The metastatic odyssey: The integrin connection

Hopefully, this article has affirmed the potential contribution of one class of surface receptors to the progression of human carcinoma. Although more issues have been raised than have been resolved, a blueprint for future studies on the molecular cell biology of progression is emerging. First and foremost, progression appears to be a web of many strands. Surface receptors, the ECM, signaling molecules and the cytoskeleton are some of the major strands that form the web of progression. Studies on one strand inevitably lead to other strands as work on the α6 integrins has demonstrated. Another theme that is emerging is that the key functional components of progression such as invasion and survival may result from stimulation of a common signaling pathway. In this direction, the argument can be made that the PI3-K pathway is a major determinant of progression because the effectors of PI3-K signaling regulate invasion and survival (see Fig. 3). One direction for future work is to define further the contribution of effector molecules to specific aspects of progression. There is much to be learned, for example, from studies on the small G proteins and specific PKC isoforms with respect to cytoskeletal dynamics, migration, and invasion. Also, studies investigating how Akt/PKB isoforms are regulated, positively by integrin and growth factor receptor signaling and negatively by tumor suppressors, will clarify understanding of the mechanisms by which tumor cells survive in hostile environments that normally promote apoptosis. From the clinical perspective, the mechanistic understanding of progression that is emerging provides an array of targets for rational drug design.