Inhibition of cyclo-oxygenase 2 reduces tumor metastasis and inflammatory signaling during blockade of vascular endothelial growth factor

Fisher, Jason C; Gander, Jeffrey W; Haley, Mary Jo; Hernandez, Sonia L; Huang, Jianzhong; Chang, Yan-Jung; Johung, Tessa B; Guarnieri, Paolo; O'Toole, Kathleen; Yamashiro, Darrell J; Kandel, Jessica J

doi:10.1186/2045-824X-3-22

Table 1 The addition of SC236 alters expression of gene sets associated with macrophage recruitment pathways in BV-treated tumors

From: Inhibition of cyclo-oxygenase 2 reduces tumor metastasis and inflammatory signaling during blockade of vascular endothelial growth factor

POSITIVELY ENRICHED GENE SETS
NAME	ES	NES	NOM p-val	FDR q-val	FWER p-val	oddRatios
DNA_METABOLIC_PROCESS	0.3612	1.8297	0.0000	0.0074	0.0134	1.9304
APOPTOSIS_KEGG	0.3195	1.2502	0.1253	0.2551	0.6220	1.9831
SOLUBLE_FRACTION	0.2035	0.9724	0.5341	0.8663	0.9962	1.5214
NEGATIVE_REGULATION_OF_PROGRAMMED_CELL_DEATH	0.1657	0.7811	0.9662	0.8935	1.0000	1.2876
NEGATIVELY ENRICHED GENE SETS
NAME	ES	NES	NOM p-val	FDR q-val	FWER p-val	oddRatios
*HSA04060_CYTOKINE_CYTOKINE_RECEPTOR_INTERACTION*	*-0.5365*	*-2.2777*	*0.0000*	*0.0000*	*0.0000*	*3.5618*
*CYTOKINE_ACTIVITY*	*-0.5464*	*-2.1044*	*0.0000*	*0.0000*	*0.0000*	*3.3868*
IMMUNE_RESPONSE	-0.4609	-1.9351	0.0000	0.0007	0.0018	2.3685
DEFENSE_RESPONSE	-0.4529	-1.9243	0.0000	0.0006	0.0022	2.2449
*INFLAMMATORY_RESPONSE_PATHWAY*	*-0.6176*	*-1.9127*	*0.0009*	*0.0006*	*0.0026*	*3.4287*
REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS	-0.4773	-1.9076	0.0000	0.0005	0.0026	2.0887
CYTOKINE_PRODUCTION	-0.5188	-1.8253	0.0005	0.0017	0.0108	3.8765
HSA04514_CELL_ADHESION_MOLECULES	-0.4568	-1.7974	0.0002	0.0020	0.0144	1.7020
IMMUNE_SYSTEM_PROCESS	-0.4064	-1.7650	0.0000	0.0029	0.0230	1.8520
RESPONSE_TO_EXTERNAL_STIMULUS	-0.4064	-1.7482	0.0000	0.0032	0.0286	2.0471
INFLAMMATORY_RESPONSE	-0.4473	-1.7450	0.0000	0.0031	0.0300	2.1490
POSITIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS	-0.4977	-1.7303	0.0016	0.0035	0.0374	1.5006
RECEPTOR_BINDING	-0.3842	-1.6798	0.0000	0.0058	0.0648	1.7643
RESPONSE_TO_WOUNDING	-0.4071	-1.6678	0.0000	0.0064	0.0766	2.1108
IMMUNE_EFFECTOR_PROCESS	-0.5187	-1.6357	0.0081	0.0082	0.1052	2.5265
LYMPHOCYTE_ACTIVATION	-0.4637	-1.6207	0.0046	0.0090	0.1222	1.4574
CELL_ACTIVATION	-0.4436	-1.6042	0.0048	0.0102	0.1460	1.9692
LEUKOCYTE_ACTIVATION	-0.4516	-1.6008	0.0054	0.0100	0.1516	2.0518
ADAPTIVE_IMMUNE_RESPONSE_GO_0002460	-0.5491	-1.5398	0.0294	0.0181	0.2656	2.1055
ADAPTIVE_IMMUNE_RESPONSE	-0.5268	-1.4882	0.0446	0.0280	0.3934	2.3657

To assess the possibility that SC236 improves control of metastasis in the context of VEGF blockade by broadly reducing expression of inflammation-related genes, we used gene set expression analysis (GSEA) and a matrix of 67 gene sets representing pathways linked to macrophage recruitment selected from the Molecular Signatures Database (MSigDB, Broad Institute, Cambridge, MA) to explore this possibility in Affymetrix HGU133A microarray datasets from xenografts (N = 3, 4 respectively, for BV, and BV+SC236 groups). 20 gene sets were significantly negatively enriched (repressed) in combination in SC236+BV treated as compared to BV-treated tumors; no positively enriched gene set had an odds ratio > 2.0 (Table 1). Among the negatively enriched sets, we selected those with odds ratios > 3.0 in the top 5 for further analysis. Thus, it is possible that, in the context of VEGF inhibition, SC236 acts in part by limiting the ability of tumors to promote recruitment of macrophages, key elements in an inflammatory state that facilitates metastasis.

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ISSN: 2045-824X

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