Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene

Cancer Cell. 2003 Apr;3(4):347-61. doi: 10.1016/s1535-6108(03)00085-0.


Hypoxia unleashes the invasive and metastatic potential of tumor cells by largely unknown mechanisms. The Met tyrosine kinase, a high affinity receptor for hepatocyte growth factor (HGF), plays a crucial role in controlling invasive growth and is often overexpressed in cancer. Here we show that: (1) hypoxia activates transcription of the met protooncogene, resulting in higher levels of Met; (2) hypoxic areas of tumors overexpress Met; (3) hypoxia amplifies HGF signaling; (4) hypoxia synergizes with HGF in inducing invasion; (5) the proinvasive effects of hypoxia are mimicked by Met overexpression; and (6) inhibition of Met expression prevents hypoxia-induced invasive growth. These data show that hypoxia promotes tumor invasion by sensitizing cells to HGF stimulation, providing a molecular basis to explain Met overexpression in cancer.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Blotting, Northern
  • Blotting, Western
  • Cell Movement / physiology
  • Cells, Cultured
  • Fluorescent Antibody Technique
  • Gene Transfer Techniques
  • Hepatocyte Growth Factor / physiology
  • Humans
  • Hypoxia / physiopathology*
  • Molecular Sequence Data
  • Neoplasm Invasiveness*
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-met / genetics*
  • Proto-Oncogene Proteins c-met / metabolism*
  • RNA, Messenger / analysis
  • Transcription, Genetic
  • Tumor Cells, Cultured


  • RNA, Messenger
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met