Tumour metastasis to the liver, and the roles of proteinases and adhesion molecules: New concepts from in vivo videomicroscopy

Most preclinical studies of tumour metastasis and effects of molecular inte rventions have been based on end point assays, and little is known about th e fate of cells at sequential steps in the metastatic process. In vivo vide omicroscopy permits direct observations of sequential steps in hematogenous metastasis as they occur in living animals over time. These steps include initial arrest of cells in the microcirculation, extravasation, postextrava sation migration and growth in the target organ. In the mouse liver model, cells are arrested in periportal sinusoids based on size restriction, survi ve in the circulation and extravasate into the tissue by 48 to 72 h regardl ess of metastatic potential. Thereafter, cells may migrate to preferred sit es for growth. Critical steps responsible for cell losses and metastatic in efficiency occur at the level of postextravasation cell growth. Many extrav asated cells may remain dormant, and growth to form micrometastases is init iated in only a small subset of cells. Most early micrometastases may disap pear after a few days, and only a small subset continue growth into macrosc opic rumours. Angiogenesis is a prerequisite for continued growth of metast ases, as shown previously by others. Integrin-based interventions can modul ate postextravasation cell migration and cell growth. Matrix metalloprotein ase inhibitors can inhibit tumour angiogenesis and thus reduce growth. Key targets against which future therapeutic strategies should be directed incl ude the initiation and maintenance of growth of micrometastases, and the ac tivation of dormant solitary cells.