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Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian
Chunhua Lu1, Tomas Bonome, Yang Li
1Departments of Gynecologic Oncology and Cancer Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
Therapeutic strategies based on antiangiogenic approaches are beginning to show great promise in clinical studies. However, full realization of these approaches requires identification of key differences in gene expression between endothelial cells from tumors versus their normal counterparts. Here, we examined gene expression differences in purified endothelial cells from 10 invasive epithelial ovarian cancers and 5 normal ovaries using Affymetrix U133 Plus 2.0 microarrays. More than 400 differentially expressed genes were identified in tumor-associated endothelial cells. We selected and validated 23 genes that were overexpressed by 3.6- to 168-fold using real-time reverse transcription-PCR and/or immunohistochemistry. Among these, the polycomb group protein enhancer of Zeste homologue 2 (EZH2), the Notch ligand Jagged1, and PTK2 were elevated 3- to 4.3-fold in tumor-associated endothelial cells. Silencing these genes individually with small interfering RNA blocked endothelial cell migration and tube formation in vitro. The present study shows that tumor and normal endothelium differ at the molecular level, which may have significant implications for the development of antiangiogenic therapies.
Insights
Tumor endothelial cells show distinct gene expression compared to normal cells, impacting antiangiogenic therapy development. Key genes like EZH2 and Jagged1 are crucial for tumor angiogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Antiangiogenic therapies show promise but require understanding tumor-specific endothelial cell differences.
- Identifying molecular distinctions between tumor and normal endothelium is crucial for effective antiangiogenesis strategies.
Purpose of the Study:
- To identify and validate differentially expressed genes in endothelial cells from ovarian tumors compared to normal ovaries.
- To investigate the functional role of specific overexpressed genes in tumor endothelial cell behavior.
Main Methods:
- Gene expression profiling using Affymetrix U133 Plus 2.0 microarrays on purified endothelial cells from 10 ovarian cancers and 5 normal ovaries.
- Validation of 23 overexpressed genes using real-time reverse transcription-PCR and immunohistochemistry.
- Functional assessment of key genes (EZH2, Jagged1, PTK2) using small interfering RNA to silence their expression and evaluate endothelial cell migration and tube formation in vitro.
Main Results:
- Over 400 differentially expressed genes were identified in tumor-associated endothelial cells.
- Twenty-three genes were validated as overexpressed, with Enhancer of Zeste homologue 2 (EZH2), Jagged1, and PTK2 showing 3- to 4.3-fold elevation.
- Silencing EZH2, Jagged1, or PTK2 individually inhibited endothelial cell migration and in vitro tube formation.
Conclusions:
- Tumor-associated endothelial cells exhibit significant molecular differences compared to normal endothelium.
- Specific genes, including EZH2, Jagged1, and PTK2, play critical roles in tumor angiogenesis.
- These findings have significant implications for developing targeted antiangiogenic therapies.
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