title: Caveolin-1 is critical for the maturation of tumor blood vessels through the regulation of both endothelial tube formation and mural cell recruitment.
abstract: In the normal microvasculature, caveolin-1, the structural protein of caveolae, modulates transcytosis and paracellular permeability. Here, we used caveolin-1-deficient mice (Cav(-/-)) to track the potential active roles of caveolin-1 down-modulation in the regulation of vascular permeability and morphogenesis in tumors. In B16 melanoma-bearing Cav(-/-) mice, we found that fibrinogen accumulated in early-stage tumors to a larger extent than in wild-type animals. These results were confirmed by the observations of a net elevation of the interstitial fluid pressure and a relative deficit in albumin extravasation in Cav(-/-) tumors (versus healthy tissues). Immunostaining analyses of Cav(-/-) tumor sections further revealed a higher density of CD31-positive vascular structures and a dramatic deficit in alpha-smooth muscle actin-stained mural cells. The increase in blood plasma volume in Cav(-/-) tumors was confirmed by dynamic contrast enhanced-magnetic resonance imaging and found to be associated with a more rapid tumor growth. Finally, an in vitro wound test and the aorta ring assay revealed that silencing caveolin expression could directly impair the migration and the outgrowth of smooth muscle cells/pericytes, particularly in response to platelet-derived growth factor. In conclusion, a decrease in caveolin abundance, by promoting angiogenesis and preventing its termination by mural cell recruitment, appears as an important control point for the formation of new tumor blood vessels. Caveolin-1 therefore has the potential to be a marker of tumor vasculature maturity that may help adjusting anticancer therapies.
authors.affiliation: Unit of Pharmacology and Therapeutics (UCL-FATH 5349), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Dewever
authors.forename: Françoise
authors.initials: F
authors.lastname: Frérart
authors.forename: Caroline
authors.initials: C
authors.lastname: Bouzin
authors.forename: Christine
authors.initials: C
authors.lastname: Baudelet
authors.forename: Réginald
authors.initials: R
authors.lastname: Ansiaux
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.forename: Bernard
authors.initials: B
authors.lastname: Gallez
authors.forename: Chantal
authors.initials: C
authors.lastname: Dessy
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D051242:Caveolin 1 / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000502:physiology*; D004730:Endothelium, Vascular / Q000473:pathology*; D005340:Fibrinogen / Q000378:metabolism; D008546:Melanoma, Experimental / Q000098:blood supply*; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D020286:Pericytes / Q000502:physiology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000502:physiology; D014183:Transplantation, Heterologous
chemical_list: D051242:Caveolin 1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010982:Platelet-Derived Growth Factor; D005340:Fibrinogen