The metastatic spread of
cancer is a complex process that involves the combination of different cellular actions including cell adhesion to the extracellular matrix (ECM), breakdown of the ECM by specific matrix-degrading
proteinases, and active cell locomotion.
Contortrostatin (CN), a homodimeric
snake venom disintegrin, has previously been demonstrated to be effective in blocking
vitronectin/
fibronectin-dependent adhesion and invasion of T98G human
glioblastoma cells through
Matrigel using in vitro studies. However, it is not known at what step of the invasion process CN exerts its inhibitory effect. In the present report, CN is shown to decrease invasion of various
glioma cell lines through
Matrigel affecting neither cell adhesion, nor cell viability. While CN had no effect on cell binding to
laminin and
type IV collagen, it blocked adhesion of alphav beta3-positive, but not alphav beta3-negative cells, to
vitronectin and
fibronectin. Furthermore, members of the
matrix metalloproteinase (
MMP) family and their physiological inhibitors, and of the
plasminogen activator (PA)/
plasmin system were demonstrated not to be involved in CN-induced loss of
glioma cell invasiveness. Instead, CN inhibited active locomotion of cells on
Matrigel. These data suggest that CN-mediated inhibition of
glioma cell invasion through
Matrigel is a direct result of impaired cell motility. Moreover, use of several
glioma cell lines and
integrin antibodies strongly indicates the versatility of CN in inhibiting the invasion process based on the ability of CN to interact with different
integrins, including alphav beta3, alphav beta5, and alpha5beta1.