Vascular Mimicry: The Next Big Glioblastoma Target

Glioblastoma (GBM), a grade IV glioma classified by World Health Organization (WHO), is considered highly malignant, vascular and invasive subtype [1]. GBM is most lethal during first year after initial diagnosis despite surgical resection, radiotherapy and/or chemotherapy [1,2]. Median survival of patients diagnosed with GBM is only 12 to 15 months [1,2]. Anti-angiogenic therapies (AAT) were used as an adjuvant mainly against vascular endothelial growth factor and its receptors (VEGF-VEGFRs) to normalize tumor vasculatures in GBM patients. However, all of them provided minimal to none effect with no change in overall survival [3]. Hypoxia and neovascularization are histopathologic features of GBM [4]. Hypoxia activated proangiogenic, invasion and metastasis associated gene signatures, enabling tumor to become more angiogenic, invasive and malignant in a compromised microenvironment [5,6]. GBM tumor vessels are tortuous, disorganized, highly permeable, and have abnormal endothelial cells (ECs), pericyte coverage, and basement membrane structure [7,8]. Conventionally, tumor vessel formation occurs through angiogenesis, which is mediated by proliferation and migration of resident ECs [9]. Instead, vasculogenesis originates from circulating bone marrow derived cells (BMDCs) or endothelial progenitor cells (EPCs), which express VEGFR2, are recruited by VEGF followed by differentiation and incorporation into new tumor blood vessels [10].