title: Lysyl oxidase plays a critical role in endothelial cell stimulation to drive tumor angiogenesis.
abstract: Identification of key molecules that drive angiogenesis is critical for the development of new modalities for the prevention of solid tumor progression. Using multiple models of colorectal cancer, we show that activity of the extracellular matrix-modifying enzyme lysyl oxidase (LOX) is essential for stimulating endothelial cells in vitro and angiogenesis in vivo. We show that LOX activates Akt through platelet-derived growth factor receptor β (PDGFRβ) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRβ, Akt, and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient samples. Finally, we validate our findings in a breast cancer model, showing the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types.
authors.affiliation: Hypoxia and Metastasis Team, The Institute of Cancer Research, London, UK.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Baker
authors.forename: Demelza
authors.initials: D
authors.lastname: Bird
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Welti
authors.forename: Morgane
authors.initials: M
authors.lastname: Gourlaouen
authors.forename: Georgina
authors.initials: G
authors.lastname: Lang
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Murray
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Reynolds
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Cox
authors.forename: Janine T
authors.initials: JT
authors.lastname: Erler
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D008249:Protein-Lysine 6-Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D042461:Vascular Endothelial Growth Factor A; D008249:Protein-Lysine 6-Oxidase