Gene and cytokine expression profiles of metastatic colorectal cancer patients post reovirus administration

Figure 1 The expression of 17 significantly altered cytokines relative to pre-values (by mean expression across all reovirus-treated patients) over time. Statistically significant increases were observed for interferon gamma and interleukin-6 during the 15-day period. Statistically significant decreases as compared to baseline were observed for vascular endothelial growth factor, interleukin-8, and regulated upon activation, normal T-cell expressed and secreted during the 15-day period. GM-CSF: Granulocyte-macrophage colony-stimulating factor; IFN: Interferon; IL: Interleukin; MCP: Monocyte chemoattractant protein; MIP: Macrophage inflammatory proteins; RANTES: Regulated upon activation, normal T-cell expressed and secreted; VEGF: Vascular endothelial growth factor.

Figure 2 Alterations of IGF2, PTENP1, and RICTOR expression are correlated with reductions in vascular endothelial growth factor expression. A: The relative change in IGF2, PTENP1, and RICTOR over time. Statistically significant reductions were observed for IGF2 expression on day 2 (P = 0.02); and days 2 (P = 0.04) and 8 (0.86-fold change; P = 0.04) for RICTOR. A statistically significant increase was observed for PTENP1 on day 2 (P = 0.02). Error bars represent one standard error of the mean of the data; B: The relative change in vascular endothelial growth factor expression (by mean expression across all reovirus-treated patients) over time. Statistically significant decreases were observed for vascular endothelial growth factor at 24 hours (P = 0.0003), day 2 (P = 0.007), and day 3 (P = 0.002). Error bars represent one standard error of the mean of the data.

Figure 3 Alterations of GSK3β expression are correlated with alterations in interferon gamma, interleukin-8, regulated upon activation, normal T-cell expressed and secreted, and interleukin-6 expression. A: The relative change GSK3β (by delta-delta cycle three hold calculations) over time. Expression of the GSK3β gene was significantly upregulated on day 2 (P = 0.03) and significantly downregulated on days 8 (P = 0.008) and 15 (P = 0.03). Error bars represent one standard error of the mean of the data; B: The relative changes in interferon gamma (IFN-γ), interleukin (IL)-8, regulated upon activation, normal T-cell expressed and secreted (RANTES), and IL-6 expression (by mean expression across all reovirus-treated patients) over time. Statistically significant increases were observed for RANTES on day 2 (P = 0.04); IL-6 on day 8 (P = 0.0001); and IFN-γ on day 15 (0.0004). Statistically significant decreases were observed for RANTES on day 8 (P = 0.02); IFN-γ on day 3 (P = 0.0001); and IL-8 on days 3 (P = 0.02), 4 (P = 0.00003), and 15 (P = 0.03). Error bars represent one standard of mean of the data. IFN: Interferon; IL: Interleukin; RANTES: Regulated upon activation, normal T-cell expressed and secreted.

Figure 4 Upregulation of AKT1, NFKBIA, and interleukin-6 are correlated with increased signal transducer and activator of transcription 3 expression. A: The relative change AKT1, NFKBIA, and signal transducer and activator of transcription 3 (STAT3) expression (by delta-delta cycle threshold calculations) over time. Statistically significant increases were observed in AKT1 on day 2 (P = 0.004); NFKBIA on days 2 (P = 0.004) and 8 (P = 0.03); and STAT3 on days 8 (P = 0.008) and 15 (P = 0.05). Error bars represent one standard error of the mean of the data; B: The relative change in interleukin-6 expression (by mean expression across all reovirus-treated patients) over time. Statistically significant increases were observed for interleukin-6 on day 8 (P = 0.0001). Error bars represent one standard error of the mean of the data. IL: Interleukin; STAT3: Signal transducer and activator of transcription 3.

Figure 5 Depicts proposed interactions between reovirus and the phosphoinositide 3-kinase-alpha serine/threonine-protein kinase pathway. Reovirus results in alterations of PTENP1 and/or RICTOR to catalyze intracellular changes via the phosphoinositide 3-kinase-alpha serine/threonine-protein kinase pathway. The exact interactions between reovirus and the phosphoinositide 3-kinase-alpha serine/threonine-protein kinase pathway remain unclear. PI3K: Phosphoinositide 3-kinase; AKT: Threonine-protein kinase; VEGF: Vascular endothelial growth factor; PTEN: Phosphatase and tensin homolog.