Malignant glioma biology: Role for TGF-? in growth, motility, angiogenesis, and immune escape

Abstract

Characteristics of human malignant glioma are excessive proliferation, infiltrative growth, angiogenesis and suppression of anti‐tumor immune surveillance. Transforming growth factor‐beta (TGF‐β), a versatile cytokine, is intimately involved in the regulation of these processes. Here, we discuss the interactions of TGF‐β with growth factors, such as basic fibroblast growth factor (bFGF), epidermal growth factor (EGF) and platelet derived growth factor (PDGF), metalloproteinases (MMP‐2, MMP‐9) and their inhibitor, plasmin activator inhibitor‐1 (PAI‐1), and immune cells, like natural killer cells, T‐cells and microglia. The differential effects of TGF‐β in glioma biology are outlined with emphasis on the induction of a survival advantage for glioma cells by enforced cell growth, migration, invasion, angiogenesis and immune paralysis. By virtue of its growth regulatory and immunomodulatory properties, TGF‐β promises to become a novel target for the experimental therapy of human malignant glioma. Microsc. Res. Tech. 52:401–410, 2001. © 2001 Wiley‐Liss, Inc.

The role of versican isoforms V0/V1 in glioma migration mediated by transforming growth factor-β2

“…TGF-b2 is known to induce a malignant phenotype in glioma cell lines using exogenous TGF-b2 (Platten et al, 2001). Brockmann et al (2003) detected motogenic effects of TGF-b2 in glioblastoma cell lines and our results demonstrate that exogenous TGF-b2 induces migration of glioma cells significantly via two different migration assays.…”

“…TGF-b2-derived immunosuppression of glioma patients is well described (Jachimczak et al, 1993;Grauer et al, 2006) and plays a pivotal role in glioma progression. In addition, there is increasing evidence for a prominent role of TGF-b2 in glioma cell motility (Platten et al, 2001;Uhl et al, 2004). TGF-b-triggered glioma cell motility is based on a very complex system consisting of a step-like process of attachment and migration, which involves components of ECM, proteases and integrins as well as the tumour cells (Platten et al, 2001).…”

“…In addition, there is increasing evidence for a prominent role of TGF-b2 in glioma cell motility (Platten et al, 2001;Uhl et al, 2004). TGF-b-triggered glioma cell motility is based on a very complex system consisting of a step-like process of attachment and migration, which involves components of ECM, proteases and integrins as well as the tumour cells (Platten et al, 2001). Understanding the functions and regulatory processes of glioma cell migration is critical for developing appropriate antiinvasive therapies.…”

The possible role of matrix metalloproteinase (MMP)-2 and MMP-9 in cancer, e.g. acute leukemia

“…However, not only mast cells are capable of excreting MMPs and other pro-angiogenic factors, also tumor associated macrophages (TAMs), neutrophils and activated T lymphocytes can contribute to angiogenesis by releasing MMPs and angiogenic factors [127][128][129][130]. In a number of cancers, inflammatory cell infiltration correlated with the degree of tumor angiogenesis [131][132][133][134]. The role of inflammatory cell derived MMPs is largely the same compared to tumor cell derived MMPs.…”

Tumor-Induced Apoptosis of Human IL-2-Activated NK Cells: Role of Natural Cytotoxicity Receptors

“…Indeed, CTL-mediated control can be broken out as tumor cells down-regulate HLA class I expression affecting the recognition of tumor Ag peptides (2)(3)(4)(5). This can be also accomplished by the lack, at the tumor cell surface, of costimulatory molecules and/or by the production of immunosuppressive cytokines such as TGF-␤, or by the induction of suppressor T cells (9,10). Also, tumors can release soluble molecules, which are ligands of surface receptors involved in the triggering of cytolytic activity, and this can lead to the down-regulation of effector cell activation (11).…”