脳腫瘍の血管障壁の組織学的な特徴と薬剤による治療の展望

//Background//---
 The intracranial region is specific hallmarks, the cell component of which is different from the other region. Therefore, we need to control and limit the chemical products which flows into brain parenchyma, which is made in blood brain barrier. On the other hand, tumor development and metastasis in/to this region induce angiogenesis like cancer cell development in the other region. Therefore, even in the intracranial region where blood brain barrier is formed, we need to specially consider about the blood system near/around brain tumor region. This blood system is called the blood-tumor barrier.
 Patricia S. Steeg review about the blood-tumor barrier especially in the brain cancer(1). I fucus on the histologic contents and show the brief drug-mediate clinical strategy.
 
//Hallmarks of intercranial tumor//---
Ref.(1)(See Fig.1 and Fig.2)
(Brain parenchyma region)
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*Activate astrocyte and microglia is emerged.
 Activated astrocytes express glial fibrillary acidic protein (GFAP). These activated non-neuronal cells induced neuroinflammatory response, resulting influence brain tumor barrier and blood brain barrier permeability(2). GFAP is involved in cell communication and the functioning of the blood brain barrier.
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*Activated microglia contacts (function) to neuron.
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*Leukocyte including T cell arises and functions to tumor.
 Blood brain barrier endothelial cells lack luminal expression of E-selectin, intercellular cell adhesion molecule 1(ICAM1) preventing leukocyte attachment and ingress into blood brain barrier and transcytosis. However, tumor evolution condition induces luminal expression of these leukocyte ingress-inducing receptor(1)(See Fig.2b). Leukocyte attaches VCAM1 and ICAM1 in an integrin-mediated manner.
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*Activated and dense astrocyte around tumor tissue.
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*Dysfunction of Astrocyte foot process (endfeet) around blood brain barrier. In normal condition, astrocyte endfeet entirely covers around blood brain barrier.
 Pericytes contribute to basement membrane formation and guide astrocyte endfeet to the blood brain barrier and have stem cell properties and regulate angiogenesis(3,4). Therefore, pericyte dysfunction may occur in the tumor microenvironment. The endfeet processes of astrocyte ensheath(cover by capsule) neurons as well as blood vessels. In glioma, overall levels of pericyte ensheathment is low(10), which disrupt the blood-tumor barrier and elevate permeability(11).
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*AQP4 locational abnormal-expression aside from endfeet region.
 Aquaporin 4(AQP4) is a water channel that localizes to the endfeet and regulates water homeostasis within the CNS31. AQP4 expressed in endfeet region with binding to Agrin. Water homeostasis may affect endfeet integrity entirely around the blood brain barrier. Agrin play central role in the development of the neuromuscular junction during embryogenesis. This expression level in the blood-tumor barrier is decreased to 10-30% of the blood brain barrier, resulting misalignment of astrocyte endfeet(5).
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*Basement membranes are altered.
 Cancer cells express extra-cellular matrix to parenchyma region. In expressed proteins, tenascin C by glioma cells increases basement membrane stiffness and induces vascular collapse(12).
 
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(Blood and endothelial region)
*The activate expression of receptors(#1) on the endothelial tissue.
(#1)VEGFR, Angioprotein receptor, VCAM1, ICAM1, TNFR
They(#1) attract VEGF, ANG2, Leukocyte(integrin mediated), TNF, respectively.
 Vascular endothelial growth factor(VEGF) expression is a consistent feature of primary and metastatic brain tumor(5,6). VEGF regulates both angiogenesis and vascular permeability.
 Angioprotein 2 has been demonstrated in a model of brain metastasis and regulates vessel stability(7).
 TNF receptors 1 and 2 are expressed in the brain tumor battier of brain metastasis but are absent from the blood brain barrier and regulate the expression of cell junction protein(9). Therefore, these receptors could affect binding state between endothelial cells.
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*Binding condition of cell junction receptor(#2) become poor.
(#2)Claudins, JAMs, PCEAM1, VE cadherin
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*Actin cytoskeleton in endothelial cell is upregulated near cell junction region.
Actin cytoskeleton plays critical role in modulating blood brain barrier.
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*Downregulation of ABCB1 and ABCG2
ABCB is ATP-binding cassette transporters and makes chemical material flow out from intra-cellular region to extra-cellular region in an ATP dependent way. ABCG2 is ATP-binding cassette transporters and play protective roles in blood-brain barriers.
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(Transcytosis through blood brain barrier)
*Increased caveolin-mediated transport
This is cargo-specific mechanisms of endocytosis, as well as bulk fluid entry by macropinocytosis.
*Micropinocytosis increased(8)
 
//Discussion//---
 We can consider about possible clinical strategy focusing on “difference” of “normal” blood brain barrier and blood-tumor barrier. For example, if drug penetration rate of blood-tumor barrier is significantly higher than blood brain barrier, lesion specific drug-mediated treatment could be realized. Therefore, comparison of tissue hallmarks around blood vessel is important as focusing on this Letter. Furthermore, after success of cancer regression, we may need to regenerate and recover the vascular system.
 It is suggested that vascular opening by focused ultrasound gather interest in glioblastoma. Furthermore, microbubble drug formulation significantly reduces the energy for vascular opening by ultrasound. In preclinical experiment, single-digit-fold increasing of drug distribution was realized(13,14).
 
//The cell-specific delivery system//---
 As receptor expression is activated in the luminal region of endothelial tissue in the blood-tumor barrier, these receptors can be utilized as “an anchor” of the nanoparticle into which the brain anti-tumor drugs are infused. In this concept, on-site specificity could be improved, but these receptors may be expressed in the other vascular system. Therefore, brain tropism of nanoparticles including a virus and a cell needs to be considered. On the other hand, it is important to find the binding site (epitope) specific to the blood-tumor barrier.
 
(Reference)
(1)
Patricia S. Steeg
The blood–tumour barrier in cancer biology and therapy
Nature Reviews Clinical Oncology (2021)
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Author information
Affiliations
Women’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
Patricia S. Steeg
Acknowledgements
The author thanks M. Gilbert, A. Zimmer, W. D. Figg, B. Gril, I. Khan and S. Lipkowitz for critical review of the manuscript.
(2)
Gril, B. et al.
Reactive astrocytic S1P3 signaling modulates the blood-tumor barrier in brain metastases.
Nat. Commun. 9, 2705 (2018).
(3)
Winkler, E. A., Bell, R. D. & Zlokovic, B. V.
Central nervous system pericytes in health and disease. 
Nat. Neurosci. 14, 1398–1405 (2011).
(4)
Zhou, W. C. et al.
Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy.
Cell Stem Cell  21, 591–603.e4 (2017).
(5)
Lyle, L. et al.
Alterations in pericyte subpopulations are associated with elevated blood-tumor barrier permeability in experimental brain metastasis of breast cancer.
Clin. Cancer Res. 22, 5287–5299 (2016).
(6)
Kealy, J. & Campbell, M.
in Resistance to Targeted Therapies against Adult Brain Cancers Vol. 11  (ed Tivnan, A.) 69–87 (Springer, 2016).
(7)
Avraham, H. K. et al.
Angiopoietin-2 mediates blood-brain barrier impairment and colonization of triple-negative breast cancer cells in brain.
J. Pathol. 232, 369–381 (2014).
(8)
Pernet-Gallay, K. et al.
Vascular permeability  in the RG2 glioma model can be mediated by macropinocytosis and be independent of the opening of the tight junction.
J. Cereb. Blood Flow Metab. 37, 1264–1275 (2017).
(9)
Connell, J. J. et al.
Selective permeabilization of the bloodbrain barrier at sites of metastasis. 
J. Natl Cancer Inst. 105, 1634–1643 (2013).
(10)
Gargini, R., Segura-Collar, B. & Sanchez-Gomez, P.
Cellular plasticity and tumor microenvironment in gliomas: the struggle to hit a moving target.
Cancers 12, 24 (2020).
(11)
Zhou, W. C. et al.
Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy.
Cell Stem Cell  21, 591–603.e4 (2017).
(12)
Miroshnikova, Y. A. et al.
Tissue mechanics promote IDH1-dependent HIF1α-tenascin C feedback to regulate glioblastoma aggression.
Nat. Cell Biol. 18, 1336–1345 (2016).
(13)
Lin, Y. L., Wu, M. T. & Yang, F. Y.
Pharmacokinetics  of doxorubicin in glioblastoma multiforme following ultrasound-Induced blood-brain barrier disruption as determined by microdialysis.
J. Pharm. Biomed. Anal. 149, 482–487 (2018).
(14)
Arvanitis, C. D. et al.
Mechanisms of enhanced drug delivery in brain metastases with focused ultrasound- induced blood-tumor barrier disruption.
Proc. Natl Acad. Sci. USA 115, E8717–E8726 (2018).