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| Status |
Public on Oct 20, 2012 |
| Title |
Transcriptional reprogramming of tumor-associated endothelial cells by disruption of TNF-α signaling |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by array
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| Summary |
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-α, 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-α 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-α 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.
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| Overall design |
To investigate the genes associated with TNF-α 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 GeneChip® Mouse Genome 430 2.0 Arrays.
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| Contributor(s) |
Pitroda SP, Labay E, Beckett MA, Mauceri HJ, Khodarev NN, Weichselbaum RR |
| Citation(s) |
23056240 |
| Submission date |
Oct 26, 2011 |
| Last update date |
Feb 11, 2019 |
| Contact name |
Sean Pravin Pitroda |
| E-mail(s) |
spitroda@uchicago.edu
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| Organization name |
The University of Chicago
|
| Department |
Radiation and Cellular Oncology
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| Street address |
5841 South Maryland Avenue, MC 1105
|
| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60637 |
| Country |
USA |
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| Platforms (1) |
| GPL1261 |
[Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA149037 |
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