Adhesion of tumor cells to host cell layers and subsequent transcellular
migration are pivotal steps in cancer invasion and metastasis1,
2,
3.
The small GTPase Rho controls cell adhesion and motility through reorganization
of the actin cytoskeleton and regulation of actomyosin contractility4. Cultured rat MM1 hepatoma cells migrate through a mesothelial cell
monolayer in vitro in a serum−dependent, Rho−mediated manner5. Among several proteins isolated as putative target molecules of
Rho, the ROCK (ROK) family of Rho−associated serine−threonine
protein kinases6,
7,
8 are thought to participate in the induction
of focal adhesions and stress fibers in cultured cells9, and
to mediate calcium sensitization of smooth muscle contraction by enhancing
phosphorylation of the regulatory light chain of myosin10. Transfection
of MM1 cells with cDNA encoding a dominant active mutant of ROCK conferred
invasive activity independently of serum and Rho. In contrast, expression
of a dominant negative, kinase−defective ROCK mutant substantially attenuated
the invasive phenotype. A specific ROCK inhibitor (Y−27632; ref. 11) blocked both Rho−mediated activation of
actomyosin and invasive activity of these cells. Furthermore, continuous delivery
of this inhibitor using osmotic pumps considerably reduced the dissemination
of MM1 cells implanted into the peritoneal cavity of syngeneic rats. These
results indicate that ROCK plays an essential part in tumor cell invasion,
and demonstrate its potential as a therapeutic target for the prevention of
cancer invasion and metastasis.
