Generic placeholder image

Current Pharmaceutical Design

Editor-in-Chief

ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

Expression of P-gp in Glioblastoma: What we can Learn from Brain Development

Author(s): Ignazio de Trizio, Mariella Errede, Antonio d'Amati, Francesco Girolamo and Daniela Virgintino*

Volume 26, Issue 13, 2020

Page: [1428 - 1437] Pages: 10

DOI: 10.2174/1381612826666200318130625

Price: $65

Abstract

P-Glycoprotein (P-gp) is a 170-kDa transmembrane glycoprotein that works as an efflux pump and confers multidrug resistance (MDR) in normal tissues and tumors, including nervous tissues and brain tumors. In the developing telencephalon, the endothelial expression of P-gp, and the subcellular localization of the transporter at the luminal endothelial cell (EC) plasma membrane are early hallmarks of blood-brain barrier (BBB) differentiation and suggest a functional BBB activity that may complement the placental barrier function and the expression of P-gp at the blood-placental interface. In early fetal ages, P-gp has also been immunolocalized on radial glia cells (RGCs), located in the proliferative ventricular zone (VZ) of the dorsal telencephalon and now considered to be neural progenitor cells (NPCs). RG-like NPCs have been found in many regions of the developing brain and have been suggested to give rise to neural stem cells (NSCs) of adult subventricular (SVZ) neurogenic niches. The P-gp immunosignal, associated with RG-like NPCs during cortical histogenesis, progressively decreases in parallel with the last waves of neuroblast migrations, while ‘outer’ RGCs and the deriving astrocytes do not stain for the efflux transporter. These data suggest that in human glioblastoma (GBM), P-gp expressed by ECs may be a negligible component of tumor MDR. Instead, tumor perivascular astrocytes may dedifferentiate and resume a progenitor-like P-gp activity, becoming MDR cells and contribute, together with perivascular P-gpexpressing glioma stem-like cells (GSCs), to the MDR profile of GBM vessels. In conclusion, the analysis of Pgp immunolocalization during brain development may contribute to identify the multiple cellular sources in the GBM vessels that may be involved in P-gp-mediated chemoresistance and can be responsible for GBM therapy failure and tumor recurrence.

Keywords: P-glycoprotein, blood-brain barrier, endothelial cells, astrocytes, radial glia-like neural progenitor cells, glioma stem cells, developing brain, adult brain, glioblastoma.

[1]
Cordon-Cardo C, O’Brien JP, Boccia J, Casals D, Bertino JR, Melamed MR. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem 1990; 38: 1277-87.
[2]
Hegmann EJ, Bauer HC, Kerbel RS. Expression and functional activity of P-glycoprotein in cultured cerebral capillary endothelial cells. Cancer Res 1992; 52: 6969-75.
[3]
Tatsuta T, Naito M, Oh-hara T, Sugawara I, Tsuruo T. Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem 1992; 267: 20383-91.
[4]
Tsuji A, Tamai II. Carrier-mediated or specialized transport of drugs across the blood-brain barrier. Adv Drug Deliv Rev 1999; 36: 277-90.
[5]
Schinkel AH, Smit JJ, van Tellingen O, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994; 77: 491-502.
[6]
Schinkel AH. P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev 1999; 36: 179-94.
[7]
Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 1987; 84: 7735-8.
[8]
Cordon-Cardo C, O’Brien JP, Casals D, et al. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 1989; 86: 695-8.
[9]
Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013; 13: 714.
[10]
Munoz JL, Walker ND, Scotto KW, Rameshwar P. Temozolomide competes for P-glycoprotein and contributes to chemoresistance in glioblastoma cells. Cancer Letters 2015; 367: 69-75.
[11]
Zhang X, Ding K, Wang J, Li X, Zhao P. Chemoresistance caused by the microenvironment of glioblastoma and the corresponding solutions. Biomed Pharmaco 2019; 109: 39-46.
[12]
Qin Y, Sato TN. Mouse multidrug resistance 1a/3 gene is the earliest known endothelial cell differentiation marker during blood-brain barrier development. Dev Dyn 1995; 202: 172-80.
[13]
Matsuoka Y, Okazaki M, Kitamura Y, Taniguchi T. Developmental expression of P-glycoprotein (multidrug resistance gene product) in the rat Brain. 1999; 39: 383-92.
[14]
Tsai CE, Daood MJ, Lane RH, Hansen TWR, Gruetzmacher EM, Watchko JF. P-Glycoprotein expression in mouse brain increases with maturation. Neonatology 2002; 81: 58-64.
[15]
Rosati A, Maniori S, Decorti G, Candussio L, Giraldi T, Bartoli F. Physiological regulation of P-glycoprotein, MRP1, MRP2 and cytochrome P450 3A2 during rat ontogeny. 2003; 45: 377-87.
[16]
Virgintino D, Errede M, Girolamo F, et al. Fetal blood-brain barrier P-glycoprotein contributes to brain protection during human development. J Neuropathol Exp Neurol 2008; 67: 50-61.
[17]
Schumacher U, Møllgård K. The multidrug-resistance P-glycoprotein (Pgp, MDR1) is an early marker of blood-brain barrier development in the microvessels of the developing human brain. Histochem Cell Biol 1997; 108: 179-82.
[18]
van Kalken CK, Giaccone G, van der Valk P, et al. Multidrug resistance gene (P-glycoprotein) expression in the human fetus. Am J Pathol 1992; 141: 1063-72.
[19]
Daood M, Tsai C, Ahdab-Barmada M, Watchko JF. ABC transporter (P-gp/ABCB1, MRP1/ABCC1, BCRP/ABCG2) expression in the developing human CNS. Neuropediatrics 2008; 39: 211-8.
[20]
Lam J, Baello S, Iqbal M, et al. The ontogeny of P-glycoprotein in the developing human blood-brain barrier: implication for opioid toxicity in neonates. Pediatr Res 2015; 78: 417-21.
[21]
Novotna M, Libra A, Kopecky M, et al. P-glycoprotein expression and distribution in the rat placenta during pregnancy. Reprod Toxicol 2004; 18: 785-92.
[22]
Sun M, Kingdom J, Baczyk D, Lye SJ, Matthews SG, Gibb W. Expression of the multidrug resistance P-glycoprotein, (ABCB1 glycoprotein) in the human placenta decreases with advancing gestation. Placenta 2006; 27: 602-9.
[23]
Cameron PL, Ruffin JW, Bollag R, Rasmussen H, Cameron RS. Identification of caveolin and caveolin-related proteins in the brain. J Neurosci 1997; 17: 9520-35.
[24]
Ikezu T, Ueda H, Trapp BD, et al. Affinity-purification and characterization of caveolins from the brain: differential expression of caveolin-1, -2, and -3 in brain endothelial and astroglial cell types. Brain Res 1998; 804: 177-92.
[25]
Virgintino D, Robertson D, Errede M, et al. Expression of caveolin-1 in human brain microvessels. Neuroscience 2002; 115: 145-52.
[26]
Engelman JA, Chu C, Lin A, et al. Caveolin-mediated regulation of signaling along the p42/44 MAP kinase cascade in vivo. A role for the caveolin-scaffolding domain. FEBS Lett 1998; 428: 205-11.
[27]
Sui H, Fan ZZ, Li Q. Signal transduction pathways and transcriptional mechanisms of ABCB1/Pgp-mediated multiple drug resistance in human cancer cells. J Inter Med Res 2012; 40: 426-35.
[28]
Virgintino D, Robertson D, Errede M, et al. Expression of P-glycoprotein in human cerebral cortex microvessels. J Histochem Cytochem 2002; 50: 1671-6.
[29]
Demeule M, Jodoin J, Gingras D, Béliveau R. P-glycoprotein is localized in caveolae in resistant cells and in brain capillaries. FEBS Lett 2000; 466: 219-24.
[30]
Jodoin J, Demeule M, Fenart L, et al. P-glycoprotein in blood-brain barrier endothelial cells: interaction and oligomerization with caveolins. J Neurochem 2003; 87: 1010-23.
[31]
Lee H, Volonte D, Galbiati F, et al. Constitutive and growth factor-regulated phosphorylation of caveolin-1 occurs at the same site (Tyr-14) in vivo: identification of a c-Src/Cav-1/Grb7 signaling cassette. Mol Endocrinol 2000; 14: 1750-75.
[32]
Barakat S, Demeule M, Pilorget A, et al. Modulation of p-glycoprotein function by caveolin-1 phosphorylation. J Neurochem 2007; 101: 1-8.
[33]
Drion N, Risede P, Cholet N, Chanez C, Scherrmann JM. Role of P-170 glycoprotein in colchicine brain uptake. J Neurosci Res 1997; 49: 80-8.
[34]
Regina A, Koman A, Piciotti M, et al. Mrp1 multidrug resistance-associated protein and P-glycoprotein expression in rat brain microvessel endothelial cells. J Neurochem 1998; 71: 705-15.
[35]
Bendayan R, Lee G, Bendayan M. Functional expression and localization of P-glycoprotein at the blood brain barrier. Microsc Res Tech 2002; 57: 365-80.
[36]
Pardridge WM, Golden PL, Kang YS, Bickel U. Brain microvascular and astrocyte localization of P-glycoprotein. J Neurochem 1997; 68: 1278-85.
[37]
Golden PL, Pardridge WM. P-Glycoprotein on astrocyte foot processes of unfixed isolated human brain capillaries. Brain Res 1999; 819: 143-6.
[38]
Schlachetzki F, Pardridge WM. P-glycoprotein and caveolin-1alpha in endothelium and astrocytes of primate brain. Neuroreport 2003; 14: 2041-6.
[39]
Bendayan R, Ronaldson PT, Gingras D, Bendayan M. In situ localization of P-glycoprotein (ABCB1) in human and rat brain. J Histochem Cytochem 2006; 54: 1159-67.
[40]
Karssen AM, Meijer O, Pons D, De Kloet ER. Localization of mRNA expression of P-glycoprotein at the blood-brain barrier and in the hippocampus. Ann N Y Acad Sci 2004; 1032: 308-11.
[41]
Westerlund M, Belin AC, Olson L, Galter D. Expression of multi-drug resistance 1 mRNA in human and rodent tissues: reduced levels in Parkinson patients. Cell Tissue Res 2008; 334: 179-85.
[42]
Yousif S, Saubaméa B, Cisternino S, et al. Effect of chronic exposure to morphine on the rat blood-brain barrier: focus on the P-glycoprotein. J Neurochem 2008; 107: 647-57.
[43]
Yu ZY, Ono S, Spatz M, McCarron RM. Effect of hemorrhagic shock on apoptosis and energy-dependent efflux system in the brain. Neurochem Res 2002; 27: 1625-32.
[44]
Chiu C, Miller MC, Monahan R, Osgood DP, Stopa EG, Silverberg GD. P-glycoprotein expression and amyloid accumulation in human aging and Alzheimer’s disease: preliminary observations. Neurobiol Aging 2015; 36: 2475-82.
[45]
Jetté L, Têtu B, Béliveau R. High levels of P-glycoprotein detected in isolated brain capillaries. Biochimica et Biophysica Acta (BBA) - Biomem 1993; 1150: 147-54.
[46]
Crocetti E, Trama A, Stiller C, et al. Epidemiology of glial and non-glial brain tumours in Europe. Eur J Cancer 2012; 48: 1532-42.
[47]
Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009; 10: 459-66.
[48]
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352: 987-96.
[49]
Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 2017; 318: 2306-16.
[50]
Da Ros M, De Gregorio V, Iorio AL, et al. Glioblastoma Chemoresistance: the double play by microenvironment and blood-brain barrier. Int J Mol Sci 2018; 19.
[51]
Haar CP, Hebbar P, Wallace GC IV, et al. Drug resistance in glioblastoma: a mini review. Neurochem Res 2012; 37: 1192-200.
[52]
Balça-Silva J, Matias D, Carmo AD, Sarmento-Ribeiro AB, Lopes MC, Moura-Neto V. Cellular and molecular mechanisms of glioblastoma malignancy: Implications in resistance and therapeutic strategies. Semin Cancer Biol 2019; 58: 130-41.
[53]
Shin S, Lim S, Song JY, et al. Development of an aryloxazole derivative as a brain-permeable anti-glioblastoma agent. Pharmaceutics 2019; 11.
[54]
Birner P, Piribauer M, Fischer I, et al. Vascular patterns in glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins: evidence for distinct angiogenic subtypes. Brain Pathol 2003; 13: 133-43.
[55]
Chen L, Lin ZX, Lin GS, et al. Classification of microvascular patterns via cluster analysis reveals their prognostic significance in glioblastoma. Hum Pathol 2015; 46: 120-8.
[56]
McConnell HL, Kersch CN, Woltjer RL, Neuwelt EA. The translational significance of the neurovascular unit. J Biol Chem 2017; 292: 762-70.
[57]
Watkins S, Robel S, Kimbrough IF, Robert SM, Ellis-Davies G, Sontheimer H. Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells. Nat Commun 2014; 5: 4196.
[58]
Sawada T, Kato Y, Sakayori N, Takekawa Y, Kobayashi M. Expression of the multidrug-resistance P-glycoprotein (Pgp, MDR-1) by endothelial cells of the neovasculature in central nervous system tumors. Brain Tumor Pathol 1999; 16: 23-7.
[59]
Fattori S, Becherini F, Cianfriglia M, Parenti G, Romanini A, Castagna M. Human brain tumors: multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells. Virchows Arch 2007; 451: 81-7.
[60]
Tanaka Y, Abe Y, Tsugu A, et al. Ultrastructural localization of P-glycoprotein on capillary endothelial cells in human gliomas. Virchows Arch 1994; 425: 133-8.
[61]
Agarwal S, Manchanda P, Vogelbaum MA, Ohlfest JR, Elmquist WF. Function of the blood-brain barrier and restriction of drug delivery to invasive glioma cells: findings in an orthotopic rat xenograft model of glioma. Drug Metab Dispos 2013; 41: 33-9.
[62]
Lin F, de Gooijer MC, Roig EM, et al. ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin Cancer Res 2014; 20: 2703-13.
[63]
Nabors MW, Griffin CA, Zehnbauer BA, et al. Multidrug resistance gene (MDR1) expression in human brain tumors. J Neurosurg 1991; 75: 941-6.
[64]
Ishihara H, Kubota H, Lindberg RLP, et al. Endothelial cell barrier impairment induced by glioblastomas and transforming growth factor β2 involves matrix metalloproteinases and tight junction proteins. J Neuropathol Exp Neurol 2008; 67: 435-48.
[65]
Girolamo F, Dallatomasina A, Rizzi M, et al. Diversified expression of NG2/CSPG4 isoforms in glioblastoma and human foetal brain identifies pericyte subsets. PLoS One 2013; 8: e84883
[66]
Perazzoli G, Prados J, Ortiz R, et al. Temozolomide resistance in glioblastoma cell lines: implication of MGMT, MMR, P-Glycoprotein and CD133 expression. PLoS One 2015; 10: e0140131
[67]
Quann K, Gonzales DM, Mercier I, et al. Caveolin-1 is a negative regulator of tumor growth in glioblastoma and modulates chemosensitivity to temozolomide. Cell Cycle 2013; 12: 1510-20.
[68]
Brandao M, Simon T, Critchley G, Giamas G. Astrocytes, the rising stars of the glioblastoma. Microenvironment. 2019; 67: 779-90.
[69]
Chen W, Wang D, Du X, et al. Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes. Med Oncol 2015; 32: 43.
[70]
Yang N, Yan T, Zhu H, et al. A co-culture model with brain tumor-specific bioluminescence demonstrates astrocyte-induced drug resistance in glioblastoma. J Transl Med 2014; 12: 278.
[71]
Mega A, Hartmark Nilsen M, Leiss LW, et al. Astrocytes enhance glioblastoma growth. Glia 2019; 68(2): 316-27.
[72]
Priego N, Zhu L, Monteiro C, et al. STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nature Medicine 2018; 24: 1024-35.
[73]
Henrik Heiland D, Ravi VM, Behringer SP, et al. Tumor-associated reactive astrocytes aid the evolution of immunosuppressive environment in glioblastoma. Nature Communications 2019; 10: 2541.
[74]
Wurm J, Behringer SP, Ravi VM, et al. Astrogliosis releases pro-oncogenic chitinase 3-Like 1 causing MAPK signaling in glioblastoma. Cancers (Basel) 2019; 11.
[75]
Oushy S, Hellwinkel JE, Wang M, et al. Glioblastoma multiforme-derived extracellular vesicles drive normal astrocytes towards a tumour-enhancing phenotype. Philos Trans R Soc Lond B Biol Sci 2018; 373.
[76]
Proia P, Schiera G, Mineo M, et al. Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor. Int J Mol Med 2008; 21: 63-7.
[77]
Guo Z, Zhu J, Zhao L, Luo Q, Jin X. Expression and clinical significance of multidrug resistance proteins in brain tumors. J Exp Clin Cancer Res 2010; 29: 122.
[78]
Schott B, Bennis S, Pourquier P, Ries C, Londos-Gagliardi D, Robert J. Differential over-expression of mdr1 genes in multidrug-resistant rat glioblastoma cell lines selected with doxorubicin or vincristine. Int J Cancer 1993; 55: 115-21.
[79]
Kolchinsky A. First gene involved in glioblastoma progression identified. Surg Neurol 1999; 52: 19-20.
[80]
Declèves X, Fajac A, Lehmann-Che J, et al. Molecular and functional MDR1-Pgp and MRPs expression in human glioblastoma multiforme cell lines. Int J Cancer 2002; 98: 173-80.
[81]
Demeule M, Shedid D, Beaulieu E, et al. Expression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumors. Int J Cancer 2001; 93: 62-6.
[82]
von Bossanyi P, Diete S, Dietzmann K, Warich-Kirches M, Kirches E. Immunohistochemical expression of P-glycoprotein and glutathione S-transferases in cerebral gliomas and response to chemotherapy. Acta Neuropathol 1997; 94: 605-11.
[83]
Salaroglio IC, Abate C, Rolando B, et al. Validation of thiosemicarbazone compounds as P-Glycoprotein inhibitors in human primary brain-blood barrier and glioblastoma stem cells. Mol Pharm 2019; 16: 3361-73.
[84]
Suzuki T, Maruno M, Wada K, et al. Genetic analysis of human glioblastomas using a genomic microarray system. Brain Tumor Pathol 2004; 21: 27-34.
[85]
Kirches E, Oda Y, Von Bossanyi P, et al. Mdr1 mRNA expression differs between grade III astrocytomas and glioblastomas. Clin Neuropathol 1997; 16: 34-6.
[86]
Cho DY, Lin SZ, Yang WK, et al. Targeting cancer stem cells for treatment of glioblastoma multiforme. Cell Transplant 2013; 22: 731-9.
[87]
Liu G, Yuan X, Zeng Z, et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 2006; 5: 67.
[88]
Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006; 444: 756-60.
[89]
Huang Z, Cheng L, Guryanova OA, Wu Q, Bao S. Cancer stem cells in glioblastoma--molecular signaling and therapeutic targeting. Protein Cell 2010; 1: 638-55.
[90]
Nakai E, Park K, Yawata T, et al. Enhanced MDR1 expression and chemoresistance of cancer stem cells derived from glioblastoma. Cancer Invest 2009; 27: 901-8.
[91]
Steinbichler TB, Dudás J, Skvortsov S, Ganswindt U, Riechelmann H, Skvortsova I-I. Therapy resistance mediated by exosomes. Molecular cancer 2019; 18: 58-8.
[92]
Westphal M, Lamszus K. Circulating biomarkers for gliomas. Nat Rev Neurol 2015; 11: 556-66.
[93]
Anthony TE, Klein C, Fishell G, Heintz N. Radial glia serve as neuronal progenitors in all regions of the central nervous system. Neuron 2004; 41: 881-90.
[94]
Gotz M, Hartfuss E, Malatesta P. Radial glial cells as neuronal precursors: a new perspective on the correlation of morphology and lineage restriction in the developing cerebral cortex of mice. Brain Res Bull 2002; 57: 777-88.
[95]
Malatesta P, Appolloni I, Calzolari F. Radial glia and neural stem cells. Cell Tissue Res 2008; 331: 165-78.
[96]
Sanai N, Alvarez-Buylla A, Berger MS. Neural stem cells and the origin of gliomas. New Engl J Med 2005; 353: 811-22.
[97]
Malatesta P, Hartfuss E, Götz M. Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 2000; 127: 5253-63.
[98]
Malatesta P, Hack MA, Hartfuss E, et al. Neuronal or glial progeny: regional differences in radial glia fate. Neuron 2003; 37: 751-64.
[99]
Matarredona ER, Pastor AM. Neural stem cells of the subventricular zone as the origin of human glioblastoma stem cells. Therapeutic implications. Front Oncol 2019; 9
[100]
Holland EC. Gliomagenesis: genetic alterations and mouse models. Nat Rev Genet 2001; 2: 120-9.
[101]
Martínez-Cerdeño V, Noctor SC. Neural Progenitor Cell Terminology. Front Neuroanat 2018; 12
[102]
Li F, Liu X, Sampson JH, Bigner DD, Li C-Y. Rapid reprogramming of primary human astrocytes into potent tumor-initiating cells with defined genetic factors. Cancer Res 2016; 76: 5143-50.
[103]
Friedmann-Morvinski D, Bushong EA, Ke E, et al. Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 2012; 338: 1080-4.
[104]
Makrides V, Dolgodilina E, Virgintino D. Blood-brain barrier transporters and neuroinflammation: partners in neuroprotection and in pathology The blood brain barrier and inflammation. Springer International Publishing: Cham. 2017; pp. 103-51.
[105]
Callaghan R, Luk F, Bebawy M. Inhibition of the multidrug resistance P-glycoprotein: time for a change of strategy? Drug Metab Dispos 2014; 42: 623-31.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy