title: Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion.
abstract: Endothelial connexin40 (Cx40) contributes to regulate the structure and function of vessels. We have examined whether the protein also modulates the altered growth of vessels in tumor models established in control mice (WT), mice lacking Cx40 (Cx40-/-), and mice expressing the protein solely in endothelial cells (Tie2-Cx40). Tumoral angiogenesis and growth were reduced, whereas vessel perfusion, smooth muscle cell (SMC) coverage and animal survival were increased in Cx40-/- but not Tie2-Cx40 mice, revealing a critical involvement of endothelial Cx40 in transformed tissues independently of the hypertensive status of Cx40-/- mice. As a result, Cx40-/- mice bearing tumors survived significantly longer than corresponding controls, including after a cytotoxic administration. Comparable observations were made in WT mice injected with a peptide targeting Cx40, supporting the Cx40 involvement. This involvement was further confirmed in the absence of Cx40 or by peptide-inhibition of this connexin in aorta-sprouting, matrigel plug and SMC migration assays, and associated with a decreased expression of the phosphorylated form of endothelial nitric oxide synthase. The data identify Cx40 as a potential novel target in cancer treatment.
authors.affiliation: Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Florian
authors.initials: F
authors.lastname: Alonso
authors.affiliation: Department of Urology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Domingos-Pereira
authors.affiliation: Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Gal
authors.affiliation: Department of Urology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Derré
authors.affiliation: Department of Cell Physiology and Metabolism, University of Geneva, Medical Center, Geneva, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.affiliation: Department of Urology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Patrice
authors.initials: P
authors.lastname: Jichlinski
authors.affiliation: Department of Urology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Denise
authors.initials: D
authors.lastname: Nardelli-Haefliger
authors.affiliation: Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Jacques-Antoine
authors.initials: JA
authors.lastname: Haefliger
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D001808:Blood Vessels / Q000502:physiology*; D049109:Cell Proliferation; D017630:Connexins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D010477:Perfusion; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000473:pathology / Q000517:prevention & control*; D000097003:Gap Junction alpha-5 Protein
chemical_list: D014408:Biomarkers, Tumor; D017630:Connexins; D000097003:Gap Junction alpha-5 Protein
keywords: angiogenesis; cell-cell communication; connexins; transgenic mice; tumors