Cancer cells rely on intercellular communication throughout the different stages of their transformation and progression into
metastasis. They do so by co-opting different processes such as cell-cell junctions,
growth factors, receptors, and vesicular release. Initially characterized in neuronal and vascular tissues, Ephs and
Ephrins, the largest family of
receptor tyrosine kinases, comprised of two classes (i.e., A and B types), is increasingly scrutinized by
cancer researchers. These
proteins possess the particular features of both the receptors and
ligands being membrane-bound which, via mandatory direct cell-cell interactions, undergo a bidirectional signal transduction initiated from both the receptor and the
ligand. Following cell-cell interactions, Ephs/
Ephrins behave as guidance molecules which trigger both repulsive and attractive signals, so as to direct the movement of cells through their immediate microenvironment. They also direct processes which include sorting and positioning and cytoskeleton rearrangements, thus making them perfect candidates for the control of the metastatic process. In fact, the role of Ephs and
Ephrins in
cancer progression has been demonstrated for many of the family members and they, surprisingly, have both
tumor promoter and suppressor functions in different cellular contexts. They are also able to coordinate between multiple processes including cell survival, proliferation, differentiation, adhesion, motility, and invasion. This review is an attempt to summarize the data available on these Ephs/
Ephrins'
biological functions which contribute to the onset of aggressive
cancers. I will also provide an overview of the factors which could explain the functional differences demonstrated by Ephs and
Ephrins at different stages of
tumor progression and whose elucidation is warranted for any future therapeutic targeting of this signaling pathway in
cancer metastasis.