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

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• 作者：Justin V. Joseph^a ; Veerakumar Balasubramaniyan^b ; Annemiek Walenkamp^a ; Frank A.E. Kruyt^a ; ^{f.a.e.kruyt@umcg.nl}
• 关键词：TGF-¦Â ; Glioma ; Cancer stem cells ; Microenvironment ; Therapy
• 刊名：Biochemical Pharmacology
• 出版年：2013
• 出版时间：15 February, 2013
• 年：2013
• 卷：85
• 期：4
• 页码：478-485
• 全文大小：636 K

文摘

Transforming growth factor-¦Â (TGF-¦Â) is a cytokine with a key role in tissue homeostasis and cancer. TGF-¦Â 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-¦Â and its possible promise as a therapeutic target in high grade gliomas, including glioblastoma multiforme (GBM), a disease with very poor prognosis. TGF-¦Â signaling is highly active in high grade gliomas and elevated TGF-¦Â 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-¦Â pathway. TGF-¦Â 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-¦Â signaling and the underlying mechanisms identified thus far, the promise of TGF-¦Â targeted therapy in malignant gliomas is discussed. Several drugs targeting TGF-¦Â 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-¦Â-targeted therapy is given.