CommentaryTGF-β as a therapeutic target in high grade gliomas – Promises and challenges☆
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TGF-β signaling in cancer
Transforming growth factor-β (TGF-β) represents a member of a large family of cytokines that include the bone morphogenic protein (BMPs), nodals and activins, which are involved in the regulation of embryonic development and tissue homeostasis [1]. There are three isoforms of TGF-β in mammals, namely TGF-β1, -β2 and -β3, which are all synthesized as latent dimers. Latent TGF-βs need to be converted into their active forms by processing of precursors by proteases [2]. At the cellular level TGF-β
Malignant gliomas
Malignant gliomas account for 80% of malignant tumors that develop in the central nervous system and are essentially incurable, constituting a spectrum of clinicopathological entities, from low-to high-grade malignancies, and almost all low-grade tumors eventually progress to high-grade malignancy [15]. These tumors progress through a series of developmental steps, which include the transformation from a cell of origin, activation of cellular proliferation signals and abrogation of cell cycle
TGF-β and glioblastoma
GBM is characterized by extensive heterogeneity at the cellular and molecular levels. There is compelling evidence suggesting that the different tumor cell populations can establish a complex network of interactions between each other and with the tumor microenvironment that promote tumor growth and providing an increased chance to escape therapy [20]. The traditional idea that tumors are composed of a mass of malignant cells is drastically changing. It is now increasingly appreciated that
TGF-β affects chemo- and radio-resistance
In glioma cells treated with a large dose of radiation the secretion of TGF-β remained intact and, moreover, the level of TGF-β secretion per glioma cell was found to increase [69]. Therefore, methods to inhibit TGF-β or downregulate its expression are thought to be of additional benefit in improving the efficacy of radiation therapy. Two recent studies provided evidence for this notion [70], [71]. The first study by Zhang et al. provide evidence that TGF-β signaling blockade by the small
TGF-β-targeted therapy in high grade gliomas
From the preclinical data presented above it is clear that TGF-β-targeted therapy may be of great value for the treatment of gliomas. A list of therapeutics targeting the TGF-β pathway that have been tested, or are currently being studied in glioma patients is summarized in Table 1.
AP12009, an antisense oligonucleotide targeting TGF-β2 mRNA, was examined in three phase 1/2 open-label dose-escalation studies in recurrent or refractory WHO grade III and IV glioma patients (n = 24) [75]. AP12009,
Summary and perspectives
High grade gliomas are characterized by a high degree of therapy resistance followed by inevitable local and/or disseminated recurrence. Over the past two decades researchers have witnessed many new approaches to study and understand the molecular basis of malignant gliomas. Amongst them, the observation that TGF-β acts on multiple levels to promote the malignant phenotype of gliomas including angiogenesis, invasiveness, stemness and immunosuppression, has prompted the development of approaches
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Supported by Grant RUG2011-5150 from the Dutch Cancer Society. The authors declare that they have no competing interests. We would like to thank Tushar Tomar for help with the figures.