Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis

EMBO J. 2001 Feb 15;20(4):672-82. doi: 10.1093/emboj/20.4.672.

Abstract

Metastasis is a frequent and lethal complication of cancer. Vascular endothelial growth factor-C (VEGF-C) is a recently described lymphangiogenic factor. Increased expression of VEGF-C in primary tumours correlates with dissemination of tumour cells to regional lymph nodes. However, a direct role for VEGF-C in tumour lymphangiogenesis and subsequent metastasis has yet to be demonstrated. Here we report the establishment of transgenic mice in which VEGF-C expression, driven by the rat insulin promoter (Rip), is targeted to beta-cells of the endocrine pancreas. In contrast to wild-type mice, which lack peri-insular lymphatics, RipVEGF-C transgenics develop an extensive network of lymphatics around the islets of Langerhans. These mice were crossed with Rip1Tag2 mice, which develop pancreatic beta-cell tumours that are neither lymphangiogenic nor metastatic. Double-transgenic mice formed tumours surrounded by well developed lymphatics, which frequently contained tumour cell masses of beta-cell origin. These mice frequently developed pancreatic lymph node metastases. Our findings demonstrate that VEGF-C-induced lymphangiogenesis mediates tumour cell dissemination and the formation of lymph node metastases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Complementary
  • Endothelial Growth Factors / genetics
  • Endothelial Growth Factors / physiology*
  • Humans
  • Immunohistochemistry
  • Lymphatic System / growth & development*
  • Mice
  • Mice, Transgenic
  • Neoplasm Metastasis*
  • Pancreas / ultrastructure
  • Vascular Endothelial Growth Factor C

Substances

  • DNA, Complementary
  • Endothelial Growth Factors
  • Vascular Endothelial Growth Factor C