Epidermal growth factor receptor in glioma: signal transduction, neuropathology, imaging, and radioresistance.
Aberrant epidermal growth factor receptor (EGFR) signaling is common in cancer. Increased expression of wild type and mutant EGFR is a widespread feature of diverse types of cancer. EGFR signaling in cancer has been the focus of intense investigation for decades primarily for two reasons. First, aberrant EGFR signaling is likely to play an important role in the pathogenesis of cancer, and therefore, the mechanisms of EGFR-mediated oncogenic signaling are of interest. Second, the EGFR signaling system is an attractive target for therapeutic intervention. EGFR gene amplification and overexpression are a particularly striking feature of glioblastoma (GBM), observed in approximately 40% of tumors. GBM is the most common primary malignant tumor of the central nervous system in adults. In approximately 50% of tumors with EGFR amplification, a specific EGFR mutant (EGFRvIII, also known as EGFR type III, de2-7, Delta EGFR) can be detected. This mutant is highly oncogenic and is generated from a deletion of exons 2 to 7 of the EGFR gene, which results in an in-frame deletion of 267 amino acids from the extracellular domain of the receptor. EGFRvIII is unable to bind ligand, and it signals constitutively. Although EGFRvIII has the same signaling domain as the wild type receptor, it seems to generate a distinct set of downstream signals that may contribute to an increased tumorigenicity. In this review, we discuss recent progress in key aspects of EGFR signaling in GBM, focusing on neuropathology, signal transduction, imaging of the EGFR, and the role of the EGFR in mediating resistance to radiation therapy in GBM.
Hatanpaa
Kimmo J
KJ
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Burma
Sandeep
S
Zhao
Dawen
D
Habib
Amyn A
AA
D000328:Adult; D001932:Brain Neoplasms / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000532:radiotherapy; D003952:Diagnostic Imaging / Q000379:methods*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005910:Glioma / Q000175:diagnosis / Q000209:etiology / Q000235:genetics / Q000532:radiotherapy; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy / Q000379:methods; D050505:Mutant Proteins / Q000235:genetics / Q000502:physiology; D011836:Radiation Tolerance / Q000235:genetics* / Q000502:physiology; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D050505:Mutant Proteins; D019275:Radiopharmaceuticals; D066246:ErbB Receptors
Mol Cell Biol. 2003 Mar;23(6):2068-82
12612079
Brain. 2007 Oct;130(Pt 10):2596-606
17785346
Curr Opin Cell Biol. 1999 Aug;11(4):483-8
10449328
Exp Cell Res. 2003 Mar 10;284(1):78-88
12648467
Cancer Res. 2006 Nov 15;66(22):10815-23
17090523
Eur J Nucl Med Mol Imaging. 2007 Jun;34(6):850-8
17262214
Radiat Oncol Investig. 1997;5(4):180-6
9327497
Am J Pathol. 2000 Feb;156(2):425-32
10666371
Cancer Res. 2004 Nov 15;64(22):8292-8
15548697
Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8600-5
16361543
Cancer Res. 2001 Feb 1;61(3):1122-8
11221842
Cancer Cell. 2004 Nov;6(5):447-58
15542429
J Neuropathol Exp Neurol. 1998 Jul;57(7):684-9
9690672
Mol Cancer Ther. 2006 Feb;5(2):209-18
16505093
Acta Neuropathol. 1998 Oct;96(4):322-8
9796995
Cancer Res. 2007 Apr 15;67(8):3809-17
17440095
Oncogene. 1989 Jul;4(7):831-8
2755700
J Neurooncol. 2002 Jul;58(3):217-36
12187957
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6505-10
12734385
DNA Repair (Amst). 2006 Sep 8;5(9-10):1042-8
16822724
Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7727-31
8052651
Cancer Res. 1996 Nov 1;56(21):5079-86
8895767
Cancer Res. 2005 Oct 1;65(19):8679-89
16204036
Eur J Nucl Med Mol Imaging. 2008 Jan;35(1):186-208
17846765
Cancer. 1991 May 1;67(9):2342-9
1849447
J Neurosurg. 2009 Aug;111(2):211-8
19301967
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3775-80
16537454
Science. 2009 May 8;324(5928):804-7
19423828
Int J Radiat Biol. 2007 Nov-Dec;83(11-12):781-91
18058366
Nat Rev Cancer. 2006 Nov;6(11):876-85
17036041
Cancer Res. 2007 Jun 1;67(11):5267-74
17545606
Clin Cancer Res. 2004 May 1;10(9):3216-24
15131063
Clin Cancer Res. 2008 Jan 1;14(1):199-208
18172271
PLoS One. 2009 Aug 06;4(8):e6539
19657384
Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):966-71
14967457
Clin Cancer Res. 2004 Oct 1;10(19):6476-86
15475435
Arch Pathol Lab Med. 2005 May;129(5):624-31
15859633
J Biol Chem. 2004 Aug 6;279(32):33085-92
15159408
J Neuropathol Exp Neurol. 2004 Jul;63(7):700-7
15290895
Mol Cancer Res. 2005 Oct;3(10):541-51
16254188
Cancer Res. 1991 Apr 15;51(8):2164-72
2009534
Cancer Res. 2009 May 15;69(10):4252-9
19435898
Lab Invest. 1999 Feb;79(2):123-9
10068201
J Neuropathol Exp Neurol. 2001 Sep;60(9):863-71
11556543
Oncogene. 2003 Aug 28;22(36):5545-53
12944901
Cancer Res. 2002 Jun 15;62(12):3335-9
12067969
Oncogene. 2000 Dec 27;19(56):6550-65
11426640
Biochim Biophys Acta. 1996 Nov 8;1314(1-2):147-56
8972728
Neuro Oncol. 2009 Dec;11(6):833-41
19332771
Proc Natl Acad Sci U S A. 1998 May 12;95(10):5724-9
9576951
Oncogene. 2002 Aug 1;21(33):5038-46
12140754
Cancer Res. 2002 Dec 15;62(24):7350-6
12499279
Oncogene. 2004 Aug 12;23(36):6095-104
15221011
J Biol Chem. 2007 Jul 20;282(29):21206-12
17513297
Brain Pathol. 2004 Apr;14(2):131-6
15193025
Arch Pathol Lab Med. 2007 Oct;131(10):1585-90
17922598
Neoplasia. 2005 Aug;7(8):717-22
16207473
Acta Neuropathol. 2007 Aug;114(2):97-109
17618441
Radiother Oncol. 2005 Aug;76(2):157-61
16024112
Oncogene. 2004 Feb 19;23(7):1448-56
14973554
Cancer Cell. 2007 Jan;11(1):83-95
17222792
Nat Clin Pract Oncol. 2006 Apr;3(4):170-1
16596125
N Engl J Med. 2005 Nov 10;353(19):1997-9
16282174
Biochem J. 1997 Jun 15;324 ( Pt 3):855-61
9210410
FEBS Lett. 2001 Feb 16;490(3):142-52
11223029
Ann Oncol. 2009 Feb;20(2):213-26
18842614
Clin Cancer Res. 2003 Sep 15;9(11):4247-54
14519652
Clin Cancer Res. 1999 Oct;5(10):2884-90
10537357
Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2965-9
1557402
Neuro Oncol. 2005 Apr;7(2):122-33
15831231
DNA Repair (Amst). 2004 Aug-Sep;3(8-9):909-18
15279776
Clin Cancer Res. 2004 Jan 1;10(1 Pt 1):228-33
14734474
N Engl J Med. 2009 Sep 3;361(10):958-67
19692684
J Biol Chem. 1997 Jan 31;272(5):2927-35
9006938
Cancer. 2004 Nov 15;101(10):2318-26
15470710
Am J Pathol. 2007 May;170(5):1445-53
17456751
Int J Cancer. 1998 Feb 9;75(4):626-34
9466667
Mol Cancer Ther. 2008 Jul;7(7):1772-81
18644989
Biochim Biophys Acta. 2001 Feb 5;1538(1):1-9
11341977
J Biol Chem. 1998 Jan 16;273(3):1568-73
9430697
J Neuropathol Exp Neurol. 2001 Nov;60(11):1099-104
11706939
J Neurooncol. 2003 Jul;63(3):247-56
12892230
Cancer Res. 2003 Jan 15;63(2):413-6
12543796
Cancer Lett. 2006 Nov 18;243(2):145-59
16530325
J Cell Biol. 1988 Aug;107(2):801-10
3262110
Cancer Res. 2006 Jan 15;66(2):867-74
16424019
Genes Dev. 1998 Dec 1;12(23):3675-85
9851974
Oncogene. 1997 Sep 4;15(10):1191-7
9294612
Cancer Res. 2002 Aug 15;62(16):4671-7
12183424
Oncogene. 2005 Nov 14;24(50):7455-64
16288292
Cancer Res. 1987 Jul 15;47(14):3847-50
3594441
J Biol Chem. 1990 May 15;265(14):7709-12
2186024
Mol Cancer Res. 2009 Jul;7(7):1000-12
19584260
Cancer Res. 2009 Oct 1;69(19):7548-56
19773446
Science. 2004 Jun 4;304(5676):1497-500
15118125
Cancer Res. 2006 Feb 15;66(4):2116-28
16489012
Lancet Oncol. 2006 May;7(5):359-60
16648038
Mol Cancer Res. 2005 Apr;3(4):237-49
15831677
JAMA. 2005 Feb 16;293(7):855-62
15713776
Cancer Biol Ther. 2009 Apr;8(8):730-8
19252415
Mol Cell Neurosci. 2003 Dec;24(4):1116-30
14697673
Small. 2009 Feb;5(2):235-43
19089838
Mol Imaging Biol. 2006 Sep-Oct;8(5):262-77
16897320
J Nucl Med. 2005 Nov;46(11):1881-8
16269603
J Biol Chem. 2005 Sep 2;280(35):31182-9
16000298
J Nucl Med. 2009 Feb;50(2):274-83
19164241
Brain Pathol. 2000 Apr;10(2):249-59
10764044
Nat Cell Biol. 2007 May;9(5):493-505
17450133
Cancer Res. 2003 Jun 1;63(11):2742-6
12782577
J Natl Cancer Inst. 2001 Aug 15;93(16):1246-56
11504770
J Biol Chem. 1990 Sep 15;265(26):15713-23
1975591
Mol Biol Cell. 1999 Aug;10(8):2493-506
10436007
Hum Reprod. 2005 Apr;20(4):852-63
15705628
Cancer Res. 2003 Oct 15;63(20):6962-70
14583498
J Biomed Opt. 2007 Mar-Apr;12(2):024017
17477732
J Neuropathol Exp Neurol. 2004 Mar;63(3):210-22
15055445
Oncogene. 1996 Jul 4;13(1):85-96
8700557
Cancer Cell. 2008 May;13(5):379-80
18455120
Curr Pharm Des. 2008;14(28):2983-98
18991714
Cancer Res. 2003 Nov 15;63(22):7870-5
14633715
Oncogene. 2002 Jun 6;21(25):4032-41
12037685
J Biol Chem. 1998 Jan 2;273(1):200-6
9417065
J Neurooncol. 1997 Dec;35(3):303-14
9440027
Oncogene. 1993 Apr;8(4):1017-22
8455929
J Clin Oncol. 2006 Dec 1;24(34):5419-26
17135643
Cancer Res. 2006 Oct 1;66(19):9601-8
17018617
Mol Cancer Res. 2003 Jan;1(3):219-33
12556561
Science. 1991 Nov 22;254(5035):1146-53
1659742
Cancer Res. 2002 Nov 15;62(22):6764-9
12438278
J Clin Oncol. 2008 Dec 1;26(34):5603-9
18955445
Carcinogenesis. 2005 Jul;26(7):1224-32
15760917
Cell Growth Differ. 1995 Oct;6(10):1251-9
8845302
J Neurosci. 2008 Jun 4;28(23):5870-8
18524891
Sci Signal. 2009 Sep 08;2(87):re6
19738203
Cancer Res. 2001 Mar 1;61(5):2301-6
11280802
N Engl J Med. 2004 May 20;350(21):2129-39
15118073
Proc Natl Acad Sci U S A. 2008 Jun 3;105(22):7785-90
18505846
N Engl J Med. 1980 Oct 9;303(15):878-80
7412807
N Engl J Med. 2005 Nov 10;353(19):2012-24
16282176
Br Med Bull. 1991 Jan;47(1):87-98
1863851
Brain Pathol. 1996 Jul;6(3):217-23; discussion 23-4
8864278
Clin Cancer Res. 2006 Dec 15;12(24):7261-70
17189397
Cancer Cell. 2009 Jul 7;16(1):9-20
19573808
Radiat Res. 1996 Jan;145(1):81-5
8532841
Oncogene. 2004 Jun 3;23(26):4594-602
15077177
Oncogene. 2006 Nov 2;25(52):6986-96
16715132
Neuro Oncol. 2009 Jun;11(3):274-80
18981259
Mol Cell. 2008 Apr 25;30(2):203-13
18439899
J Nucl Med. 2009 Feb;50(2):303-8
19164239
J Biol Chem. 1996 Oct 11;271(41):25639-45
8810340
Clin Cancer Res. 2005 Feb 15;11(4):1462-6
15746047