Glioblastomas (GBM) are the most aggressive and lethal primary brain tumors. There are many obstacles when it comes to treating GBM, including their rapid proliferation, extensive invasion, and resistance to conventional therapies. Furthermore, factors such as cellular heterogeneity, immune evasion, and hypoxia continue to contribute to tumor progression and resistance to treatment. These are major limiting factors of surgical resection, radiotherapy, and chemotherapy, despite the advances made in those respective fields in the last few decades. Our lack of understanding of the underlying mechanisms associated with the GBM tumor microenvironment hinders the development of more effective targeted therapies. Many progressions have been made in recent years regarding the understanding of the underlying mechanisms of GBM. Hormones such as progesterone (P4), thought commonly to be a sex hormone, as well as the protein Brain-Derived Neurotrophic Factor (BDNF), associated with neurogenesis, learning and memory, synaptic plasticity, and various other processes, have been found to play a role in GBM tumor progression.
Dr. Singh and his colleagues address the neuroprotective effects of P4 and BDNF's role as a neuroprotectant in the article titled “Brain-derived neurotrophic factor and related mechanisms that mediate and influence P4-induced neuroprotection.” This must raise the question of its role in various neurological diseases. The article addresses the neuroprotective effects of P4 in different neurological conditions such as traumatic brain injury (TBI), stroke, Alzheimer’s disease (AD), and Parkinson’s disease (PD). Regarding ischemic stroke, P4 has been shown to reduce infarct size and improve functional outcomes in animal models. Additionally, it enhances neuronal survival and promotes recovery when it is administered pre and post-stroke. In TBI experimental models, P4 was found to reduce inflammation, cerebral edema, and oxidative stress while improving cognitive function. Dr. Singh and his team outline the mechanisms of Neuroprotection associated with P4 and BDNF. P4 upregulates BDNF expression by activating TrkB receptors, leading to downstream pro-survival pathways like ERK/MAPK and PI3K/Akt. Another key factor in these mechanisms is allopregnanolone (3α-THP), which is a metabolite or P4 that reduces excitotoxicity, improves cognitive function, and promotes neurogenesis in neurodegenerative disease models. These neuroprotective effects of P4 regarding neurodegenerative diseases raise the question of what its role may be, or if it even has a role, in the case of GBM. Does P4 have any underlying neuroprotective mechanisms in the case of an aggressive cancer such as GBM?
Unfortunately, according to recent data and a study conducted by Claudia Bello-Alvarez, Carmen J. Zamora-Sánchez, and their team. In their article, they explain that P4 and 3α-THP promote GBM cell invasion by activating CSrc kinase and upregulating matrix metalloproteinase-9 (MMP-9). P4 activates cSrc and focal adhesion kinase (Fak) proteins involved in focal adhesion complexes and cancer cell motility in the cSrc and Fak pathway, which results in an increase in GBM cell invasion. They used PP2, a kinase inhibitor responsible for the inhibition cSrc, and found that this significantly reduced P4 and 3α-THP-induced migration and invasion. MMP-9 is an enzyme associated with extracellular matrix degradation and tumor invasiveness. Its primary role in the case of GBM is the facilitation of tumor cell invasion and metastasis. It does this by degrading the extracellular matrix, which allows cancer cells to spread more easily within the brain. Therefore, higher levels of MMP-9 correlate with increased motility and invasiveness of GBM. P4 and 3α-THP increase the protein expression of MMP-9, which further displays P4 and 3α-THP’s role in the promotion of GBM cellular invasion. However, Claudia Bello-Alvarez, Carmen J. Zamora-Sánchez, and their team discovered that the increase in MMP-9 expression can be blocked when cSrc or the intercellular progesterone receptor is silenced.
P4 and 3α-THP play a vital role in the neuroprotective mechanisms in the brain associated with neurodegeneration, but we see them play a tumor-biased role in the case of GBM. Both these articles are pieces of the puzzle that contribute to the overall mechanism of GBM and the various factors that affect it. As we make these strides to fully understanding the problem of GBM we tread closer and closer to finding a solution and providing hope in the lives of patients around the world.
References: Bello-Alvarez, Claudia, et al. “Progesterone and Its Metabolite Allopregnanolone Promote Invasion of Human Glioblastoma Cells through Metalloproteinase‑9 and CSRC Kinase.” Oncology Letters, U.S. National Library of Medicine, 13 Apr. 2023, pmc.ncbi.nlm.nih.gov/articles/PMC10157356/. Singh, Meharvan, et al. “Brain-derived Neuerotrophic Factor and Related Mechanisms That Mediate and Influence Progesterone-induced Neuroprotection.” Frontiers in Endocrinology, vol. 15, Feb. 2024, https://doi.org/10.3389/fendo.2024.1286066.
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