Abstract
IntroductionAngiogenesis represents a potential therapeutic target in breast cancer. However, responses to targeted antiangiogenic therapies have been reported to vary among patients. This suggests that the tumor vasculature may be heterogeneous and that an appropriate choice of treatment would require an understanding of these differences.MethodsTo investigate whether and how the breast tumor vasculature varies between individuals, we isolated tumor-associated and matched normal vasculature from 17 breast carcinomas by laser-capture microdissection, and generated gene-expression profiles. Because microvessel density has previously been associated with disease course, tumors with low (n = 9) or high (n = 8) microvessel density were selected for analysis to maximize heterogeneity for this feature.ResultsWe identified differences between tumor and normal vasculature, and we describe two subtypes present within tumor vasculature. These subtypes exhibit distinct gene-expression signatures that reflect features including hallmarks of vessel maturity. Potential therapeutic targets (MET, ITGAV, and PDGFRβ) are differentially expressed between subtypes. Taking these subtypes into account has allowed us to derive a vascular signature associated with disease outcome.ConclusionsOur results further support a role for tumor microvasculature in determining disease progression. Overall, this study provides a deeper molecular understanding of the heterogeneity existing within the breast tumor vasculature and opens new avenues toward the improved design and targeting of antiangiogenic therapies.
Highlights
Angiogenesis represents a potential therapeutic target in breast cancer
Because our goal was to investigate the heterogeneity of the tumor microvasculature in invasive ductal carcinomas, samples with high and low microvessel density (MVD) were chosen to maximize the spectrum of heterogeneity present within the sample cohort
Most previous signatures of tumor vascular cells identify only tumor vascular subtype B Previous studies have generated signatures that segregate tumor versus normal vascular samples, but have not identified distinct subtypes within the tumor vasculature. To test whether these signatures can differentiate between our tumor vascular subtypes, we examined the clustering induced by previously reported tumor vascular signatures [17,18,21,22,23] in our dataset
Summary
Responses to targeted antiangiogenic therapies have been reported to vary among patients This suggests that the tumor vasculature may be heterogeneous and that an appropriate choice of treatment would require an understanding of these differences. The growth of tumors beyond a certain size requires the recruitment of an adequate blood supply, which is supplied by abnormal angiogenesis This involves the triggering of an “angiogenic switch” [1], whereby the tumor microenvironment enters a proangiogenic mode in response to hypoxia. This process is accompanied by increased levels of multiple proangiogenic factors, including vascular endothelial growth factor A (VEGFA) and platelet-derived growth factor B (PDGFB), as well as decreases in antiangiogenic factors such as endostatin. A more complete understanding of vascular heterogeneity is required
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