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Abstract
BackgroundVascular endothelial cells contribute to the pathogenesis of numerous human diseases by actively regulating the stromal inflammatory response; however, little is known regarding the role of endothelial inflammation in the growth of human tumors and its influence on the prognosis of human cancers.MethodsUsing an experimental model of tumor necrosis factor-alpha (TNF-α)-mediated inflammation, we characterized inflammatory gene expression in immunopurified tumor-associated endothelial cells. These genes formed the basis of a multivariate molecular predictor of overall survival that was trained and validated in four types of human cancer.ResultsWe report that expression of experimentally derived tumor endothelial genes distinguished pathologic tissue specimens from normal controls in several human diseases associated with chronic inflammation. We trained these genes in human cancer datasets and defined a six-gene inflammatory signature that predicted significantly reduced overall survival in breast cancer, colon cancer, lung cancer, and glioma. This endothelial-derived signature predicted outcome independently of, but cooperatively with, standard clinical and pathological prognostic factors. Consistent with these findings, conditioned culture media from human endothelial cells stimulated by pro-inflammatory cytokines accelerated the growth of human colon and breast tumors in immunodeficient mice as compared with conditioned media from untreated endothelial cells.ConclusionsThis study provides the first prognostic cancer gene signature derived from an experimental model of tumor-associated endothelial inflammation. These findings support the notion that activation of inflammatory pathways in non-malignant tumor-infiltrating endothelial cells contributes to tumor growth and progression in multiple human cancers. Importantly, these results identify endothelial-derived factors that could serve as potential targets for therapy in diverse human cancers.
Highlights
Over the last decade, our understanding of tumor biology has expanded to include host stromal elements as important determinants in malignant transformation and progression [1]
We demonstrate that the induction of inflammatory gene expression in tumor-associated endothelial cells significantly accelerates the growth of human tumors
Characterization of inflammatory gene expression in tumor-associated endothelium To examine the role of tumor necrosis factor-alpha (TNF-a)-mediated stromal inflammation in tumor growth, we used a syngeneic tumor model of B16-F1 murine melanoma established in wild-type (WT) mice and mice with immune dysfunction as a result of germline deletions of both TNF-a receptors (TNFR 1, 22/2, referred to as knockout [KO])
Summary
Our understanding of tumor biology has expanded to include host stromal elements as important determinants in malignant transformation and progression [1]. The most well-characterized actions of malignant cellderived TNF-a are on vascular endothelial cells. Vascular endothelial cells actively participate in and regulate the inflammatory response in both normal and diseased tissues [4], and emerging data suggests that endothelial cells directly influence tumor behavior [5,6,7]. Little is known regarding the role of endothelial inflammation in promoting tumor growth and its influence on the prognosis of human cancers. Vascular endothelial cells contribute to the pathogenesis of numerous human diseases by actively regulating the stromal inflammatory response; little is known regarding the role of endothelial inflammation in the growth of human tumors and its influence on the prognosis of human cancers
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