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1.
Nat Med ; 14(1): 28-36, 2008 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-18157142

RESUMEN

In spite of their having sufficient immunogenicity, tumor vaccines remain largely ineffective. The mechanisms underlying this lack of efficacy are still unclear. Here we report a previously undescribed mechanism by which the tumor endothelium prevents T cell homing and hinders tumor immunotherapy. Transcriptional profiling of microdissected tumor endothelial cells from human ovarian cancers revealed genes associated with the absence or presence of tumor-infiltrating lymphocytes (TILs). Overexpression of the endothelin B receptor (ET(B)R) was associated with the absence of TILs and short patient survival time. The ET(B)R inhibitor BQ-788 increased T cell adhesion to human endothelium in vitro, an effect countered by intercellular adhesion molecule-1 (ICAM-1) blockade or treatment with NO donors. In mice, ET(B)R neutralization by BQ-788 increased T cell homing to tumors; this homing required ICAM-1 and enabled tumor response to otherwise ineffective immunotherapy in vivo without changes in systemic antitumor immune response. These findings highlight a molecular mechanism with the potential to be pharmacologically manipulated to enhance the efficacy of tumor immunotherapy in humans.


Asunto(s)
Inmunoterapia/métodos , Receptor de Endotelina B/fisiología , Linfocitos T/metabolismo , Animales , Complejo CD3/biosíntesis , Adhesión Celular , Línea Celular Tumoral , Endotelio/embriología , Endotelio/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Sistema Inmunológico , Molécula 1 de Adhesión Intercelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Neoplasias/inmunología , Receptor de Endotelina B/metabolismo
3.
J Clin Oncol ; 25(7): 852-61, 2007 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-17327606

RESUMEN

PURPOSE: This study aimed to identify novel ovarian cancer biomarkers and potential therapeutic targets through molecular analysis of tumor vascular cells. METHODS: Immunohistochemistry-guided laser-capture microdissection and genome-wide transcriptional profiling were used to identify genes that were differentially expressed between vascular cells from human epithelial ovarian cancer and healthy ovaries. Tumor vascular markers (TVMs) were validated through quantitative real-time polymerase chain reaction (qRT-PCR) of immunopurified tumor endothelial cells, in situ hybridization, immunohistochemistry, and Western blot analysis. TVM expression in tumors and noncancerous tissues was assessed by qRT-PCR and was profiled using gene expression data. RESULTS: We identified a tumor vascular cell profile of ovarian cancer that was distinct from the vascular profile of normal ovary and other tumors. We validated 12 novel ovarian TVMs. These were expressed by immunopurified tumor endothelial cells and localized to tumor vasculature. Select TVMs were found to be specifically expressed in ovarian cancer and were absent in all normal tissues tested, including female reproductive tissues with physiologic angiogenesis. Many ovarian TVMs were expressed by a variety of other solid tumors. Finally, overexpression of any one of three ovarian TVMs by vascular cells was associated with decreased disease-free interval (all P < .005). CONCLUSION: We have identified for the first time the molecular profile of ovarian tumor vasculature. We demonstrate that TVMs may serve as potential biomarkers and molecular targets for ovarian cancer and a variety of other solid tumors.


Asunto(s)
Biomarcadores de Tumor/análisis , Proteínas de Neoplasias/análisis , Neoplasias Ováricas/química , Proteínas de Unión al Calcio , Moléculas de Adhesión Celular , Colágeno/análisis , Colágeno/genética , Colágeno Tipo XI/análisis , Colágeno Tipo XI/genética , Femenino , Técnica del Anticuerpo Fluorescente , Perfilación de la Expresión Génica , Glicoproteínas/análisis , Humanos , Péptidos y Proteínas de Señalización Intercelular , Glicoproteínas de Membrana/análisis , Glicoproteínas de Membrana/genética , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/genética , Reacción en Cadena de la Polimerasa , Receptores del Factor de Necrosis Tumoral/análisis , Receptores del Factor de Necrosis Tumoral/genética
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