Aracterization of tumor-stromal interactions. There is considerable evidence that stromal inflammation contributes to the proliferation and survival of malignant cells, facilitates genomic instability, stimulates angiogenesis and metastasis, and alters theresponse to 4EGI-1 site anti-cancer therapies [2,3]. When chronically produced in the tumor microenvironment, TNF-a is a major mediator of stromal inflammation [3]. TNF-a is important in early events in tumorigenesis, controlling a cascade of cytokines, chemokines, adhesion molecules, and pro-angiogenic activities [2,3]. The most well-characterized actions of malignant cellderived TNF-a are on vascular endothelial cells. Vascular endothelial cells AZ-876 chemical information actively participate in and regulate the inflammatory response in both normal and diseased tissues [4], and emerging data suggests that endothelial cells directly influenceTumor Endothelial Inflammation in Cancer Prognosistumor behavior 1326631 [5?]. Nevertheless, little is known regarding the role of endothelial inflammation in promoting tumor growth and its influence on the prognosis of human cancers. Gene expression profiling of clinical tumors has led to the discovery of numerous molecular signatures. One limitation of current gene expression profiling studies is a lack of validation in independent clinical datasets [8,9]. Importantly, many empirically derived clinical signatures are specific to a single cancer type and often do not provide insight into relevant biological pathways affecting cancer prognosis. We utilized an experimental 
model of TNF-a-mediated inflammation to characterize inflammatory gene expression in tumor-associated endothelial cells. In this study, we demonstrate that the induction of inflammatory gene expression in tumor-associated endothelial cells significantly accelerates the growth of human tumors. Notably, we derive the first cancer gene signature associated with endothelial inflammation that predicts 15755315 clinical outcome in four types of human cancers independently of standard clinical and pathological prognostic factors. Our findings provide a new biologically derived method of cancer prognostication and suggest potential pathways for the development of anti-cancer therapies targeting the tumor stroma.Vanderbilt Medical Center (VMC; Nashville, TN) and H. Lee Moffitt Cancer Center (MCC; Tampa, FL); GSE17538 [177 from MCC; 55 from VMC]), the tumor samples were randomly separated into two parts (2/3 for training and 1/3 for validation) using computer-generated random numbers to assign specimens to training or validation cohorts. For glioma, distinct datasets [12,13] were used for training (n = 77; University of California at San Francisco and MD Anderson Cancer Center; GSE4271) and validation (n = 50; Canadian Brain Tumor Tissue Bank (London, Ontario, Canada), Massachusetts General Hospital (Boston, MA), Brigham and Women’s Hospital (Boston, MA), and Charite’ Hospital (Berlin, Germany)); http://www.broadinstitute.org/cgibin/cancer/datasets.cgi). Lastly, for lung cancer [14], four datasets (n = 441) were available from a single study and separated into training (n = 257) and validation cohorts (n = 184) as was described in the original publication. These datasets were obtained from the University of Michigan Cancer Center, Moffitt Cancer Center, Memorial Sloan-Kettering Cancer Center and the Dana-Farber Cancer Institute (available at https://caarraydb.nci.nih.gov/ caarray/publicExperimentDetailAction.do?expId1/ 41015945236141280. Clinic.Aracterization of tumor-stromal interactions. There is considerable evidence that stromal inflammation contributes to the proliferation and survival of malignant cells, facilitates genomic instability, stimulates angiogenesis and metastasis, and alters theresponse to anti-cancer therapies [2,3]. When chronically produced in the tumor microenvironment, TNF-a is a major mediator of stromal inflammation [3]. TNF-a is important in early events in tumorigenesis, controlling a cascade of cytokines, chemokines, adhesion molecules, and pro-angiogenic activities [2,3]. 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 influenceTumor Endothelial Inflammation in Cancer Prognosistumor behavior 1326631 [5?]. Nevertheless, little is known regarding the role of endothelial inflammation in promoting tumor growth and its influence on the prognosis of human cancers. Gene expression profiling of clinical tumors has led to the discovery of numerous molecular signatures. One limitation of current gene expression profiling studies is a lack of validation in independent clinical datasets [8,9]. Importantly, many empirically derived clinical signatures are specific to a single cancer type and often do not provide insight into relevant biological pathways affecting cancer prognosis. We utilized an experimental model of TNF-a-mediated inflammation to characterize inflammatory gene expression in tumor-associated endothelial cells. In this study, we demonstrate that the induction of inflammatory gene expression in tumor-associated endothelial cells significantly accelerates the growth of human tumors. Notably, we derive the first cancer gene signature associated with endothelial inflammation that predicts 15755315 clinical outcome in four types of human cancers independently of standard clinical and pathological prognostic factors. Our findings provide a new biologically derived method of cancer prognostication and suggest potential pathways for the development of anti-cancer therapies targeting the tumor stroma.Vanderbilt Medical Center (VMC; Nashville, TN) and H. Lee Moffitt Cancer Center (MCC; Tampa, FL); GSE17538 [177 from MCC; 55 from VMC]), the tumor samples were randomly separated into two parts (2/3 for training and 1/3 for validation) using computer-generated random numbers to assign specimens to training or validation cohorts. For glioma, distinct datasets [12,13] were used for training (n = 77; University of California at San Francisco and MD Anderson Cancer Center; GSE4271) and validation (n = 50; Canadian Brain Tumor Tissue Bank (London, Ontario, Canada), Massachusetts General Hospital (Boston, 
MA), Brigham and Women’s Hospital (Boston, MA), and Charite’ Hospital (Berlin, Germany)); http://www.broadinstitute.org/cgibin/cancer/datasets.cgi). Lastly, for lung cancer [14], four datasets (n = 441) were available from a single study and separated into training (n = 257) and validation cohorts (n = 184) as was described in the original publication. These datasets were obtained from the University of Michigan Cancer Center, Moffitt Cancer Center, Memorial Sloan-Kettering Cancer Center and the Dana-Farber Cancer Institute (available at https://caarraydb.nci.nih.gov/ caarray/publicExperimentDetailAction.do?expId1/ 41015945236141280. Clinic.
