Abstract
The vasculature serves as the main conduit for breast tumor metastases and is a target of therapeutics in many tumor types. In this study, we aimed to determine if tumor-associated vascular properties could help to explain the differences observed in metastagenicity across the intrinsic subtypes of human breast tumors. Analysis of gene expression signatures from more than 3,000 human breast tumors found that genomic programs that measured vascular quantity, vascular proliferation, and a VEGF/Hypoxia-signature were the most highly expressed in claudin-low and basal-like tumors. The majority of the vascular gene signatures added metastasis-predictive information to immunohistochemistry-defined microvessel density scores and genomically defined-intrinsic subtype classification. Interestingly, pure claudin-low cell lines, and subsets of claudin-low-like cells within established basal-like cancer cell lines, exhibited endothelial/tube-like morphology when cultured on Matrigel. In vivo xenografts found that claudin-low tumors, but not luminal tumors, extensively perfused injected contrast agent through paracellular spaces and non-vascular tumor-lined channels. Taken together, the endothelial-like characteristics of the cancer cells, combined with both the amount and the physiologic state of the vasculature contribute to breast cancer metastatic progression. We hypothesize that the genetic signatures we have identified highlight patients that should respond most favorably to anti-vascular agents.Electronic supplementary materialThe online version of this article (doi:10.1007/s10585-013-9607-4) contains supplementary material, which is available to authorized users.
Highlights
There are at least five genomically distinct subtypes of human breast tumors [1, 2]
Since the results from this assay can vary depending on the vascular antibody utilized and/or one’s definition of a vascular hot-spot, we aimed to determine if vascular gene expression signatures could serve as an alternative biomarker to identify patients with an increased likelihood of distant metastasis or death
To contrast how the vascular signatures were expressed in normal breast samples, breast tumors, and pure endothelial cell lines, we determined average gene expression signature scores for each sample and in three endothelial cells (EC) lines (HUVEC, Blood microvascular endothelial cells (BEC), and lymphatic microvascular endothelial cells (LEC))
Summary
Each tumor subtype interacts with endothelial cells (EC) via secreted factors and directly by cell–cell contact (reviewed in [3]). These associations facilitate cancer cell entry into blood- and lymphatic-vessels, which initiates the metastatic cascade and results in the death of *400,000 people worldwide each year [4]. It is possible that some breast cancer subtypes are predisposed to metastasize more readily than others due to the amount of vasculature present within and surrounding the primary tumor. We hypothesized that basal-like and claudin-low tumors, as compared to luminal tumors, preferentially attract increased numbers of blood- and lymphatic-endothelial cells (BEC, LEC, collectively EC), which facilitates their metastasis via vessel association, intra/extravasation and dissemination. There may be no major difference in the amount of vasculature present within different subtypes, but instead, the physiologic properties of the cancer cells regulate how different subtypes interact with ECs
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