Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion
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Florian Alonso1,*, Sonia Domingos-Pereira2,*, Loïc Le Gal1, Laurent Derré2, Paolo Meda3, Patrice Jichlinski2, Denise Nardelli-Haefliger2,#, Jacques-Antoine Haefliger1,#
1Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland
2Department of Urology, Lausanne University Hospital, Lausanne, Switzerland
3Department of Cell Physiology and Metabolism, University of Geneva, Medical Center, Geneva, Switzerland
*Contributed equally to this work as first authors
#Contributed equally to this work as senior authors
Jacques-Antoine Haefliger, e-mail: [email protected]
Keywords: cell-cell communication, connexins, angiogenesis, tumors, transgenic mice
Received: October 19, 2015 Accepted: January 29, 2016 Published: February 13, 2016
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.
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