Dissecting the process of metastasis
Metastasis, the migration of tumour cells to distant sites, is a fatal complication of cancer development. This accounts for more than 90 % of cancer-related deaths worldwide. The EU-funded ‘HGF/SF and MET in metastasis’ (SFMET) project addressed the role of the hepatocyte growth factor/scatter factor (HGF/SF) and its receptor MET in cancer metastasis. In normal cells, this HGF-MET interaction defines a paracrine signalling system which controls the migration of several cell lineages during embryogenesis and tissue repair. Evidence shows that in a large number of human tumours, this signalling is hijacked in order to invade adjacent tissue and initiate metastasis. Among the SFMET project objectives was to delineate the mechanism by which HGF/SF and MET cause tumour invasion. More specifically, scientists discovered that local low oxygen tension (hypoxia) encountered in tumours is responsible for MET activation. Additionally, the MET seemed to cooperate with other signalling pathways implicated in cancer homeostasis, possibly exacerbating tumour growth. The characterisation of the HGF/SF-MET complex crystal structure showed that MET was activated by the physiological ligand HGF/SF expressed by the cancer microenvironment. This paved the way for the development of anti-MET antibodies and other antagonistic compounds as a means for blocking MET signalling in cancer cells. Based on these findings, the SFMET study lay out the foundations for developing drug inhibitors, namely compounds that might bind key downstream effectors of HGF/SF-MET signalling. Most importantly, it demonstrated the potential of inhibiting MET with specific pharmacological agents as a valid therapeutic approach for interfering with tumour invasion and metastasis.
