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Published on: January 9, 2019
Apoptosis in gliomas: molecular mechanisms and therapeutic implications
Joachim P Steinbach1, Michael Weller
1Hertie Institute for Clinical Brain Research, Department of General Neurology, School of Medicine, University of Tübingen, Tübingen, Germany.
Abstract:
Understanding apoptosis is often considered a key to understand the genesis of tumors and to devise innovative strategies for their treatment. Similar to other types of cancer, essential pathways regulating apoptosis are also disrupted in malignant gliomas, notably the cell cycle control mechanisms regulated by the p53 and retinoblastoma (RB) proteins and their homologs. Moreover, cultured glioma cells appear not to activate the extrinsic death receptor-dependent apoptotic pathway in response to irradiation or cytotoxic drugs. A preferential expression of antiapoptotic rather than proapoptotic BCL-2 family proteins and high level expression of inhibitor-of-apoptosis proteins (IAP) may be responsible for the failure of glioma cells to activate caspases in response to apoptotic stimuli. Although apoptosis does occur spontaneously in malignant gliomas in vivo, there is little evidence that the current modes of non-surgical treatment, radiotherapy and chemotherapy, mediate their effects via induction of apoptosis, with the possible exception of anaplastic oligodendrogliomas which often show striking tumor regression on neuroimaging. Yet, the induction of apoptosis plays a conceptual role in the majority of novel experimental approaches to malignant glioma which are currently evaluated in cell culture and preclinical rodent models.
Insights
Understanding apoptosis, programmed cell death, is crucial for cancer genesis and treatment. Malignant gliomas disrupt apoptosis pathways, hindering effective treatment strategies and suggesting new therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Cell Death Research
Background:
- Apoptosis is critical for understanding tumor development and designing cancer treatments.
- Malignant gliomas exhibit disrupted apoptosis pathways, particularly involving p53 and retinoblastoma (RB) proteins.
- Glioma cells often fail to initiate apoptosis in response to conventional therapies like irradiation and chemotherapy.
Purpose of the Study:
- To explore the role and regulation of apoptosis in malignant gliomas.
- To identify molecular mechanisms underlying resistance to apoptosis in glioma cells.
- To evaluate the potential of apoptosis induction as a therapeutic strategy for malignant gliomas.
Main Methods:
- Review of existing literature on apoptosis pathways in cancer, with a focus on malignant gliomas.
- Analysis of molecular mechanisms, including BCL-2 family proteins and inhibitor-of-apoptosis proteins (IAP), affecting glioma cell apoptosis.
- Examination of the efficacy of current treatments (radiotherapy, chemotherapy) in inducing apoptosis in gliomas.
Main Results:
- Malignant gliomas show dysregulation of key apoptosis regulators, including p53 and RB pathways.
- Cultured glioma cells exhibit resistance to extrinsic death receptor-mediated apoptosis.
- Elevated levels of antiapoptotic proteins (BCL-2 family) and IAPs contribute to apoptosis evasion in gliomas.
- While spontaneous apoptosis occurs in vivo, current non-surgical treatments show limited evidence of apoptosis induction, except possibly in anaplastic oligodendrogliomas.
Conclusions:
- Disruption of apoptosis pathways is a hallmark of malignant gliomas, contributing to therapeutic resistance.
- Targeting apoptosis, particularly by overcoming resistance mechanisms involving BCL-2 family and IAP proteins, is a promising strategy for novel glioma therapies.
- Further research into apoptosis induction is essential for developing effective treatments for malignant gliomas, with ongoing preclinical evaluations.
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