Event

Transcriptional profile of vascular tissue identifies distinct subtypes of vasculature and predicts clinical outcome in breast cancer

Wednesday, October 22, 2008 14:30to16:00
McIntyre Medical Building 3655 promenade Sir William Osler, Montreal, QC, H3G 1Y6, CA

Background: Angiogenesis plays an important role in the progression of solid tumors, providing both nutrients required for growth and a way to escape the tumor bed. The level of vascularization, as measured by microvessel density, varies greatly between breast cancer patients. A high microvessel density significantly predicts poor survival in breast cancer, but between-study variation is high. It is also known that the tumor vasculature differs significantly from its normal counterpart. Among other changes, it is often leaky and generally less mature, lacking the functional pericytes that help stabilize the vessels. Exploitation of these differences has led to the development of several therapeutic avenues to target the tumor vasculature, most notably antivascular endothelial growth factor therapy. Several studies have helped characterize the gene expression of tumor endothelial cells in different cancers and identify tumor-specific endothelial markers. However, none had sufficient samples to investigate the variations that exist between patients.

Methods: To study endothelial gene expression, we performed microarray hybridization (N=32) of laser capture microdissected endothelial cells from invasive ductal carcinomas and matched endothelial morphologically normal adjacent tissue. We used various statistical techniques to analyze the data and compare it with the additional datasets from the published literature. Immunohistochemistry and polymerase chain reaction were used to validate the results.

Results: We identified two distinct subtypes of tumor endothelial cells in breast cancer patients. They are associated with tumors of high and low vascular density but not with recurrence. The gene expression and immunohistochemistry of pericyte markers offer evidence that the subtypes are also associated with vessel maturity. Surprisingly, most of the published markers of tumor endothelial cells are specifically associated with the low vascular density group. We also identified differences in the Notch and transforming growth factor-beta signaling pathways. Using the information from the subtypes, we developed a prognostic predictor of recurrence based on tumor vascular gene expression. Interestingly, this is independent of the microvessel density, identifying the recurrences in high and low density patients. The genes in this predictor are linked to several pathways linked to DNA repair, apoptosis, and energy production.

Relevance: This project will help us clarify our understanding of the process of vascularization in breast cancer and its role in tumor progression and metastasis. The identification of distinct tumor endothelial classes will help clarify the complex role that the vasculature plays in tumor progression. Our prognostic predictor reinforces that view and identifies differences in tumor vascular gene expression can be linked to distant recurrences. This differential expression points to pathways that could be involved in metastasis. This could lead to more individualized and potentially new treatment options.

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