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Intravital Microscopy of Tumor-associated Vasculature Using Advanced Dorsal Skinfold Window Chambers on Transgenic Fluorescent Mice
Published on: January 19, 2018
Targeting endothelial connexin40 inhibits tumor growth by reducing angiogenesis and improving vessel perfusion
Florian Alonso1, Sonia Domingos-Pereira2, Loïc Le Gal1
1Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
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.
Insights
Endothelial connexin40 (Cx40) inhibition reduces tumor growth and enhances survival by decreasing tumoral angiogenesis. Targeting Cx40 presents a potential strategy for cancer treatment.
Area of Science:
- Cardiovascular Biology
- Oncology
- Cell Biology
Background:
- Endothelial connexin40 (Cx40) plays a role in regulating blood vessel structure and function.
- Altered vessel growth is a hallmark of tumor development.
Purpose of the Study:
- To investigate the role of endothelial Cx40 in modulating tumor angiogenesis and growth.
- To determine if Cx40 is a viable therapeutic target in cancer treatment.
Main Methods:
- Tumor models were established in wild-type (WT), Cx40-deficient (Cx40-/-), and endothelial-specific Cx40-expressing (Tie2-Cx40) mice.
- Assays included aorta-sprouting, matrigel plug, and smooth muscle cell (SMC) migration.
- Cx40 involvement was assessed via genetic deletion and peptide inhibition.
Main Results:
- Tumoral angiogenesis and growth were reduced in Cx40-/- mice.
- Vessel perfusion, SMC coverage, and animal survival were increased in Cx40-/- mice.
- Cx40 inhibition, via genetic means or peptide, decreased phosphorylated endothelial nitric oxide synthase expression.
Conclusions:
- Endothelial Cx40 critically influences tumor growth and vascularization independently of hypertension.
- Cx40 deficiency or inhibition significantly improves survival in tumor-bearing mice.
- Connexin40 emerges as a promising therapeutic target for cancer treatment.
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