This may be partially attributed to BEV decreasing vessel permeability, affecting contrast enhancementCbased assessments of treatment response (Figure?1)

This may be partially attributed to BEV decreasing vessel permeability, affecting contrast enhancementCbased assessments of treatment response (Figure?1). c-MET tyrosine kinase pathway; shifts in cellular metabolism, including up-regulation of hypoxia inducible factor-1’s downstream processes and the Warburg effect; induction of autophagy; augmentation of GBM stem cell self-renewal; possible implications of GBM-endothelial cell transdifferentiation; and vasoformative responses, including vasculogenesis, alternative angiogenic pathways, and vascular mimicry. Juxtaposing recent studies on well-established resistance pathways with that of emerging mechanisms highlights the overall complexity of GBM treatment resistance while also providing direction for further investigation. Glioblastomas (GBMs) are the most prevalent primary brain tumors. Even with a standard treatment entailing surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ), the average survival for GBM patients is only 12 to 15 months.1 GBMs are classified as either primary GBMs, which develop mutated, or as secondary GBMs, which slowly develop from low-grade astrocytomas, and are most often mutated. Histologically, primary and secondary GBMs are identical, both possessing the defining characteristics of hypercellularity, cellular pleomorphism, mitotic figures, necrosis that may be surrounded by pseudopalisading cells, and extensive yet abnormal vasculature.2 GBM cells initially associate along normal blood vessels to procure their oxygen and nutrient requirements for growth through diffusion. The rapidly proliferating GBM cells may compromise the integrity of the vessels they grow around, eventually leading to vascular collapse. The resulting reduced tumor perfusion initially kills a fraction of GBM cells in the vicinity, while selecting for cells that are able to survive in the ensuing hypoxic environment.3 Alternatively, rapidly growing tumor cells may become localized too far from the most nearby vessel to maintain normoxia. Under reduced oxygen tensions, the remaining GBM cell cohort initiates the hypoxia-inducible factor (HIF)-1 pathway, endowing cells with the ability to adapt to hypoxic environments, among others, by inducing expression of vascular endothelial growth factor (VEGF)-A. Effects of Neovascularization The use of angiogenesis to overcome nutrient and oxygen limitations leads to exponential tumor growth. VEGF-A, expressed by hypoxic cancer cells, causes a loss of blood brain barrier (BBB) integrity, resulting from heterogeneity in basement membrane thickness and abnormal or absent endothelial cell (EC) and pericyte coverage.4, 5, 6 These irregular blood vessels are morphologically compromised and dysfunctional with large diameters, highly permeable walls, and tortuous, disorganized, and blind loops.7 Intratumoral blood flow is thus impeded, creating a heterogeneous tumor environment with respect to oxygenation and interstitial fluid pressure.5 Inconsistent Amprenavir intratumoral Amprenavir oxygenation leads to hypoxia, acidosis, and necrosis, whereas the increased hydrostatic pressure outside of the GBM vasculature promotes intratumoral edema, a major cause of morbidity for GBM patients.7 VEGF The most thoroughly studied proangiogenic pathway is that initiated by the VEGF family of growth factors, whose members, structure, function, and regulation have been described previously.8 VEGF is produced by several GBM components, including tumor, stromal, and inflammatory cells, stimulating microvascular EC VEGF receptor (VEGFR) expression, and leading to EC proliferation, migration, survival, and tube formation. VEGF both dilates vessels and increases their permeability, potentially increasing tumor perfusion, but it may also increase interstitial pressure.5, 9, 10 In addition, VEGF can stimulate EC nitric oxide synthase expression, leading to production of nitric oxide, a gasotransmitter involved in a plethora of physiological pathways, including vasodilation.10 These abilities underlie VEGF’s predominant role in forming the immature, dysfunctional Amprenavir vasculature, and impaired BBB that contributes to vasogenic edema. AAT Rationale for Use Targeting angiogenesis is considered a promising method to halt angiogenesis-dependent tumor growth. Because angiogenesis plays a limited physiological role in adults, antiangiogenic therapy (AAT) should be tumor specific with limited adverse effects. Potential AAT interventions include the following: administering or overexpressing angiogenic inhibitors (eg, neutralizing antibodies against VEGF-A, or its receptor VEGFR2 via VEGFR2 kinase inhibitors), interfering with the functions of EC adhesion molecules and extracellular matrix components (eg, using RGD peptides, interfering with integrin-fibronectin interactions), and inhibiting production of proangiogenic factors. Most antiangiogenic strategies historically concentrated on inhibiting binding of the VEGF ligand to its cognate receptor(s). Specifically inhibiting VEGFRs expressed on tumor microvascular ECs (TMVECs) is potentially therapeutically advantageous. Unlike Rabbit Polyclonal to Cyclin H neoplastic GBM cells, TMVECs can be accessed without bypassing the BBB. TMVECs are also thought to be genetically stable; therefore, there is less risk of developing therapeutic resistance. Utilizing this approach, a number of inhibitors are currently undergoing phase 2 or 3 3 clinical trials. This includes the tyrosine kinase inhibitor.