Key points are not available for this paper at this time.
Glioblastoma (GB) remains one of the most aggressive and lethal human tumors, displaying a pronounced predominance among men that suggests a potential involvement of sex hormones, particularly testosterone (TST), in its pathogenesis. The present review summarizes and integrates current evidence regarding the dual role of testosterone in GB biology. On the one hand, testosterone promotes oncogenic progression by stimulating the proliferation, survival, and invasion of cancer stem cells (CSCs) through the activation of androgen receptors (ARs) and subsequent conversion to estradiol, which triggers proliferative signaling cascades. On the other hand, testosterone exhibits potent neuroprotective properties and contributes to the maintenance of central nervous system homeostasis by modulating neurogenesis, attenuating neuroinflammatory responses and enhancing the reparative potential of normal neural and mesenchymal stem cells (MSCs). This dualism creates a complex therapeutic dilemma. The review discusses the potential of antiandrogen therapy and aromatase inhibitors as targeted approaches with their effect largely depending on the molecular context of the tumor. As an innovative strategy for mitigation of the neurotoxicity associated with standard treatment, a novel biomedical approach is proposed, based on the use of a functionally enhanced secretome of ex vivo hypoxia-preconditioned mesenchymal stem cells (MSC), treated with testosterone. This approach aims to achieve localized delivery of neurotrophic and anti-inflammatory factors to protect brain tissue and expand the therapeutic window for aggressive cytostatic therapy. Collectively, these insights underscore the need for integration of personalized antiandrogen therapy with adjunctive neuroprotective strategies to develop more effective, comprehensive treatment paradigms for GB patients. • Testosterone dually promotes glioblastoma stem proliferation via AR/estradiol while neuroprotecting CNS elements. • Net effect context-dependent: steroidogenesis, aromatase, hypoxia/cytokines dictate glioblastoma stem cell niches. • Antiandrogens show promise but face BBB, AR variants, plasticity, and toxicity barriers in glioblastoma. • Biomarker-guided AR/CXCR4 inhibition with chemo or immunotherapy may improve antitumor efficacy.
Bryukhovetskiy et al. (Wed,) studied this question.