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The soluble fragment of VE-cadherin inhibits angiogenesis by reducing endothelial cell proliferation and tube capillary formation

Cancer Gene Therapy volume 17, pages 700–707 (2010)Cite this article

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Abstract

Vascular endothelial-specific cadherin (VE-cadherin) is an endothelial cell-specific adhesion molecule, localized at cell–cell contact sites. It is involved in physiological and pathological angiogenesis. In this study, we showed that in vitro a soluble N-terminal fragment of VE-cadherin (EC1–3) corresponding to cadherin 1–3 ectodomains inhibited vascular endothelial growth factor-stimulated endothelial cell proliferation and capillary tube structure formation in the matrigel model. In vivo, EC1–3 was tested in a murine colon cancer model. EC1–3-expressing colon cancer C51 cells were subcutaneously grafted into nude mice, and tumor growth and angiogenesis were evaluated. At day 33, the mean volume of the tumors developed was reduced (510±104 versus 990±120 mm3 for control). Similarly, injection of EC1–3 virus-producing cells into established C51 tumors resulted in an inhibition by 33% of tumor growth. Immunohistological staining of vessels on tumor sections showed a significantly reduced intratumoral angiogenesis. Furthermore, EC1–3 did not induce vessel injury in the lung, liver, spleen, heart and brain in the mice. These results suggest that the soluble N-terminal fragment of VE-cadherin EC1–3 could exert an antitumoral effect by targeting tumor angiogenesis, which included blocking endothelial cell proliferation and capillary tube formation with no obvious toxicity on normal organs.

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Abbreviations

CD31 (PECAM-1):

platelet-endothelial cell adhesion molecule 1

CPAE:

calf pulmonary aortic endothelial cell

EC1–3:

N-terminal fragment of VE-cadherin corresponding to cadherin ectodomains 1–3

GFP:

green fluorescent protein

HMEC-1:

human microvascular endothelial cell line

HUVEC:

human umbilical venous endothelial cell

IRES:

internal ribosome entry site

VEGF:

vascular endothelial growth factor

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Acknowledgements

We are grateful to F Larbret and Cathrine Buguet for assistance with cell sorting. We thank Patrice Ardouin (IGR, Villejuif) for animal care, and Lorna Saint-Ange for editing (IGR, Villejuif). We also thank l’Institut de Cancer (INCA PL06_130) for their support.

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Author notes

  1. X Shi: X Shi is working at present at the Department of Anatomy and Embryology, Medical College of Nanchang University, China.

  2. X Zhang: X Zhang is working at present at the Institute of Biochemistry and Cell Biology, Shanghai, Chinese Academy of Sciences.

Authors and Affiliations

  1. MERCI EA 3829, Faculté de Médecine et de Pharmacie, Université de Rouen, Rouen, France

    H Li, J-P Vannier & C Soria

  2. INSERM U728, Institut d’Hématologie, Hôpital Saint-Louis, Université Paris 7, Paris cedex, France

    X Shi, J Liu, C Hu, X Zhang, H Liu, J Jin, A Janin, C Soria & H Lu

  3. CNRS UMR 8121, Institut Gustave Roussy, Villejuif, France

    H Li, P Opolon & M Perricaudet

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Correspondence to H Lu.

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Li, H., Shi, X., Liu, J. et al. The soluble fragment of VE-cadherin inhibits angiogenesis by reducing endothelial cell proliferation and tube capillary formation. Cancer Gene Ther 17, 700–707 (2010). https://doi.org/10.1038/cgt.2010.26

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