title: Endothelial-like properties of claudin-low breast cancer cells promote tumor vascular permeability and metastasis.
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.
authors: Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Campus Box 7295, 450 West Drive, Chapel Hill, NC, 27599, USA, harrellc@email.unc.edu.
authors: J Chuck
authors: JC
authors: Harrell
authors: Adam D
authors: AD
authors: Pfefferle
authors: Nicole
authors: N
authors: Zalles
authors: Aleix
authors: A
authors: Prat
authors: Cheng
authors: C
authors: Fan
authors: Andrey
authors: A
authors: Khramtsov
authors: Olufunmilayo I
authors: OI
authors: Olopade
authors: Melissa A
authors: MA
authors: Troester
authors: Andrew C
authors: AC
authors: Dudley
authors: Charles M
authors: CM
authors: Perou
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002199:Capillary Permeability / Q000502:physiology; D045744:Cell Line, Tumor; D057167:Claudins / Q000378:metabolism; D004727:Endothelium / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009374:Neoplasms, Experimental / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics*; D059467:Transcriptome
chemical_list: D057167:Claudins
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