Glioma cell invasion: regulation of metalloproteinase activity by TGF-beta

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.