Study of Vasculogenic Mimicry in Glioma

Glioma is the most common adult primary malignant tumor of the central nervous system. Despite aggressive surgical resection followed by adjuvant therapies such as radiotherapy and chemotherapy, the prognosis remains poor, with the five-year survival rate for highly malignant glioblastoma being less than 10%. Novel therapeutic approaches, such as anti-angiogenic therapies, have been gradually explored as part of glioma treatment strategies. However, clinical studies have shown that anti-angiogenic therapies primarily extend PFS (progressionfree survival) in glioma patients without significantly improving OS (overall survival). While anti-angiogenic treatments have shown promising clinical results in other solid tumors, their efficacy in gliomas remains limited. To address this clinical challenge, they have initiated a series of investigations since 2004. First, they identified a phenomenon of VM (vasculogenic mimicry) in gliomas, where in tumor cells-derived vascular-like channels. The presence of VM could be found throughout the various stages of tumorigenesis and provides essential nutrients for tumor growth apart from the endothelial-independent vascular structure. They further analyzed the glioma microcirculation and identified four distinct microvascular structures: (1) endothelial cell-dependent vessels; (2) tumor cell-dependent channels (VM); (3) ECM (extracellular matrix)-dependent channels; and (4) mosaic vessels (a combination of endothelial cells and tumor cells). Further studies revealed that glioma stem cells can form VM and differentiate into endothelial cells by the stimulation of VEGF, suggesting that VM can evolve into classical tumor vasculature. Additionally, they found that the extracellular matrix protein Tenascin-C promotes the formation of VM in gliomas. Tenascin-C facilitates this process by binding to the membranes EGFR via EGF-like domains, thereby activating the downstream Akt/Raf/MMP2/MMP9 signaling axis to promote VM formation. Their research theoretically refines and expands upon classical tumor angiogenesis models, and clinically, it explains for the limited efficacy of current anti-angiogenic therapies in gliomas. These findings offer a theoretical foundation for future strategies targeting glioma stem cells to inhibit VM, potentially improving anti-angiogenic treatment outcomes in

glioma therapy.

CSTR: 32200.14.cjcb.2025.03.0024