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Targeting Semaphorin-plexin Signaling in Glioblastoma: Implications for Tumor Invasion, Angiogenesis, and Treatment
Shatrudhan Prajapati1, Ajay Pal Singh1, Vashnavi Tripathi1
1School of Pharmacy, Lingaya's Vidyapeeth, Faridabad, Haryana, 121002, India.
Introduction:
Glioblastoma (GBM) is the most aggressive and malignant primary brain tumor in adults, characterized by rapid growth, diffuse invasion, marked intratumoral heterogeneity, and resistance to conventional therapies. Semaphorin-Plexin signaling, originally identified as a key regulator of axonal guidance during nervous system development, has subsequently emerged as a critical pathway involved in multiple aspects of cancer biology, including tumor proliferation, invasion, angiogenesis, immune modulation, and therapeutic resistance.
Methods:
This review provides a comprehensive overview of recent findings on the role of semaphorin- plexin interactions in Glioblastoma (GBM), integrating evidence from in vitro and in vivo studies together with clinical data to highlight their biological and therapeutic significance.
Results:
Semaphorin-plexin signaling regulates several biological processes involved in Glioblastoma (GBM) progression, including cytoskeletal remodeling, angiogenesis, and immune modulation. Distinct semaphorin receptor axes, such as Sema3A/NRP1, Sema3F/NRP2, and Sema4D/Plexin-B1, exhibit context-dependent functions and may act as either tumor suppressors or tumor promoters depending on the molecular and cellular environment. Furthermore, crosstalk between semaphorin signaling and the Vascular Endothelial Growth Factor (VEGF) pathway through neuropilins, together with the regulation of Rho family GTPases, represents a key mechanism underlying GBM angiogenesis, cell migration, and invasion.
Discussion:
Despite its therapeutic potential, the context-dependent and bidirectional nature of semaphorin-plexin signaling poses significant challenges for clinical targeting. Resistance to therapy may arise from pathway redundancy, intratumoral heterogeneity, and dynamic interactions within the tumor microenvironment, particularly following anti-angiogenic treatment.
Conclusion:
Semaphorin-plexin signaling represents a promising yet complex therapeutic target in Glioblastoma (GBM). Future therapeutic strategies should focus on the selective modulation of this signaling pathway and its integration with combination therapies to enhance treatment efficacy and overcome therapeutic resistance.
Insights
Semaphorin-Plexin signaling influences Glioblastoma (GBM) growth and invasion. Targeting this pathway offers therapeutic potential but faces challenges due to its complex, context-dependent nature in GBM.
Area of Science:
- Neuroscience
- Cancer Biology
- Molecular Signaling
Background:
- Glioblastoma (GBM) is a highly aggressive brain tumor known for rapid growth, invasion, and treatment resistance.
- Semaphorin-Plexin signaling, crucial for nervous system development, is implicated in various cancer processes, including GBM proliferation, invasion, angiogenesis, immune evasion, and therapeutic resistance.
Purpose of the Study:
- To provide a comprehensive review of Semaphorin-Plexin signaling in Glioblastoma (GBM).
- To integrate in vitro, in vivo, and clinical data to elucidate the biological and therapeutic significance of these interactions in GBM.
Main Methods:
- Literature review of recent findings on Semaphorin-Plexin interactions in GBM.
- Integration of evidence from in vitro, in vivo, and clinical studies.
- Analysis of biological mechanisms and therapeutic implications.
Main Results:
- Semaphorin-Plexin signaling regulates GBM progression via cytoskeletal remodeling, angiogenesis, and immune modulation.
- Specific axes like Sema3A/NRP1, Sema3F/NRP2, and Sema4D/Plexin-B1 have context-dependent roles as tumor suppressors or promoters.
- Crosstalk with VEGF and Rho GTPases is key to GBM angiogenesis, migration, and invasion.
Conclusions:
- The context-dependent nature of Semaphorin-Plexin signaling presents challenges for clinical targeting in GBM.
- Therapeutic resistance can stem from pathway redundancy, tumor heterogeneity, and microenvironment interactions, especially after anti-angiogenic therapy.
- Future strategies require selective pathway modulation and combination therapies to improve GBM treatment efficacy.
