lioblastoma (GBM) is considered as hypervascular, hypoxic
and most malignant form of glioma. GBM is most lethal during first year after
initial diagnosis despite surgical resection, radiotherapy and/ or chemotherapy.
Anti-Angiogenic Therapies (AAT) are being used as an adjuvant mainly against
Vascular Endothelial Growth Factor and its receptors (VEGF-VEGFRs) in
endothelial cells to normalize tumor vasculatures. Due to lower genetic
instability in endothelial cells compared to in tumor cells, it was anticipated
that targeting VEGFVEGFR pathways, primarily in endothelial cells, would
decrease tumor vasculature without imposing drug resistance. However,
treatments provided minimal to none effect with no change in overall patients
survival.
Similar data was obtained from preclinical studies. For
example, VEGFR2 blockade in GBM through vatalanib, a receptor tyrosine kinase
inhibitor, increased tumor size through hypoxia mediated overexpression of
VEGF, SDF-1α, HIF-1α, VEGFR2, VEGFR3 and EGFR at peripheral part of tumors
compared to central part. Activation of alternative pathways of angiogenesis,
vasculogenesis and involvement of stem cells were observed following AAT in GBM,
which was associated with overexpression of bFGF, angiopoietin1/2, GCSF, and
SDF1α.
Conventionally, tumor vessel formation occurs through angiogenesis,
which is mediated by proliferation and migration of resident ECs.However, at a cellular level, up-regulation of HIF- 1α and
SDF-1α by tumor cells resulted into recruitment of CXCR4+ Bone Marrow Derived
Cells (BMDCs) to the tumor. BMDCs play a pivotal role in tumor development.
Endothelial Progenitor Cells (EPCs) from BM pool are recruited in Tumor
Microenvironment and contributed to vasculogenesis.
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