Gene-expression profiling of microdissected breast cancer microvasculature identifies distinct tumor vascular subtypes.
BACKGROUND
Angiogenesis 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.


METHODS
To 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.


RESULTS
We 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.


CONCLUSIONS
Our 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.
François
F
Pepin
Nicholas
N
Bertos
Julie
J
Laferrière
Svetlana
S
Sadekova
Margarita
M
Souleimanova
Hong
H
Zhao
Greg
G
Finak
Sarkis
S
Meterissian
Michael T
MT
Hallett
Morag
M
Park
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D016000:Cluster Analysis; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009389:Neovascularization, Pathologic / Q000235:genetics*; D063868:Patient Outcome Assessment; D011379:Prognosis