HGF/SF and MET
in Metastasis

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  • Hypoxia. MET and cancer invasion
  • WNT, chemokines and MET in cancer invasion
  • Structure of HGF/SF and MET
  • Engineering protein antagonists of MET
  • Small molecules MET antagonists
  • SHP-2 inhibitors
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  • MRC Centre, Cambridge
  • Institute for Cancer Research, Turin
  • Max-Delbrueck Institute, Berlin
  • University of Cambridge
  • Centre for Nuclear Magnetic Resonance, Florence
  • Leibniz Institute for Molecular Pharmacology, Berlin
  • Cambridge Molecular Therapeutics Programme
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Hypoxia, MET and tumour invasion

The discovery that tumour-associated hypoxia causes transcription of the MET gene and amplifies the invasive response of tumour cells to HGF/SF has provided the rationale for investigating the significance of hypoxia-induced MET activation in vivo. This is the scope of this work which involves four tasks:

1. Development of in vivo models of tumor hypoxia
   
   Hypoxia is a common feature of solid tumours but the degree of hypoxia varies between tumour types and between different individuals with the same tumour. In real tissues, hypoxia is defined as a concentration of oxygen which is lower than the physiological partial pressure of oxygen (pO₂). This varies greatly from tissue to tissue. In the alveoli, pO2 is about 12%. In other organs, the mean pO₂ is considered 5% but there are tissues where oxygen is normally much less concentrated. Cells do not really feel hypoxia until it gets lower than 7-8%. Cell proliferation usually does get affected only at a pO₂ lower than 1%. Survival is usually a problem in extreme hypoxia conditions.
   
   In our work with cells in culture that led to the discovery that hypoxia controls transcription of the MET gene, experimental hypoxia was achieved using an automated hypoxic workstation that can control temperature, humidity, CO₂ concentration and O₂ concentration.
   
   The new goal is to develop animal models that will enable analysis of different degrees of hypoxia on the metastatic ability of tumour cells. These include in vivo studies with cell lines which over-express wild-type or mutant forms of Hypoxia Inducible Factor-1a (HIF-1a) or in which the pVHL tumor suppressor protein has been inactivated. Alternatively, mice in which a chronic state of hypoxia is induced with anti-angiogenic therapies will be used for studying invasion/metastasis of established cancer cell lines.
   
   
2. Biological analysis of primary tumors subjected to hypoxia-inducing conditions
   
   Primary tumors obtained from the experimental mouse models will be scored for their hypoxic state using antibodies directed against HIF-1a (a sensitive marker of the hypoxic regions of a tumour) and studied for apoptosis, proliferation and MET expression.
   
   
3. Analysis of tumor invasiveness and metastatic spreading induced by hypoxia
   
   The invasive and metastatic behaviour of these tumours will be studied next by measuring the number of circulating tumor cells in blood using real-time PCR. Colonisation will be studied in suitable target organs, typically the lung, using histopathology as well as DNA based techniques.
   
   
4. Inhibition of hypoxia-induced invasion and metastasis using selective MET inhibitors
   
   Based on the earlier findings with tumour cells in culture it is expected that MET inhibition in vivo may block hypoxia-induced tumour invasion and metastasis. Thus several MET inhibitors developed in the laboratory will be used in order to inhibit MET expression in tumour cell lines introduced in vivo and an assessment will be made of the consequence of such treatments on tumour invasiveness and metastasise under hypoxic conditions.