TGF-β as a therapeutic target in high grade gliomas - Promises and challenges

Transforming growth factor-beta (TGF-beta) is a cytokine with a key role in tissue homeostasis and cancer. TGF-beta elicits both tumor suppressive and tumor promoting functions during cancer progression, in a wide range of cancers. Here, we review the tumor promoting function of TGF-beta and its possible promise as a therapeutic target in high grade gliomas, including glioblastoma multiforme (GBM), a disease with very poor prognosis. TGF-beta signaling is highly active in high grade gliomas and elevated TGF-beta activity has been associated with poor clinical outcome in this deadly disease. Common features of GBMs include fast cell proliferation, invasion into normal brain parenchyma, hypoxia, high angiogenic - and immunosuppressive activity, characteristics that all have been linked to activation of the TGF-beta pathway. TGF-beta signaling has also been connected with the cancer stem cell (CSC) phenotype in GBM. CSCs represent a subset of GBM cells thought to be responsible for tumor initiation, progression and relapse of disease. Following the description of these different properties of TGF-beta signaling and the underlying mechanisms identified thus far, the promise of TGF-beta targeted therapy in malignant gliomas is discussed. Several drugs targeting TGF-beta signaling have been developed that showed potent antitumor activity in preclinical models. A number of agents are currently evaluated in early clinical studies in glioma patients. Available results of these studies are highlighted and a perspective on the promise of TGF-beta-targeted therapy is given. (C) 2012 Elsevier Inc. All rights reserved.