Angiomotin expression promotes hemangioendothelioma invasion

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Abstract
Angiomotin was identified by its ability to bind angiostatin and has been shown to mediate its activity in vitro. The family of angiomotin-like protein consists of three members that have coiled-coil domains and conserved c-terminal PDZ-binding motifs. We show here that expression of angiomotin in mouse aortic endothelial (MAE) cells results in stabilization of tubes in the Matrigel assay. Control tubes start to regress after 72 h, whereas MAE-angiomotin (MAE Amot) tubes were stable for over 30 days. In contrast, cells expressing a functional mutant lacking the PDZ protein interaction motif did not migrate and form tubes. Cells from the established tubes invaded into the solidified matrigel. We therefore tested whether angiomotin promotes endothelial invasion. In microcarrier-based invasion in vitro assay, angiomotin-expressing cells invaded collagen matrix and formed tube-like branches. This was confirmed in vivo as injection of MAE-Amot cells promoted tumor growth and invasion into surrounding muscle tissue. Injection of cells transfected with the functional mutant resulted in establishment of noninvasive tumors surrounded by a capsule of fibrous tissue. These tumors remained in constant size or dormant over 3 weeks. Zymogel analysis of the transfected cells did not reveal any differences in proteolytic activity. However, time-lapse photography showed a significant increase in random motility in MAE-Amot cells. We conclude that angiomotin may promote angiogenesis by both stimulating invasion as well as stabilizing established tubes.