Tumor Endothelial Inflammation Predicts Clinical Outcome in Diverse Human Cancers
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{"title"=>"Tumor Endothelial Inflammation Predicts Clinical Outcome in Diverse Human Cancers", "type"=>"journal", "authors"=>[{"first_name"=>"Sean P.", "last_name"=>"Pitroda", "scopus_author_id"=>"25628420100"}, {"first_name"=>"Tong", "last_name"=>"Zhou", "scopus_author_id"=>"7402989477"}, {"first_name"=>"Randy F.", "last_name"=>"Sweis", "scopus_author_id"=>"57060156400"}, {"first_name"=>"Matthew", "last_name"=>"Filippo", "scopus_author_id"=>"54794094000"}, {"first_name"=>"Edwardine", "last_name"=>"Labay", "scopus_author_id"=>"6506125890"}, {"first_name"=>"Michael A.", "last_name"=>"Beckett", "scopus_author_id"=>"7006200256"}, {"first_name"=>"Helena J.", "last_name"=>"Mauceri", "scopus_author_id"=>"6603986077"}, {"first_name"=>"Hua", "last_name"=>"Liang", "scopus_author_id"=>"57059681500"}, {"first_name"=>"Thomas E.", "last_name"=>"Darga", "scopus_author_id"=>"6507979062"}, {"first_name"=>"Samantha", "last_name"=>"Perakis", "scopus_author_id"=>"54794461700"}, {"first_name"=>"Sajid A.", "last_name"=>"Khan", "scopus_author_id"=>"56669074000"}, {"first_name"=>"Harold G.", "last_name"=>"Sutton", "scopus_author_id"=>"7005209201"}, {"first_name"=>"Wei", "last_name"=>"Zhang", "scopus_author_id"=>"54963907100"}, {"first_name"=>"Nikolai N.", "last_name"=>"Khodarev", "scopus_author_id"=>"7007168886"}, {"first_name"=>"Joe G.N.", "last_name"=>"Garcia", "scopus_author_id"=>"35233141600"}, {"first_name"=>"Ralph R.", "last_name"=>"Weichselbaum", "scopus_author_id"=>"35403900900"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84867132769", "doi"=>"10.1371/journal.pone.0046104", "pui"=>"365784405", "pmid"=>"23056240", "scopus"=>"2-s2.0-84867132769", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)"}, "id"=>"b0db654a-2cdb-399b-8186-a1aa3186dcb2", "abstract"=>"BACKGROUND: Vascular 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.\\n\\nMETHODS: Using 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.\\n\\nRESULTS: We 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.\\n\\nCONCLUSIONS: This 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.", "link"=>"http://www.mendeley.com/research/tumor-endothelial-inflammation-predicts-clinical-outcome-diverse-human-cancers", "reader_count"=>24, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Ph. D. Student"=>6, "Student > Master"=>5, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>1, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Researcher"=>7, "Student > Ph. D. Student"=>6, "Student > Master"=>5, "Student > Bachelor"=>1, "Lecturer"=>1, "Professor"=>1, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>11, "Medicine and Dentistry"=>3, "Chemistry"=>1, "Psychology"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Chemistry"=>{"Chemistry"=>1}, "Psychology"=>{"Psychology"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>11}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"United States"=>1, "Poland"=>1, "Mexico"=>1}, "group_count"=>2}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/564111"], "description"=>"<p>IREG expression is associated with poor prognosis in (A) breast cancer (n = 98), (B) colon cancer (n = 78), (C) glioma (n = 50), and (D) lung cancer (n = 184). Kaplan-Meier survival curves for patient groups identified by IREG score. P-values indicate significant differences in overall survival as measured by log-rank tests. Red = IREG+, blue = IREG−. (E–H) Expression of the six-gene IREG score was positively correlated with VCAM1 gene expression in each tumor type. Shown is the Pearson correlation coefficient.</p>", "links"=>[], "tags"=>["endothelium-derived"], "article_id"=>234586, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Sean P. Pitroda", "Tong Zhou", "Randy F. Sweis", "Matthew Filippo", "Edwardine Labay", "Michael A. Beckett", "Helena J. Mauceri", "Hua Liang", "Thomas E. Darga", "Samantha Perakis", "Sajid A. Khan", "Harold G. Sutton", "Wei Zhang", "Nikolai N. Khodarev", "Joe G. N. Garcia", "Ralph R. Weichselbaum"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046104.g003", "stats"=>{"downloads"=>1, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Expression_of_a_tumor_endothelium_derived_gene_signature_predicts_poor_clinical_outcome_in_multiple_human_cancers_/234586", "title"=>"Expression of a tumor endothelium-derived gene signature predicts poor clinical outcome in multiple human cancers.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-04 01:16:26"}
  • {"files"=>["https://ndownloader.figshare.com/files/563706"], "description"=>"<p>(A) B16-F1 melanoma tumor growth was significantly suppressed in TNFR 1, 2−/− mice (KO) with disrupted stromal TNF-α signaling as compared to that in wild-type mice (WT). Tumor volume was measured relative to Day 0 volume, which was equal in WT and KO mice (p = 0.19; 2-tailed Student's t-test). Day 7, p = 0.002. Data are mean ± SEM. (B) Tumor-associated endothelial cells (TAECs) in KO mice have significantly reduced expression of the pro-inflammatory enzyme COX2. Representative images of immunohistochemistry for COX2 carried out on B16-F1 tumors (Day 7) and (C) quantification of COX2-positive TAECs. Scale bar, 20 µm. Data are mean ± SEM. P = 0.0014 (2-tailed Student's t-test). (D) WT TAECs overexpress a highly significant “inflammatory response” gene network (p = 10<sup>−38</sup>; Fisher's exact test). Solid lines represent direct relationships, while dashed lines represent indirect relationships. Red color indicates overexpression in WT TAECs. (E) Stimulation of human umbilical vein endothelial cells (HUVECs) with a combination of the pro-inflammatory cytokines TNF-α, IFNβ, and IFNγ induced the expression of both experimentally derived endothelial inflammatory genes (black bars), as well as, known markers of endothelial inflammation (white bars). Total RNA was analyzed by quantitative RT-PCR. Data are mean fold-change ± SEM relative to control-treated HUVECs. P<0.01 across genes (2-tailed Student's t-test). (F) Conditioned culture media from treated HUVECs accelerated the growth of human colon tumors xenografted in athymic mice. Pre-treated indicates prior incubation of tumor cells with conditioned culture media from stimulated HUVECs, while control indicates incubation with conditioned media from mock-treated HUVECs. Tumor volume was measured relative to Day 0 volume (8 days post-injection). Data are mean ± SEM. Day 18, p = 0.0009 (2-tailed Student's t-test).</p>", "links"=>[], "tags"=>["tumor-associated", "endothelium"], "article_id"=>234182, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Sean P. Pitroda", "Tong Zhou", "Randy F. Sweis", "Matthew Filippo", "Edwardine Labay", "Michael A. Beckett", "Helena J. Mauceri", "Hua Liang", "Thomas E. Darga", "Samantha Perakis", "Sajid A. Khan", "Harold G. Sutton", "Wei Zhang", "Nikolai N. Khodarev", "Joe G. N. Garcia", "Ralph R. Weichselbaum"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046104.g001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inflammatory_gene_expression_in_tumor_associated_endothelium_is_associated_with_increased_tumor_growth_/234182", "title"=>"Inflammatory gene expression in tumor-associated endothelium is associated with increased tumor growth.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-04 01:09:42"}
  • {"files"=>["https://ndownloader.figshare.com/files/564288"], "description"=>"<p>Hazard ratio = HR. Confidence interval = CI.</p>", "links"=>[], "tags"=>["cox", "proportional", "hazards", "regression", "ireg"], "article_id"=>234754, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Sean P. Pitroda", "Tong Zhou", "Randy F. Sweis", "Matthew Filippo", "Edwardine Labay", "Michael A. Beckett", "Helena J. Mauceri", "Hua Liang", "Thomas E. Darga", "Samantha Perakis", "Sajid A. Khan", "Harold G. Sutton", "Wei Zhang", "Nikolai N. Khodarev", "Joe G. N. Garcia", "Ralph R. Weichselbaum"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046104.t001", "stats"=>{"downloads"=>4, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Univariate_Cox_proportional_hazards_regression_of_overall_survival_by_IREG_status_in_training_and_testing_cohorts_/234754", "title"=>"Univariate Cox proportional hazards regression of overall survival by IREG (+) status in training and testing cohorts.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-10-04 01:19:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/563903"], "description"=>"<p>Expressional clustering of human orthologs of the tumor endothelium-derived genes in patient tissue samples of (A) cirrhosis (153 genes), (B) inflammatory bowel disease (IBD) (140 genes), and (C) rheumatoid arthritis (RA) (106 genes) compared to normal tissue controls. Within the cluster diagram, each column represents a patient sample and each row represents a differentially expressed gene. Diseased samples are denoted by black hatches. Expression is depicted as mean-normalized, log2-transformed values. (D) Forty-nine genes were mutually dysregulated in the datasets tested and concordant in expression with the experimental model. (E) Pathway analysis of the 49-gene set demonstrating significant over-representation of several inflammation-related pathways. P-values were calculated using Fisher's exact test. Red line indicates p = 0.05.</p>", "links"=>[], "tags"=>["endothelium-derived", "genes", "diseases"], "article_id"=>234382, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Sean P. Pitroda", "Tong Zhou", "Randy F. Sweis", "Matthew Filippo", "Edwardine Labay", "Michael A. Beckett", "Helena J. Mauceri", "Hua Liang", "Thomas E. Darga", "Samantha Perakis", "Sajid A. Khan", "Harold G. Sutton", "Wei Zhang", "Nikolai N. Khodarev", "Joe G. N. Garcia", "Ralph R. Weichselbaum"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046104.g002", "stats"=>{"downloads"=>3, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Tumor_endothelium_derived_genes_are_expressed_in_multiple_human_diseases_of_chronic_inflammation_/234382", "title"=>"Tumor endothelium-derived genes are expressed in multiple human diseases of chronic inflammation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-10-04 01:13:02"}
  • {"files"=>["https://ndownloader.figshare.com/files/299404", "https://ndownloader.figshare.com/files/299627", "https://ndownloader.figshare.com/files/299814", "https://ndownloader.figshare.com/files/299874", "https://ndownloader.figshare.com/files/299925", "https://ndownloader.figshare.com/files/299983", "https://ndownloader.figshare.com/files/300037", "https://ndownloader.figshare.com/files/300106", "https://ndownloader.figshare.com/files/300170", "https://ndownloader.figshare.com/files/300317", "https://ndownloader.figshare.com/files/300497", "https://ndownloader.figshare.com/files/300541", "https://ndownloader.figshare.com/files/300593", "https://ndownloader.figshare.com/files/300643", "https://ndownloader.figshare.com/files/300693", "https://ndownloader.figshare.com/files/300743", "https://ndownloader.figshare.com/files/300795"], "description"=>"<div><h3>Background</h3><p>Vascular 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.</p> <h3>Methods</h3><p>Using 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.</p> <h3>Results</h3><p>We 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.</p> <h3>Conclusions</h3><p>This 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.</p> </div>", "links"=>[], "tags"=>["endothelial", "inflammation", "cancers"], "article_id"=>119030, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Sean P. Pitroda", "Tong Zhou", "Randy F. Sweis", "Matthew Filippo", "Edwardine Labay", "Michael A. Beckett", "Helena J. Mauceri", "Hua Liang", "Thomas E. Darga", "Samantha Perakis", "Sajid A. Khan", "Harold G. Sutton", "Wei Zhang", "Nikolai N. Khodarev", "Joe G. N. Garcia", "Ralph R. Weichselbaum"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0046104.s001", "https://dx.doi.org/10.1371/journal.pone.0046104.s002", "https://dx.doi.org/10.1371/journal.pone.0046104.s003", "https://dx.doi.org/10.1371/journal.pone.0046104.s004", "https://dx.doi.org/10.1371/journal.pone.0046104.s005", "https://dx.doi.org/10.1371/journal.pone.0046104.s006", "https://dx.doi.org/10.1371/journal.pone.0046104.s007", "https://dx.doi.org/10.1371/journal.pone.0046104.s008", "https://dx.doi.org/10.1371/journal.pone.0046104.s009", "https://dx.doi.org/10.1371/journal.pone.0046104.s010", "https://dx.doi.org/10.1371/journal.pone.0046104.s011", "https://dx.doi.org/10.1371/journal.pone.0046104.s012", "https://dx.doi.org/10.1371/journal.pone.0046104.s013", "https://dx.doi.org/10.1371/journal.pone.0046104.s014", "https://dx.doi.org/10.1371/journal.pone.0046104.s015", "https://dx.doi.org/10.1371/journal.pone.0046104.s016", "https://dx.doi.org/10.1371/journal.pone.0046104.s017"], "stats"=>{"downloads"=>35, "page_views"=>40, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Tumor_Endothelial_Inflammation_Predicts_Clinical_Outcome_in_Diverse_Human_Cancers/119030", "title"=>"Tumor Endothelial Inflammation Predicts Clinical Outcome in Diverse Human Cancers", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-10-04 02:30:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/564325"], "description"=>"<p>Shown are the number and percentages of patients in each category. For each clinical or pathological variable, p-values were calculated by Fisher's exact test comparing IREG (+) and IREG (−) patients.</p>", "links"=>[], "tags"=>["characteristics", "ireg"], "article_id"=>234803, "categories"=>["Cancer", "Cell Biology", "Genetics"], "users"=>["Sean P. Pitroda", "Tong Zhou", "Randy F. Sweis", "Matthew Filippo", "Edwardine Labay", "Michael A. Beckett", "Helena J. Mauceri", "Hua Liang", "Thomas E. Darga", "Samantha Perakis", "Sajid A. Khan", "Harold G. Sutton", "Wei Zhang", "Nikolai N. Khodarev", "Joe G. N. Garcia", "Ralph R. Weichselbaum"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0046104.t002", "stats"=>{"downloads"=>4, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_patient_characteristics_by_IREG_signature_expression_/234803", "title"=>"Comparison of patient characteristics by IREG signature expression.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-10-04 01:20:03"}

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