Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier

Ros, Martina Da; Gregorio, Veronica De; Iorio, Anna Lisa; Giunti, Laura; Guidi, Milena; Martino, Maurizio de; Genitori, Lorenzo; Sardi, Iacopo

doi:10.3390/ijms19102879

Cited by 158 publications

(138 citation statements)

References 181 publications

(227 reference statements)

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“…The best known of these transporters is P-glycoprotein (P-gp), a membrane protein belonging to the superfamily of ATP-binding cassette (ABC) transporters. The blocking of these transport proteins might be useful in the treatment of glioblastoma ( 11 – 14 ).…”

Section: Introductionmentioning

confidence: 99%

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

et al. 2020

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Glioblastoma, the most common primary central nervous system tumor, is characterized by extensive vascular neoformation and an area of necrosis generated by rapid proliferation. The standard treatment for this type of tumor is surgery followed by chemotherapy based on temozolomide and radiotherapy, resulting in poor patient survival. Glioblastoma is known for strong resistance to treatment, frequent recurrence and rapid progression. The aim of this study was to evaluate whether mifepristone, an antihormonal agent, can enhance the effect of temozolomide on C6 glioma cells orthotopically implanted in Wistar rats. The levels of the vascular endothelial growth factor (VEGF), and P-glycoprotein (P-gp) were examined, the former a promoter of angiogenesis that facilitates proliferation, and the latter an efflux pump transporter linked to drug resistance. After a 3-week treatment, the mifepristone/temozolomide regimen had decreased the level of VEGF and P-gp and significantly reduced tumor proliferation (detected by PET/CT images based on 18F-fluorothymidine uptake). Additionally, mifepristone proved to increase the intracerebral concentration of temozolomide. The lower level of O6-methylguanine-DNA-methyltransferase (MGMT) (related to DNA repair in tumors) previously reported for this combined treatment was herein confirmed. After the mifepristone/temozolomide treatment ended, however, the values of VEGF, P-gp, and MGMT increased and reached control levels by 14 weeks post-treatment. There was also tumor recurrence, as occurred when administering temozolomide alone. On the other hand, temozolomide led to 100% mortality within 26 days after beginning the drug treatment, while mifepristone/temozolomide enabled 70% survival 60–70 days and 30% survived over 100 days, suggesting that mifepristone could possibly act as a chemo-sensitizing agent for temozolomide.

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Section: Introductionmentioning

confidence: 99%

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

et al. 2020

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“…231 Interestingly, the transmembrane proteins, e.g., ABC transporter, HB-EGF, PTGS2, ST6GALNAC5, and other drug efflux transporters, are also found in the BBTB, which supports chemo-resistance. [232][233][234][235] Another important component of the glioma microenvironment is the PVN at the border area of the tumor and vasculature and is enriched with GSCs. 236 Several noncancerous cells such as macrophage, pericytes, astrocytes, and endothelial cells give support to GSCs for maintenance and proliferation in this region and maintain an immunosuppressive hypoxic environment.…”

Section: Role Of Neurovascular Unit In Ischemia and Glioma Astrocytesmentioning

confidence: 99%

The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports

Ghosh

Chakraborty

Sarkar

et al. 2019

Sig Transduct Target Ther

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Glioma and cerebral ischemic stroke are two major events that lead to patient death worldwide. Although these conditions have different physiological incidences,~10% of ischemic stroke patients develop cerebral cancer, especially glioma, in the postischemic stages. Additionally, the high proliferation, venous thrombosis and hypercoagulability of the glioma mass increase the significant risk of thromboembolism, including ischemic stroke. Surprisingly, these events share several common pathways, viz. hypoxia, cerebral inflammation, angiogenesis, etc., but the proper mechanism behind this co-occurrence has yet to be discovered. The hypercoagulability and presence of the D-dimer level in stroke are different in cancer patients than in the noncancerous population. Other factors such as atherosclerosis and coagulopathy involved in the pathogenesis of stroke are partially responsible for cancer, and the reverse is also partially true. Based on clinical and neurosurgical experience, the neuronal structures and functions in the brain and spine are observed to change after a progressive attack of ischemia that leads to hypoxia and atrophy. The major population of cancer cells cannot survive in an adverse ischemic environment that excludes cancer stem cells (CSCs). Cancer cells in stroke patients have already metastasized, but early-stage cancer patients also suffer stroke for multiple reasons. Therefore, stroke is an early manifestation of cancer. Stroke and cancer share many factors that result in an increased risk of stroke in cancer patients, and vice-versa. The intricate mechanisms for stroke with and without cancer are different. This review summarizes the current clinical reports, pathophysiology, probable causes of co-occurrence, prognoses, and treatment possibilities.

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“…In addition, the aberrant vasculature resulting from HIF-hypoxia signaling allows a higher permeability of vessels. In addition to regular vessels, in the brain, there is a specific structure named the blood-brain barrier (BBB) that is considered as the major obstacle to adequate drug delivery in brain tumors [63,64]. The BBB is a neurovascular unit composed of endothelial cells and surrounding pericytes (Figures 1 and 3).…”

Section: Hif Target Genes In Phggmentioning

confidence: 99%

Hypoxia Inducible Factors’ Signaling in Pediatric High-Grade Gliomas: Role, Modelization and Innovative Targeted Approaches

Fuchs

Pierrevelcin

Messé

et al. 2020

Cancers

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The brain tumor microenvironment has recently become a major challenge in all pediatric cancers, but especially in brain tumors like high-grade gliomas. Hypoxia is one of the extrinsic tumor features that interacts with tumor cells, but also with the blood-brain barrier and all normal brain cells. It is the result of a dramatic proliferation and expansion of tumor cells that deprive the tissues of oxygen inflow. However, cancer cells, especially tumor stem cells, can endure extreme hypoxic conditions by rescheduling various genes' expression involved in cell proliferation, metabolism and angiogenesis and thus, promote tumor expansion, therapeutic resistance and metabolic adaptation. This cellular adaptation implies Hypoxia-Inducible Factors (HIF), namely HIF-1α and HIF-2α. In pediatric high-grade gliomas (pHGGs), several questions remained open on hypoxia-specific role in normal brain during gliomagenesis and pHGG progression, as well how to model it in preclinical studies and how it might be counteracted with targeted therapies. Therefore, this review aims to gather various data about this key extrinsic tumor factor in pHGGs.

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Glioblastoma Chemoresistance: The Double Play by Microenvironment and Blood-Brain Barrier

Cited by 158 publications

References 181 publications

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

Mifepristone as a Potential Therapy to Reduce Angiogenesis and P-Glycoprotein Associated With Glioblastoma Resistance to Temozolomide

The interrelationship between cerebral ischemic stroke and glioma: a comprehensive study of recent reports

Hypoxia Inducible Factors’ Signaling in Pediatric High-Grade Gliomas: Role, Modelization and Innovative Targeted Approaches

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