Elsevier

Biochemical Pharmacology

Volume 85, Issue 4, 15 February 2013, Pages 478-485
Biochemical Pharmacology

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

https://doi.org/10.1016/j.bcp.2012.11.005Get rights and content

Abstract

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

Section snippets

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.

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