Micronodular transformation as a novel mechanism of VEGF-A-induced metastasis

Oncogene. 2007 Aug 23;26(39):5808-15. doi: 10.1038/sj.onc.1210360. Epub 2007 Mar 12.

Abstract

How and why tumors metastasize is still a matter of debate. The assumption is that mutations render tumor cells with a metastatic phenotype, enabling entrance in and transport through lymph or blood vessels. Distant outgrowth is thought to occur only in a suitable microenvironment (the seed and soil hypothesis). However, the anatomical location of most metastases in cancer patients suggests entrapment of tumor cells in the first microcapillary bed that is encountered. We here investigated how vascular endothelial growth factor-A (VEGF-A) attributes to the metastatic process. We describe here that VEGF-A enhances spontaneous metastasis by inducing intravasation of heterogeneous tumor cell clusters, surrounded by vessel wall elements, via an invasion-independent mechanism. These tumor clusters generate metastatic tissue embolisms in pulmonary arteries. Treatment of tumor-bearing mice with the antiangiogenic compound ZD6474 prevented the development of this metastatic phenotype. This work shows that tumors with high constitutive VEGF-A expression metastasize via the formation of tumor emboli and provides an alternative rationale for anti-VEGF-A therapy, namely to inhibit metastasis formation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology
  • Animals
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / prevention & control
  • Brain Neoplasms / secondary*
  • Gene Expression Regulation, Neoplastic
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary*
  • Lymphatic Metastasis / pathology
  • Male
  • Melanoma / metabolism
  • Melanoma / prevention & control
  • Melanoma / secondary*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplastic Cells, Circulating / metabolism*
  • Neoplastic Cells, Circulating / pathology
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Piperidines / pharmacology
  • Pulmonary Embolism / pathology*
  • Quinazolines / pharmacology
  • Skin Neoplasms / metabolism
  • Skin Neoplasms / pathology*
  • Skin Neoplasms / prevention & control
  • Transfection
  • Tumor Cells, Cultured
  • Vascular Endothelial Growth Factor A / physiology*

Substances

  • Angiogenesis Inhibitors
  • Piperidines
  • Quinazolines
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine