The role of biological macromolecules in the regulation of angiogenesis in glioblastoma: Focus on vascular growth factors, integrins, and extracellular matrix proteins.

Glioblastoma, classified as a grade 4 brain tumor, accounts for approximately half of all malignant central nervous system cancers. Despite extensive research and aggressive treatment modalities, much about this disease remains elusive. The proliferation of blood vessels within glioblastoma tumors significantly contributes to their invasive nature, primarily due to the influence of vascular endothelial growth factor-A (VEGF-A). As a result, the past decade has seen a concentrated effort to explore angiogenesis, especially the VEGF signaling pathway, as a therapeutic target for glioblastoma. This investigation led to the FDA approval of bevacizumab, a monoclonal antibody against VEGF-A, for the treatment of recurrent glioblastoma. However, despite promising clinical trials and theoretical research, bevacizumab has not significantly improved patient survival rates. Furthermore, other anti-angiogenic agents targeting the VEGF signaling pathway have shown limited efficacy. This suggests the existence of multiple alternative angiogenic pathways that facilitate vascularization, even when VEGF signaling is inhibited. In this study, we aim to assess the current landscape of anti-angiogenic agents, explore potential resistance mechanisms to such therapies, and suggest strategies to improve the effectiveness of these therapeutic interventions. Our goal is to provide a comprehensive understanding of the limitations of current treatments and to identify new avenues for enhancing therapeutic outcomes in glioblastoma patients.