Email updates

Keep up to date with the latest news and content from BMC Medicine and BioMed Central.

Journal App

google play app store
Open Access Highly Accessed Research article

The endogenous soluble VEGF receptor-2 isoform suppresses lymph node metastasis in a mouse immunocompetent mammary cancer model

Masa-Aki Shibata1*, Jayakrishna Ambati2, Eiko Shibata13, Romulo JC Albuquerque2, Junji Morimoto4, Yuko Ito1 and Yoshinori Otsuki1

Author Affiliations

1 Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, Osaka, Japan

2 Department of Ophthalmology and Visual Sciences and Physiology, University of Kentucky, Lexington, KY, USA

3 Laboratory for Drug Discovery Innovation, Department of Molecular Pharmacology, National Cerebral & Cardiovascular Center Research Institute, Osaka, Japan

4 Laboratory Animal Center, Osaka Medical College, Osaka, Japan

For all author emails, please log on.

BMC Medicine 2010, 8:69  doi:10.1186/1741-7015-8-69

Published: 3 November 2010

Abstract

Background

Cancer metastasis contributes significantly to cancer mortality and is facilitated by lymphangiogenesis and angiogenesis. A new splicing variant, endogenous soluble vascular endothelial growth factor receptor-2 (esVEGFR-2) that we recently identified is an endogenous selective inhibitor of lymphangiogenesis. To evaluate the antimetastatic potential of esVEGFR-2, gene therapy with vector expressing esVEGFR-2 (pesVEGFR-2) or endostatin (pEndo) as a positive control was conducted on murine metastatic mammary cancer.

Methods

Syngeneic inoculated metastatic mammary cancers received direct intratumoral injection of pesVEGFR-2, pEndo or pVec as control, once a week for six weeks. In vivo gene electrotransfer was performed on the tumors after each injection.

Results

Deaths from metastasis were much lower in the pesVEGFR-2 and pEndo groups than in those of the pVec. Tumor volume was significantly lower in the pesVEGFR-2 and the pEndo groups throughout the study. Multiplicity of lymph node and lung metastatic nodules was significantly suppressed in the pesVEGFR-2 and pEndo groups. Moreover, the total number of overall metastasis including the other organs was also decreased in these groups. However, pesVEGFR-2 was not able to decrease the number of lungs, ovaries, kidneys and adrenals with metastasis as counted by unilateral or bilateral metastasis. The number of CD34+/Lyve-1- blood microvessels was significantly decreased in the pEndo group, while the number of CD34-/Lyve-1+ lymphatic vessels was significantly decreased in the pesVEGFR-2 and pEndo groups. In addition, a significant reduction in the number of dilated lymphatic vessels containing intraluminal cancer cells was observed in the pesVEGFR-2 and pEndo groups. Levels of apoptosis were significantly increased in the pEndo group, whereas the rates of cell proliferation were significantly decreased in the pesVEGFR-2 and pEndo groups.

Conclusions

Our data demonstrate that esVEGFR-2 can inhibit mainly lymph node metastasis. The antimetastatic activity of esVEGFR-2 may be of high clinical significance in the treatment of metastatic breast cancer because lymph node involvement is a most important prognostic factor in cancer patients.