed dark blue lines), IL18 (dashed red lines), TLR3 (dashed gold lines), TLR9 (dashed magenta lines), IKBKB (dashed green lines), and NFKB (dashed teal lines), showing multi-layer cell signaling and cross-talk between regulators, as well as downstream signaling and up- or down-regulation of genes identified on the mouse array as being responsive to metronomic CPA treatment. Genes and upstream regulators shown are only those that are common across tumor models at both late time points (U251 tumors on day 18 and 9L tumors on day 24). This network identifies potential signaling in tumor cell death-induced pathways, such as interferon, cytokine, tumor necrosis factor, TLR, and NFkB signaling. Deeper shades of red and green denote human tumor genes that are up-regulated (red) or down-regulated (green) by metronomic CPA to a greater extent as compared to lighter shades, as indicated by microarray analysis. Key at the bottom: shapes used to indicate the molecular class of each factor, as defined in Figure 3.