Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptional and Phenotypic Reprogramming of Tumors by Host Stroma Deficient in TNFα Signaling

ABSTRACT: Background: We previously demonstrated that B16F1 melanoma tumors growing in syngeneic germline-deleted TNFR1,2 -/- mice were more sensitive to ionizing radiation (IR) compared to tumors growing in C57BL/6 wild-type mice; however, the mechanisms linked to this difference in radiosensitivity are not fully understood. Methodology/ Principal Findings: We used DNA microarrays to identify alterations in the expression of functional gene clusters associated with the radiosensitization of B16F1 tumors growing in TNFR1,2 -/- mice. At the basal level, disruption of host stromal TNFα signaling resulted in the over-expression of tumor genes involved in extracellular matrix remodeling and angiogenesis. Phenotypically, these tumors exhibited a reduced vascular density, which induced the expression of oxidative stress signaling pathways and increased levels of tissue hypoxia and necrosis. These alterations were paralleled by the suppression of genes involved in chromosomal stability and key effectors of the ATM-dependent/ non-homologous end-joining pathways including phosphorylated-ATM, BRCA1, and RAD51, which resulted in greater DNA double-strand breaks and caspase 3 activation following IR treatment. Conclusions/ Significance: Taken together, these results demonstrate that disruption of TNFα signaling in the host stroma mediates transcriptional and phenotypic changes in tumors which may alter tumor radiosensitivity. These results suggest a critical role for TNFα in the maintenance of tumor-associated vasculature and radioresistance. They also indicate that TNFα signaling blockade in stromal cells may represent a strategy for tumor radiosensitization. To investigate the genes associated with the radiosensitization of B16F1 melanoma tumors in the context of disrupted stromal TNFα signaling, we performed expression profiling of B16F1 tumors grown in syngeneic TNFR 1, 2 -/- and wild-type C57BL/6 mice. Tumors were lysed to collect total RNA, pooled by treatment group according to total RNA level, and analyzed in duplicates with Affymetrix GeneChip® Mouse Genome 430 2.0 Arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Sean Pitroda

PROVIDER: E-GEOD-23002 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Endothelial inflammation contributes to the pathogenesis of numerous human diseases; however, the role of tumor endothelial inflammation in the growth of experimental tumors and its influence on the prognosis of human cancers is less understood. TNF-M-NM-1, an important mediator of tumor stromal inflammation, is known to target the tumor vasculature. In this study, we demonstrate that B16-F1 melanomas grew more rapidly in C57BL/6 wild-type (WT) mice than in syngeneic mice with germline deletions of both TNF-M-NM-1 receptors (KO). This enhanced tumor growth was associated with increased COX2 inflammatory expression in WT tumor endothelium compared to endothelium in KO mice. We purified endothelial cells from WT and KO tumors and characterized dysregulated gene expression, which ultimately formed the basis of a 6-gene Inflammation-Related Endothelial-derived Gene (IREG) signature. This inflammatory signature expressed in WT tumor endothelial cells was trained in human cancer datasets and predicted a poor clinical outcome in breast cancer, colon cancer, lung cancer and glioma. Consistent with this observation, conditioned media from human endothelial cells treated with pro-inflammatory cytokines (TNF-M-NM-1 and interferons) accelerated the growth of human colon and breast tumors in immune-deprived mice as compared with conditioned media from untreated endothelial cells. These findings demonstrate that activation of endothelial inflammatory pathways contributes to tumor growth and progression in diverse human cancers. To investigate the genes associated with TNF-M-NM-1 signaling in tumor endothelium, we performed expression profiling of tumor-associated endothelial cells isolated from B16F1 tumors grown in syngeneic TNFR 1, 2 -/- (KO) and C57BL/6 (WT) mice. Tumor endothelial cells were isolated from WT and KO tumors when tumor volumes were ~180 mm^3. This was based on a stepwise immunopurification of combined tumor tissue (Seaman, S. et al. Genes that distinguish physiological and pathological angiogenesis. Cancer Cell 11, 539-54 (2007)). Tumor endothelial cells were lysed to collect total RNA and analyzed in duplicates with Affymetrix GeneChipM-BM-. Mouse Genome 430 2.0 Arrays.

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Transcriptional and Phenotypic Reprogramming of Tumors by Host Stroma Deficient in TNFα Signaling

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