Figure 5

Downstream target network for the predicted mouse (host) upstream regulators DDX58 (magenta), FADD (dark blue), MAVS (red), STAT1 (green), and IRF7 (teal blue), showing multi-layer cell signaling and cross-talk amongst regulators, as well as downstream signaling and up- or down-regulation of genes identified on the mouse array following metronomic CPA treatment. Genes and upstream regulators show only those that are common to both late time points (day 18 and day 24) across the U251 and 9L models. This network identifies potential signaling in tumor cell death-induced immunogenic pathways, such as interferon, cytokine, tumor necrosis factor, and cytolysis (i.e., killer cell lectin, granzyme and perforin) 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.