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

BMC Med. 2010 Nov 3;8:69. doi: 10.1186/1741-7015-8-69.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Genetic Therapy
  • Genetic Vectors
  • Immunocompetence
  • Lung Neoplasms / secondary
  • Lymphangiogenesis / drug effects*
  • Lymphangiogenesis / genetics
  • Lymphatic Metastasis / genetics*
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Models, Animal
  • Neoplasm Metastasis
  • Protein Isoforms
  • Receptors, Vascular Endothelial Growth Factor / genetics*
  • Receptors, Vascular Endothelial Growth Factor / pharmacology
  • Receptors, Vascular Endothelial Growth Factor / therapeutic use*
  • Tumor Burden / drug effects
  • Vascular Endothelial Growth Factor Receptor-2 / genetics*
  • Vascular Endothelial Growth Factor Receptor-2 / pharmacology
  • Vascular Endothelial Growth Factor Receptor-2 / therapeutic use*
  • Vascular Endothelial Growth Factors / genetics*

Substances

  • Protein Isoforms
  • Vascular Endothelial Growth Factors
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-2