Understanding the Role of Endothelial Cells in Glioblastoma: Mechanisms and Novel Treatments
Abstract
:1. Introduction
2. Cells of the Central Nervous System
2.1. Endothelial Cells
2.2. Neurons
2.3. Mural Cells
2.4. Astrocytes
2.5. Malignant Transformation
2.6. Tumor Vasculature
2.7. Structural Communication between TCs and ECs
3. Angiogenesis in Glioblastoma
3.1. Angiogenesis Mechanism
3.2. Anti-Angiogenic Therapies in Glioblastoma
3.3. Other Methods to Target Angiogenesis
4. Alternative Interventions
4.1. Immunotherapy for Glioblastoma
4.2. Nanoparticles and Other Novel Technologies
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Factor | Receptor | Mechanism |
---|---|---|
VEGF-A | VEGFR-1 and VEGFR-2 | Stimulates EC migration, proliferation, survival, nitric oxide production, and angiogenic response |
ARL13B | VEGFR-2 | Binds the intracellular domain of VEGFR2 on ECs to promote VEGFA-VEGFR2 signaling |
TGF-β | TβRII | Acts on both TCs and ECs to induce neovascularization and causes ECM remodeling using MMPs |
FGF2 | FGFR | Stimulates EC VEGF production and proliferation |
EGF | EGFR | Promotes EC migration and capillary tube formation |
ETV2 | Conserved ETS motifs in the ZRS | Transdifferentiates GBM stem cells to an endothelial lineage |
Pleiotrophin | ALK1 | Causes VEGF deposition at blood vessels, induces EC proliferation |
PDFG-B | PDGF receptor β | Stimulates VEGF production in ECs |
Ang-1 | EC-specific Tie receptors | Acts on ECs to stimulate angiogenesis and EC survival |
Agent | Target | Combination Therapies | NCT Trial Number | Phase | Status | Outcome (in Experimental Group Relative to Control) | Center or Company Name |
---|---|---|---|---|---|---|---|
Bevacizumab | VEGF | Temozolomide | NCT00590681 | Phase II | Completed Sept. 2014 | Prolonged PFS, no improvement in OS | University of Chicago, Genentech, Inc., Oceanside, CA, USA |
Sorafenib | NCT00621686 | Phase II | Completed Feb. 2014 | No improvement in outcome | Alliance for Clinical Trials in Oncology, NCI, Bethesda, MD, USA | ||
Erlotinib | NCT00671970 | Phase II | Completed Apr. 2010 | Similar PFS and radiographic response | Duke University, Genentech, Inc., Oceanside, CA, USA | ||
Rindopepimut (CDX-110) | NCT01498328 | Phase II | Completed May 2016 | Improved PFS, ORR, and ability to discontinue steroids for ≥6 months | Celldex Therapeutics, Hampton, NJ, USA | ||
Poly-ICLC | NCT02754362 | Phase II | Completed June 2019 | Pending | NYU Langone Health, MOUNT SINAI HOSPITAL, New York, NY, USA | ||
Optune | NCT01925573 | Interventional | Completed Aug. 2019 | Pending | University of Maryland, Baltimore, NovoCure Ltd., Portsmouth, NH, USA | ||
Trebananib | NCT01609790 | Interventional | Completed May 2022 | Shortened PFS | NCI, NRG Oncology, Columbus, OH, USA | ||
Ascorbic Acid | NCT02833701 | Phase I | Completed Mar. 2019 | Pending | University of Nebraska, NCI, Bethesda, MD, USA | ||
Retifanlimab + hypofractionated radiotherapy | NCT06160206 | Phase II | Ongoing | Pending | Academic and Community Cancer Research United, NCI, Bethesda, MD, USA | ||
VB-111 | Ad-PPE-Fas-c | NA | NCT04406272 | Phase II | Ongoing | Pending | Dana-Farber Cancer Institute, VBL Therapeutics, New York, NY, USA |
Apatinib | VEGFR-2 | Temozolomide | NCT04814329 | Observational | Ongoing | Pending | Beijing Sanbo Brain Hospital, Beijing, China |
Anlotinib | EGFR | NA | NCT04004975 | Phase II | Completed July 2021 | Pending | Shandong Cancer Hospital and Institute, Jinan, Shandong, China |
Temozolomide | NCT04547855 | Phase II | Ongoing | Pending | The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China | ||
Glasdegib | Sonic hedgehog receptor smoothened (SMO) | Temozolomide | NCT03466450 | Phase II | Completed Nov. 2023 | Pending | Hospital del Mar, Barcelona, Catalonia, Spain |
Temozolomide | DNA (alkylating agent) | Radiation therapy + bevacizumab | NCT00884741 | Phase III | Completed Mar. 2013 | No improvement in OS | Providence Hospital, Portland, OR, USA |
Napabucasin (BBI608) | STAT3 | Temozolomide | NCT02315534 | Phase II | Completed June 2019 | Pending | Laura and Isaac Perlmutter Cancer Center, New York, NY, USA |
Thrombospondin-1 analog (ABT 510) | CD36 receptor found on ECs | Radiation | NCT00584883 | Phase I | Completed July 2008 | Pending | University of Alabama at Birmingham, Birmingham, AL, USA |
Cediranib | (VEGFR)-1, VEGFR-2, VEGFR-3 | Olapirib | NCT02974621 | Phase II | Completed Dec. 2022 | Pending | UC San Diego Moores Cancer Center, San Diego, CA, USA |
TTAC-0001 (Taniburimab) | VEGFR-2 | NA | NCT03033524 | Phase II | Completed June 2017 | Pending | PharmAbcine, Yuseong-gu, Daejeon, Republic of Korea |
Bevacizumab | NCT03856099 | Phase II | Completed July 2022 | Pending | Stanford Advanced Medical Center, Palo Alto, CA, USA | ||
Pembrolizumab | NCT03722342 | Phase I | Completed Sept. 2022 | Pending | Austin Hospital, Heidelberg, VIC, Australia | ||
Recombinant Human Endostatin | Broad-spectrum angiogenesis inhibitor | Temozolomide + Irinotecan | NCT04267978 | Phase II | Ongoing | Pending | Beijing Sanbo Brain Hospital, Beijing, China |
EGFR Bi-armed Activated T-cells (BATs) | EGFR | Temozolomide + radiation | NCT03344250 | Phase I | Ongoing | Prolonged OS and PFS | University of Virginia, Charlottesville, VA, USA |
Nanoparticles | variable | Radiotherapy + Temozolomide | NCT04881032 | Phase I/II | Ongoing | Pending | CHU de Brest, Brest, Brittany, France |
hrBMP4 | VEGF | NA | NCT02869243 | Phase I | Completed June 2021 | Reduction in tumor growth; 2/15 with complete regression and extended survival | Tel Aviv Sourasky Medical Center, Tel Aviv-Yafo, Israel |
Erolotinib | EGFR | Sorafenib | NCT00445588 | Phase II | Completed Apr. 2026 | No significant survival improvement | University of Alabama at Birmingham, Birmingham, AL, USA |
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Hovis, G.; Chandra, N.; Kejriwal, N.; Hsieh, K.J.-Y.; Chu, A.; Yang, I.; Wadehra, M. Understanding the Role of Endothelial Cells in Glioblastoma: Mechanisms and Novel Treatments. Int. J. Mol. Sci. 2024, 25, 6118. https://doi.org/10.3390/ijms25116118
Hovis G, Chandra N, Kejriwal N, Hsieh KJ-Y, Chu A, Yang I, Wadehra M. Understanding the Role of Endothelial Cells in Glioblastoma: Mechanisms and Novel Treatments. International Journal of Molecular Sciences. 2024; 25(11):6118. https://doi.org/10.3390/ijms25116118
Chicago/Turabian StyleHovis, Gabrielle, Neha Chandra, Nidhi Kejriwal, Kaleb Jia-Yi Hsieh, Alison Chu, Isaac Yang, and Madhuri Wadehra. 2024. "Understanding the Role of Endothelial Cells in Glioblastoma: Mechanisms and Novel Treatments" International Journal of Molecular Sciences 25, no. 11: 6118. https://doi.org/10.3390/ijms25116118