INDEPENDENCE OF METASTATIC ABILITY AND EXTRAVASATION - METASTATIC RAS-TRANSFORMED AND CONTROL FIBROBLASTS EXTRAVASATE EQUALLY WELL

Escape of cancer cells from the circulation (extravasation) is thought to be a major rate-limiting step in metastasis, with few cells being able to extravasate, Furthermore, highly metastatic cells are believed to extravasate more readily than poorly metastatic cells. We assessed in vivo the extravasation ability of highly metastatic ras-transforme d NIH 3T3 cells (PAP2) versus control nontumorigenic nontransformed NI H 3T3 cells and primary mouse embryo fibroblasts. Fluorescently labele d cells were injected intravenously into chicken embryo chorioallantoi c membrane and analyzed by intravital videomicroscopy. The chorioallan toic membrane is an appropriate model for studying extravasation, sinc e, at the embryonic stage used, the microvasculature exhibits a contin uous basement membrane and adult permeability properties. The kinetics of extravasation were assessed by determining whether individual cell s (n = 1481) were intravascular, extravascular, or in the process of e xtravasation, at 3, 6, and 24 h after injection, Contrary to expectati ons, our results showed that all three cell types extravasated with th e same kinetics, By 24 h after injection >89% of observed cells had co mpleted extravasation from the capillary plexus, After extravasation, individual fibroblasts of all cell types demonstrated preferential mig ration within the mesenchymal layer toward arterioles, not to venules or lymphatics, Thus in this model and for these cells, extravasation i s independent of metastatic ability, This suggests that the ability to extravasate in vivo is not necessarily predictive of subsequent metas tasis formation, and that postextravasation events may be key determin ants in metastasis.