Matrix metalloproteinases (MMPs) are a family of extracellular endopeptidas
es that selectively degrade components of the extracellular matrix. MMPs ar
e implicated in tumor cell invasion because they mediate the breakdown of t
he basal membrane. In addition, they seem to be important for the creation
and maintenance of a microenvironment that facilitates tumor cell survival.
Among the essential characteristics of human malignant gliomas are infiltr
ative growth, angiogenesis and suppression of antitumor immune surveillance
. Transforming growth factor-beta (TGF-beta) is intimately involved in the
regulation of these processes. We have previously demonstrated that TGF-bet
a promotes the migration of LN-18 and LN-229 glioma cells via a process tha
t may involve the upregulation of alpha (V)beta (3) integrin expression. Fu
rthermore, we have defined a novel pathway for hepatocyte growth factor (HG
F)-induced glioma cell migration and invasion which requires the induction
of TGF-beta (2) expression. Here, we demonstrate that TGF-beta (2) induces
MMP-2 expression and suppresses tissue inhibitor of metalloproteinases (TIM
P)-2 expression and that concentration-dependently promotes the invasion of
U87MG and LN-229 glioma cells in a matrigel invasion assay. Similarly, ect
opic expression of the anti-apoptotic BCL-x(L) protein leads to enhanced ma
trigel invasion by LN-18 and LN-229 glioma cells. We outline the possible i
nterrelations of TGF-beta, proteins of the BCL-2 family, integrins and meta
lloprotease activity. By virtue of its promotion of glioma invasion and its
growth regulatory and immunomodulatory properties, TGF-beta continues to b
e one of the most promising targets for the experimental therapy of human m
alignant glioma.