Contradictory Effect of Notch1 and Notch2 on Phosphatase and Tensin Homolog and its Influence on Glioblastoma Angiogenesis

  • Mostafa Shabani 1. Medical Genomics Research Center, Tehran Medical Sciences Islamic Azad University, Tehran, Iran 2. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
  • Hamid Taghvaei Javanshir 1. Medical Genomics Research Center, Tehran Medical Sciences Islamic Azad University, Tehran, Iran 2. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
  • Ahmad Bereimipour 2. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran 3. Young Researchers and Elite Club, Tehran Medical Sciences Islamic Azad University, Tehran, Iran
  • Amin Ebrahimi Sadrabadi 2. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
  • Arsalan Jalili 2. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
  • Karim Nayernia 4. International Center for Personalized Medicine, Düsseldorf, Germany
Keywords: Glioblastoma; Angiogenesis; Notch1; Notch2


Many genes induce angiogenesis in tumors, and among them, Notch family genes have received particular attention due to their extensive network of connections with other genes active in this function. Suppression of angiogenic signaling has been studied in various cancers, confirming Notch's fundamental and extensive role. According to studies, four Notch genes work independently with many genes such as vascular endothelial growth factor, phosphatase and tensin homolog, Phosphoinositide 3-kinase/Akt, and matrix metalloproteinases, and so many other genes, as well as proteins (such as hypoxia-inducible factor-1 alpha) significantly affect tumor angiogenesis. Notch1 regular activity in a healthy person causes angiogenesis in body tissues, controlled by normal Notch2 activity. However, in many cases of glioblastoma, whether on patients or tumor xenografts or in vivo models, a mutation in one of these two essential genes or at least one of the genes and proteins that affected by them can cause better angiogenesis in hypoxic conditions and lead to become an invasive tumor. In this review, we examined the contrasting activity of Notch1 and Notch2 and the signaling cascade that each generates in the angiogenesis of glioblastoma, the most invasive cancer of the central nervous system. [GMJ.2021;10:e2091]


Yan D, Hao C, Xiao-feng L, Yu-chen L, Yu-bin F, Lei Z. Molecular mechanism of Notch signaling with special emphasis on microRNAs: Implications for glioma. J Cell Physiol. 2018;234:158-70.


Molofsky A V, Krencik R, Krenick R, Ullian EM, Ullian E, Tsai H, et al. Astrocytes and disease: a neurodevelopmental perspective. Genes Dev. 2012; 26(9):891-907.

PMid:22549954 PMCid:PMC3347787

Parpura V, Heneka MT, Montana V, Oliet SHR, Schousboe A, Haydon PG, et al. Glial cells in physiology. J Neurochem. 2012;121:4-27.

PMid:22251135 PMCid:PMC3304021

Pekny M, Wilhelmsson U, Pekna M. The dual role of astrocyte activation and reactive gliosis. Neurosci Lett. 2014;565:30-8.


Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016; 131(6):803-20.


Clarke J, Butowski N, Chang S. Recent Advances in Therapy for Glioblastoma. Arch Neurol . 2010;67(3):279-83.


Wesolowski JR, Rajdev P, Mukherji SK. Temozolomide (Temodar). AJNR Am J Neuroradiol. 2010;31(8):1383-4.

PMid:20538821 PMCid:PMC7966084

Roy S, Lahiri D, Maji T, Biswas J. Recurrent Glioblastoma: Where we stand. South Asian J Cancer. 2015;4(4):163-73.

PMid:26981507 PMCid:PMC4772393

Wilson T, Karajannis M, Harter D. Glioblastoma multiforme: State of the art and future therapeutics. Surg Neurol Int . 2014;5:64.

PMid:24991467 PMCid:PMC4078454

Mathieu P, Adami PVM, Morelli L. Notch signaling in the pathologic adult brain. Biomol Concepts. 2013;4(5):465-76.


Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7(9):678-89.


Wang J, Yan Z, Liu X, Che S, Wang C, Yao W. Alpinetin targets glioma stem cells by suppressing Notch pathway. Tumour Biol. 2016;37(7):9243-8.


Liau BB, Sievers C, Donohue LK, Gillespie SM, Flavahan WA, Miller TE, et al. Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance. Cell Stem Cell. 2017;20(2):233-46.e7.

PMid:27989769 PMCid:PMC5291795

Jin Z, Zhan T, Tao J, Xu B, Zheng H, Cheng Y, et al. MicroRNA - 34a induces transdifferentiation of glioma stem cells into vascular endothelial cells by targeting Notch pathway. Biosci Biotechnol Biochem. 2017;81(10):1899-1907.


Kanamori M, Kawaguchi T, Nigro JM, Feuerstein BG, Berger MS, Miele L, et al. Contribution of Notch signaling activation to human glioblastoma multiforme. J Neurosurg. 2007;106(3):417-27.


Hulleman E, Quarto M, Vernell R, Masserdotti G, Colli E, Kros JM, et al. A role for the transcription factor HEY1 in glioblastoma. J Cell Mol Med. 2008;13(1):136-46.

PMid:18363832 PMCid:PMC3823042

Zhang X, Chen T, Zhang J, Mao Q, Li S, Xiong W, et al. Notch1 promotes glioma cell migration and invasion by stimulating β-catenin and NF-κB signaling via AKT activation. Cancer Sci. 2012;103(2):181-90.


Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9(3):157-73.


Somasundaram K, Reddy SP, Vinnakota K, Britto R, Subbarayan M, Nambiar S, et al. Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma. Oncogene. 2005;24(47):7073-83.


Nye JS, Kopan R, Axel R. An activated Notch suppresses neurogenesis and myogenesis but not gliogenesis in mammalian cells. Development. 1994;120(9):2421-30.


Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G, et al. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells . 2000;101(5):499-510.

Xing Z, Sun L, Guo W. Elevated expression of Notch-1 and EGFR induced apoptosis in glioblastoma multiforme patients. Clin Neurol Neurosurg . 2015;131:54-8.


Han N, Hu G, Shi L, Long G, Yang L, Xi Q, Guo Q, Wang J, Dong Z, Zhang M. Notch1 ablation radiosensitizes glioblastoma cells. Oncotarget. 2017;8(50):88059-68.

PMid:29152141 PMCid:PMC5675693

Demuth T, Berens ME. Molecular Mechanisms of Glioma Cell Migration and Invasion. J Neurooncol. 2004;70(2):217-28.


Zhai H, Heppner FL, Tsirka SE. Microglia/macrophages promote glioma progression. Glia . 2011;59(3):472-85.

PMid:21264953 PMCid:PMC3080032

Alterman RL, Stanley ER. Colony stimulating factor-1 expression in human glioma. Mol Chem Neuropathol. 1994;21(2-3):177-88.


Wang Z, Li Y, Banerjee S, Kong D, Ahmad A, Nogueira V, Hay N, Sarkar FH. Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-kappaB signaling pathways. J Cell Biochem. 2010;109(4):726-36.


Graziani I, Eliasz S, De Marco MA, Chen Y, Pass HI, De May RM, et al. Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway. Cancer Res. 2008;68(23):9678-85.


Yu HP, Qi ST, Feng WF, Zhang GZ, Zhang HP, Tian JJ. Interference of Notch 2 inhibits the progression of gliomas and induces cell apoptosis by induction of the cell cycle at the G0/G1 phase. Mol Med Rep. 2015;11(1):734-8.


Dell'Albani P, Rodolico M, Pellitteri R, Tricarichi E, Torrisi SA, D'Antoni S, et al. Differential patterns of NOTCH1-4 receptor expression are markers of glioma cell differentiation. Neuro Oncol. 2014;16(2):204-16.

PMid:24305720 PMCid:PMC3895382

Tchorz JS, Tome M, Cloëtta D, Sivasankaran B, Grzmil M, Huber RM, et al. Constitutive Notch2 signaling in neural stem cells promotes tumorigenic features and astroglial lineage entry. Cell Death Dis. 2012;3(6):e325.

PMid:22717580 PMCid:PMC3388237

Guo L-Y. Notch2 regulates matrix metallopeptidase 9 via PI3K/AKT signaling in human gastric carcinoma cell MKN-45. World J Gastroenterol. 2012;18(48):7262-70.

PMid:23326131 PMCid:PMC3544028

Hofmann JJ, Iruela-Arispe ML. Notch signaling in blood vessels: who is talking to whom about what?. Circ Res. 2007;100(11):1556-68.


Liu H, Zhang W, Kennard S, Caldwell RB, Lilly B. Notch3 Is Critical for Proper Angiogenesis and Mural Cell Investment. Circ Res. 2010;107(7):860-70.

PMid:20689064 PMCid:PMC2948576

Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML, Weinmaster G. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev. 2001;108(1-2):161-4.

Loomes KM, Taichman DB, Glover CL, Williams PT, Markowitz JE, Piccoli DA, et al. Characterization of Notch receptor expression in the developing mammalian heart and liver. Am J Med Genet. 2002;112(2):181-9.


Lindsell CE, Boulter J, diSibio G, Gossler A, Weinmaster G. Expression Patterns ofJagged, Delta1, Notch1, Notch2,andNotch3Genes Identify Ligand-Receptor Pairs That May Function in Neural Development. Mol Cell Neurosci. 1996;8(1):14-27.


Joutel A, Andreux F, Gaulis S, Domenga V, Cecillon M, Battail N, et al. The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest. 2000;105(5):597-605.

PMid:10712431 PMCid:PMC289174

Wang T, Baron M, Trump D. An overview of Notch3 function in vascular smooth muscle cells. Prog Biophys Mol Biol. 2008;96(1-3):499-509.


Alqudah MAY, Agarwal S, Al-Keilani MS, Sibenaller ZA, Ryken TC, Assem M. NOTCH3 Is a Prognostic Factor That Promotes Glioma Cell Proliferation, Migration and Invasion via Activation of CCND1 and EGFR. PLoS One. 2013;8(10):e77299.

PMid:24143218 PMCid:PMC3797092

Liu H, Kennard S, Lilly B. NOTCH3 Expression Is Induced in Mural Cells Through an Autoregulatory Loop That Requires Endothelial-Expressed JAGGED1. Circ Res. 2009;104(4):466-75.

PMid:19150886 PMCid:PMC2747310

Uyttendaele H, Marazzi G, Wu G, Yan Q, Sassoon D, Kitajewski J. Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development. 1996;122(7):2251-9.


Bolós V, Grego-Bessa J, de la Pompa JL. Notch Signaling in Development and Cancer. Endocr Rev. 2007;28(3):339-63.


Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch Signaling: Cell Fate Control and Signal Integration in Development. Science. 1999;284(5415):770-6.


Hanahan D, Folkman J. Patterns and Emerging Mechanisms of the Angiogenic Switch during Tumorigenesis. Cell. 1996;86(3):353-64.

Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3(6):401-10.


Sharma A, Shiras A. Cancer stem cell-vascular endothelial cell interactions in glioblastoma. Biochem Biophys Res Commun. 2016;473(3):688-92.


Williams CK, Segarra M, De La Luz Sierra M, Sainson RCA, Tosato G, Harris AL. Regulation of CXCR4 by the Notch Ligand Delta-like 4 in Endothelial Cells. Cancer Res. 2008;68(6):1889-95.


El Hindy N, Keyvani K, Pagenstecher A, Dammann P, Sandalcioglu IE, Sure U, et al. Implications of Dll4-Notch signaling activation in primary glioblastoma multiforme. Neuro Oncol. 2013;15(10):1366-78.

PMid:23787764 PMCid:PMC3779034

Li Z, Wang J, Gong L, Wen Z, Xu C, Huang X. Correlation of Delta-like ligand 4 (DLL4) with VEGF and HIF-1α expression in human glioma. Asian Pac J Cancer Prev. 2011;12(1):215-8.

Qiu X, Chen L, Wang C, Lin Z, Zhou C, Liu S, et al. High Delta-Like Ligand 4 (DLL4) Is Correlated With Peritumoral Brain Edema and Predicts Poor Prognosis in Primary Glioblastoma. Medicine (Baltimore). 2014;93(8):e57.

PMid:25121357 PMCid:PMC4602445

Qiu X, Wang C, Lin Z, You N, Wang X, Chen Y, et al. Correlation of high delta-like ligand 4 expression with peritumoral brain edema and its prediction of poor prognosis in patients with primary high-grade gliomas. J Neurosurg. 2015;123(6):1578-85.


Li J-L, Sainson RCA, Oon CE, Turley H, Leek R, Sheldon H, et al. DLL4-Notch Signaling Mediates Tumor Resistance to Anti-VEGF Therapy In Vivo. Cancer Res. 2011;71(18):6073-83.


Kenig S, Alonso MBD, Mueller MM, Lah TT. Glioblastoma and endothelial cells cross-talk, mediated by SDF-1, enhances tumour invasion and endothelial proliferation by increasing expression of cathepsins B, S, and MMP-9. Cancer Lett. 2010;289(1):53-61


Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK, et al. Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth. Cell. 2013;153(1):139-52.

PMid:23540695 PMCid:PMC3638263

Ridgway J, Zhang G, Wu Y, Stawicki S, Liang W-C, Chanthery Y, et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444(7122):1083-7.


Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006; 444(7122):1032-7.


Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, et al. Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci. 2007;104(9):3219-24.

PMid:17296940 PMCid:PMC1805530

R B, M H. Notch as a hub for signaling in angiogenesis. Exp Cell Res. 2013;319(9):1281-8.


Qiu X, Wang C, You N, Chen B, Wang X, Chen Y, et al. High Jagged1 expression is associated with poor outcome in primary glioblastoma. Med Oncol . 2015;32(1):341.


Jubb AM, Browning L, Campo L, Turley H, Steers G, Thurston G, et al. Expression of vascular Notch ligands Delta-like 4 and Jagged-1 in glioblastoma. Histopathology. 2012;60(5):740-7.


Zhang J, Chen Y, Qiu X, Tang W, Zhang J, Huang J, et al. The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study. Tumor Biol. 2016;37(3):3797-805.


Zheng Y, Lin L, Zheng Z. TGF- α induces upregulation and nuclear translocation of Hes1 in glioma cell. Cell Biochem Funct. 2008;26(6):692-700.


Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A. 2006;103(48):18261-6.

PMid:17114293 PMCid:PMC1838740

Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. Signalling downstream of activated mammalian Notch. Nature. 1995;377(6547):355-8.


Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev . 2006;20(15):2096-109.

PMid:16847353 PMCid:PMC1536060

Satoh Y, Matsumura I, Tanaka H, Ezoe S, Sugahara H, Mizuki M, et al. Roles for c-Myc in Self-renewal of Hematopoietic Stem Cells. J Biol Chem. 2004;279(24):24986-93.


Mongiardi MP. Angiogenesis and hypoxia in glioblastoma: a focus on cancer stem cells. CNS Neurol Disord Drug Targets . 2012;11(7):878-83.


Irshad K, Mohapatra SK, Srivastava C, Garg H, Mishra S, Dikshit B, et al. A Combined Gene Signature of Hypoxia and Notch Pathway in Human Glioblastoma and Its Prognostic Relevance. PLoS One. 2015;10(3):e0118201.

PMid:25734817 PMCid:PMC4348203

Chigurupati S, Venkataraman R, Barrera D, Naganathan A, Madan M, Paul L, et al. Receptor Channel TRPC6 Is a Key Mediator of Notch-Driven Glioblastoma Growth and Invasiveness. Cancer Res. 2010;70(1):418-27.


Bar EE, Lin A, Mahairaki V, Matsui W, Eberhart CG. Hypoxia Increases the Expression of Stem-Cell Markers and Promotes Clonogenicity in Glioblastoma Neurospheres. Am J Pathol. 2010;177(3):1491-502.

PMid:20671264 PMCid:PMC2928980

Das S, Marsden PA. Angiogenesis in glioblastoma. N Engl J Med. 2013;369(16):1561-3.

PMid:24131182 PMCid:PMC5378489

Rehman AO, Wang C-Y. Notch signaling in the regulation of tumor angiogenesis. Trends Cell Biol. 2006;16(6):293-300.


Li X, He X, Tian W, Wang J. Short hairpin RNA targeting Notch2 inhibits U87 human glioma cell proliferation by inducing cell cycle arrest and apoptosis in vitro and in vivo. Mol Med Rep. 2014;10(6):2843-50.

PMid:25323114 PMCid:PMC4227426

Liu Y, Shen Y, Sun T, Yang W. Mechanisms regulating radiosensitivity of glioma stem cells. Neoplasma . 2017;64(5):655-65.


Skinner HD, Zheng JZ, Fang J, Agani F, Jiang BH. Vascular endothelial growth factor transcriptional activation is mediated by hypoxia-inducible factor 1α, HDM2, and p70S6K1 in response to phosphatidylinositol 3-kinase/AKT signaling. J Biol Chem. 2004;279(44):45643-51.


Shukla S, MacLennan GT, Hartman DJ, Fu P, Resnick MI, Gupta S. Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer. 2007;121(7):1424-32.


Chen JS, Wang Q, Fu XH, Huang XH, Chen XL, Cao LQ, et al. Involvement of PI3K/PTEN/AKT/mTOR pathway in invasion and metastasis in hepatocellular carcinoma: Association with MMP-9. Hepatol Res. 2009;39(2):177-86.


Jiang BH, Liu LZ. Chapter 2 PI3K/PTEN Signaling in Angiogenesis and Tumorigenesis. Adv Cancer Res. 2009;102:19-65.

Liu P, Cheng H, Roberts TM, Zhao JJ. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627-44.

PMid:19644473 PMCid:PMC3142564

Xu Y, Yuan F-E, Chen Q-X, Liu B-H. Molecular mechanisms involved in angiogenesis and potential target of antiangiogenesis in human glioblastomas. Glioma. 2018;1(2):35.

Matsumura S, Oue N, Nakayama H, Kitadai Y, Yoshida K, Yamaguchi Y, et al. A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer. J Cancer Res Clin Oncol. 2005;131(1):19-25.


Valastyan S, Weinberg RA. Tumor metastasis: Molecular insights and evolving paradigms. Cell. 2011; 147(2):275-92.

PMid:22000009 PMCid:PMC3261217

Tian B, Li Y, Ji XN, Chen J, Xue Q, Ye SL, et al. Basement membrane proteins play an active role in the invasive process of human hepatocellular carcinoma cells with high metastasis potential. J Cancer Res Clin Oncol. 2005;131(2):80-6.


Wroblewski LE, Pritchard DM, Carter S, Varro A. Gastrin-stimulated gastric epithelial cell invasion: The role and mechanism of increased matrix metalloproteinase 9 expression. Biochem J. 2002;365(Pt 3):873-9.

PMid:11971760 PMCid:PMC1222716

Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Niwa H, et al. Expressions of MMP-2, MMP-9 and VEGF are closely linked to growth, invasion, metastasis and angiogenesis of gastric carcinoma. Anticancer Res. 2006;26(5A):3579-83.

Lee LY, Wu CM, Wang CC, Yu JS, Liang Y, Huang KH, et al. Expression of matrix metalloproteinases MMP-2 and MMP-9 in gastric cancer and their relation to claudin-4 expression. Histol Histopathol . 2008;23(5):515-21.

Pellikainen JM, Ropponen KM, Kataja V V., Kellokoski JK, Eskelinen MJ, Kosma VM. Expression of matrix metalloproteinase (MMP)-2 and MMP-9 in breast cancer with a special reference to activator protein-2, HER2, and prognosis. Clin Cancer Res . 2004;10(22):7621-8.


Hashimoto T, Wen G, Lawton MT, Boudreau NJ, Bollen AW, Yang GY, et al. Abnormal expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in brain arteriovenous malformations. Stroke . 2003;34(4):925-31.


Sakata K, Shigemasa K, Nagai N, Ohama K. Expression of matrix metalloproteinases (MMP-2, MMP-9, MT1-MMP) and their inhibitors (TIMP-1, TIMP-2) in common epithelial tumors of the ovary. Int J Oncol. 2000;17(4):673-81.


Endersby R, Baker SJ. PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene. 2008;27(41):5416-30.


Knobbe CB, Merlo A, Reifenberger G. Pten signaling in gliomas. Neuro Oncol . Narnia. 2002;4(3):196-211.

PMid:12084351 PMCid:PMC1920635

Koul D. PTEN Signaling pathways in glioblastoma. Cancer Biol Ther . Taylor & Francis. 2008 ;7(9):1321-5.


Okumura N, Yoshida H, Kitagishi Y, Murakami M, Nishimura Y, Matsuda S. PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis. Adv Hematol. 2012;2012:843085.

PMid:22505939 PMCid:PMC3299269

Nan Y, Guo L, Song Y, Wang L, Yu K, Huang Q, et al. Combinatorial therapy with adenoviral-mediated PTEN and a PI3K inhibitor suppresses malignant glioma cell growth in vitro and in vivo by regulating the PI3K/AKT signaling pathway. J Cancer Res Clin Oncol. 2017;143(8):1477-87.


Kessler T, Sahm F, Blaes J, Osswald M, Rübmann P, Milford D, et al. Glioma cell VEGFR-2 confers resistance to chemotherapeutic and antiangiogenic treatments in PTEN-deficient glioblastoma. Oncotarget. 2015;6(31):31050-68.

PMid:25682871 PMCid:PMC4741588

Han L, Zhang AL, Xu P, Yue X, Yang Y, Wang GX, et al. Combination gene therapy with PTEN and EGFR siRNA suppresses U251 malignant glioma cell growth in vitro and in vivo. Med Oncol. 2010;27(3):843-52.


Zhou X, Ren Y, Moore L, Mei M, You Y, Xu P, et al. Downregulation of miR-21 inhibits EGFR pathway and suppresses the growth of human glioblastoma cells independent of PTEN status. Lab Investig. 2010;90(2):144-55.


Wang J, Wang C, Meng Q, Li S, Sun X, Bo Y, et al. siRNA targeting Notch-1 decreases glioma stem cell proliferation and tumor growth. Mol Biol Rep. 2012;39:2497-503.


Hosseini MM, Karimi A, Behroozaghdam M, Javidi MA, Ghiasvand S, Bereimipour A, et al. Cytotoxic and Apoptogenic Effects of Cyanidin-3-Glucoside on the Glioblastoma Cell Line. World Neurosurg. 2017;108:94-100.


How to Cite
Shabani, M., Taghvaei Javanshir, H., Bereimipour, A., Ebrahimi Sadrabadi, A., Jalili, A., & Nayernia, K. (2021). Contradictory Effect of Notch1 and Notch2 on Phosphatase and Tensin Homolog and its Influence on Glioblastoma Angiogenesis. Galen Medical Journal, 10, e2091.
Review Article