Tumor endothelial inflammation predicts clinical outcome in diverse human cancers.
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois, United States of America.
Sean P
SP
Pitroda
Tong
T
Zhou
Randy F
RF
Sweis
Matthew
M
Filippo
Edwardine
E
Labay
Michael A
MA
Beckett
Helena J
HJ
Mauceri
Hua
H
Liang
Thomas E
TE
Darga
Samantha
S
Perakis
Sajid A
SA
Khan
Harold G
HG
Sutton
Wei
W
Zhang
Nikolai N
NN
Khodarev
Joe G N
JG
Garcia
Ralph R
RR
Weichselbaum
D000328:Adult; D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D014409:Tumor Necrosis Factor-alpha