Chapter 16 - Mechanisms of glioblastoma resistance to antiangiogenic agents and reversal approaches

Abstract

Glioblastoma (GBM) is the most prevalent malignant tumor in the central nervous system. Owing to its hypervascular state and inevitable recurrence following standard therapies of surgical resection, radiation, and chemotherapies, clinicians as well as scientists have instituted antiangiogenic agents to counter the development of blood vessels in the recurrent and rapidly growing GBM. However, investigations from our group and from other laboratories, as well as from clinical data, indicate the development of therapy resistance and activation of alternate neovascularization in GBM following antiangiogenic therapies (AATs). Alternate neovascularization occurs in three distinct pathways, such as angiogenesis, vasculogenesis, and vascular mimicry. Beside angiogenesis, different mechanisms are postulated for the development of alternative neovascularization and therapy resistance in GBM following AAT including bone marrow-derived cell-mediated vasculogenesis, transdifferentiation of glioma stem cells to form vascular mimicry, and vasculogenic as well as angiogenic myeloid cell-mediated neovascularization. Specific agents that target bone marrow-derived cells, myeloid cells, and transdifferentiation of glioma stem cells could be added to current therapeutic strategies in GBM management to overcome the resistance.