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Background: The high recurrence of glioblastoma (GB) that occurs adjacent to the resection cavity within two years of diagnosis urges an improvement of therapies oriented to GB local control. Photodynamic therapy (PDT) has been proposed to cleanse infiltrating tumor cells from parenchyma to ameliorate short long-term progression-free survival. We examined 5-aminolevulinic acid (5-ALA)-mediated PDT effects as therapeutical treatment and determined optimal conditions for PDT efficacy without causing phototoxic injury to the normal brain tissue. Methods: We used a platform of Glioma Initiation Cells (GICs) infiltrating cerebral organoids with two different glioblastoma cells, GIC7 and PG88. We measured GICs-5-ALA uptake and PDT/5-ALA activity in dose-response curves and the efficacy of the treatment by measuring proliferative activity and apoptosis. Results: 5-ALA (50 and 100 µg/mL) was applied, and the release of protoporphyrin IX (PpIX) fluorescence measures demonstrated that the emission of PpIX increases progressively until its stabilization at 24 h. Moreover, decreased proliferation and increased apoptosis corroborated the effect of 5-ALA/PDT on cancer cells without altering normal cells. Conclusions: We provide evidence about the effectiveness of PDT to treat high proliferative GB cells in a complex in vitro system, which combines normal and cancer cells and is a useful tool to standardize new strategic therapies. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme, the deadliest primary brain tumor, is characterized by an excessive and aberrant neovascularization. The initial expectations raised by anti-angiogenic drugs were soon tempered due to their limited efficacy in improving the overall survival. Intrinsic resistance and escape mechanisms against anti-VEGF therapies evidenced that tumor angiogenesis is an intricate multifaceted phenomenon and that vessels not only support the tumor but exert indispensable interactions for resistance and spreading. This holistic review covers the essentials of the vascular microenvironment of glioblastoma, including the perivascular niche components, the vascular generation patterns and the implicated signaling pathways, the endothelial–tumor interrelation, and the interconnection between vessel aberrancies and immune disarrangement. The revised concepts provide novel insights into the preclinical models and the potential explanations for the failure of conventional anti-angiogenic therapies, leading to an era of new and combined anti-angiogenic-based approaches. [ABSTRACT FROM AUTHOR]