Genetically engineered mouse models in cancer research.
Mouse models of human cancer have played a vital role in understanding tumorigenesis and answering experimental questions that other systems cannot address. Advances continue to be made that allow better understanding of the mechanisms of tumor development, and therefore the identification of better therapeutic and diagnostic strategies. We review major advances that have been made in modeling cancer in the mouse and specific areas of research that have been explored with mouse models. For example, although there are differences between mice and humans, new models are able to more accurately model sporadic human cancers by specifically controlling timing and location of mutations, even within single cells. As hypotheses are developed in human and cell culture systems, engineered mice provide the most tractable and accurate test of their validity in vivo. For example, largely through the use of these models, the microenvironment has been established to play a critical role in tumorigenesis, since tumor development and the interaction with surrounding stroma can be studied as both evolve. These mouse models have specifically fueled our understanding of cancer initiation, immune system roles, tumor angiogenesis, invasion, and metastasis, and the relevance of molecular diversity observed among human cancers. Currently, these models are being designed to facilitate in vivo imaging to track both primary and metastatic tumor development from much earlier stages than previously possible. Finally, the approaches developed in this field to achieve basic understanding are emerging as effective tools to guide much needed development of treatment strategies, diagnostic strategies, and patient stratification strategies in clinical research.
Walrath
Jessica C
JC
Mouse Cancer Genetics Program, National Cancer Institute, Frederick, Maryland, USA.
Hawes
Jessica J
JJ
Van Dyke
Terry
T
Reilly
Karlyne M
KM
D000818:Animals; D035843:Biomedical Research; D004195:Disease Models, Animal; D005818:Genetic Engineering; D006801:Humans; D051379:Mice; D009374:Neoplasms, Experimental / Q000175:diagnosis* / Q000628:therapy*
Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6232-6
1631115
J Clin Invest. 2006 Apr;116(4):847-52
16585951
Nucleic Acids Res. 2001 Feb 1;29(3):E10
11160912
Semin Cell Dev Biol. 2002 Oct;13(5):335-43
12324215
Nat Med. 2004 Feb;10(2):182-6
14704791
Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10625-30
17553957
Cell Host Microbe. 2009 Jul 23;6(1):5-9
19616761
Annu Rev Genet. 2008;42:131-41
18759635
Mol Ther. 2007 Jan;15(1):139-45
17164785
Ann Surg. 1972 Mar;175(3):409-16
5077799
Biochem Biophys Res Commun. 2008 Jun 27;371(2):267-72
18439910
Mamm Genome. 2008 Jun;19(6):390-3
18716834
Cell. 2005 Dec 16;123(6):1001-11
16360031
Mamm Genome. 2009 Apr;20(4):214-23
19347398
Cell. 2004 Aug 6;118(3):285-96
15294155
Nature. 2008 Dec 4;456(7222):593-8
19052619
Biochim Biophys Acta. 1996 May 16;1287(1):29-57
8639705
Invest Ophthalmol Vis Sci. 2008 Feb;49(2):522-7
18234994
Cancer Cell. 2005 May;7(5):411-23
15894262
Cancer Res. 2004 Sep 1;64(17):5973-81
15342376
Mamm Genome. 2008 Jun;19(6):382-9
18716833
Genome Res. 2003 Jan;13(1):118-21
12529314
Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8794-7
1528894
Transgenic Res. 2009 Feb;18(1):1-5
19002597
Nat Genet. 2000 Mar;24(3):221-5
10700173
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4501-5
17360553
Genesis. 2009 Feb;47(2):107-14
19165827
Nat Genet. 2005 Nov;37(11):1281-8
16200065
J Exp Med. 2001 Mar 19;193(6):727-40
11257139
Cancer Res. 2001 Dec 15;61(24):8866-72
11751410
J Virol. 1995 Aug;69(8):5095-102
7609078
Cancer Res. 2009 Oct 15;69(20):8150-6
19808965
Annu Rev Pathol. 2006;1:119-50
18039110
Nat Cell Biol. 2000 Oct;2(10):737-44
11025665
Nature. 2004 Sep 23;431(7007):405-6
15385993
Nat Rev Genet. 2008 Apr;9(4):277-90
18283275
Lab Invest. 2006 Dec;86(12):1203-7
17075578
Nat Genet. 2005 Oct;37(10):1055-62
16142231
Mol Cell. 2002 Jun;9(6):1327-33
12086629
Leuk Lymphoma. 2007 Apr;48(4):659-68
17454623
Cancer Cell. 2008 Feb;13(2):117-28
18242512
Cell. 2006 Aug 25;126(4):663-76
16904174
Science. 2009 Jun 12;324(5933):1457-61
19460966
Methods Mol Med. 2005;105:3-22
15492385
J Natl Cancer Inst. 2005 Jun 15;97(12):880-7
15956649
Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10380-5
15240889
Cancer Res. 2001 Mar 15;61(6):2395-8
11289103
Nature. 1985 Apr 18-24;314(6012):633-6
3990796
Cancer Res. 2008 Jun 1;68(11):4018-21
18519656
Nat Genet. 2004 Nov;36(11):1133-7
15514660
Nat Genet. 2003 Jan;33(1):49-54
12469122
Nat Rev Genet. 2005 Apr;6(4):271-86
15803197
Nature. 2002 Jan 31;415(6871):530-6
11823860
Nat Genet. 2004 Aug;36(8):867-71
15235602
Cold Spring Harb Symp Quant Biol. 2005;70:241-50
16869760
Science. 2002 May 3;296(5569):920-2
11988578
Genes Dev. 1999 Jun 1;13(11):1382-97
10364156
Breast Cancer Res. 2006;8(2):R16
16563182
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4245-6
17360508
Oncogene. 1999 May 13;18(19):3047-55
10378700
Cancer Res. 1999 May 1;59(9):2217-22
10232611
Genes Dev. 2001 Jun 15;15(12):1506-17
11410531
Cell. 1995 Jun 16;81(6):957-66
7781071
J Neurosci Res. 1996 Nov 15;46(4):456-64
8950705
Methods Mol Med. 2006;129:41-67
17085804
Endocr Relat Cancer. 2009 Sep;16(3):675-702
19525314
Mol Oncol. 2007 Dec;1(3):263-4; author reply 265-6
19383300
Cancer Cell. 2004 Jul;6(1):17-32
15261139
Curr Gene Ther. 2008 Dec;8(6):483-8
19075631
Nat Methods. 2005 Jan;2(1):27-30
15782166
J Natl Cancer Inst Monogr. 2008;(39):58-63
18648005
Nat Biotechnol. 2009 Mar;27(3):264-74
19234449
Nature. 2005 Jul 14;436(7048):221-6
16015321
Cell. 2006 Jun 30;125(7):1230-3
16814709
Cancer Cell. 2003 May;3(5):449-58
12781363
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3478-83
17360669
Nat Med. 2009 Sep;15(9):1010-2
19734877
Mamm Genome. 2008 Jun;19(6):379-81
18521666
Environ Health Perspect. 2003 Apr;111(4):444-54
12676597
J Clin Invest. 2009 Oct;119(10):3160-71
19770520
Genome Res. 2008 Oct;18(10):1670-9
18799693
Nat Genet. 2008 May;40(5):494-5
18443582
Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4495-500
17360552
Nature. 2001 Apr 26;410(6832):1111-6
11323676
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D557-9
14681480
Blood. 2008 Oct 15;112(8):3138-47
18684860
Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12111-6
17626182
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8483-8
10411901
Nature. 2000 Aug 10;406(6796):641-5
10949306
Cancer Cell. 2008 Jan;13(1):69-80
18167341
Ann Hum Genet. 1996 Sep;60(5):369-76
8912789
Trends Immunol. 2008 May;29(5):242-9
18372215
Nucleic Acids Res. 2004 Jan 1;32(Database issue):D523-7
14681473
Clin Exp Metastasis. 2005;22(7):593-603
16475030
Cell. 1990 Jun 29;61(7):1199-208
2163758
Regen Med. 2008 Mar;3(2):217-35
18307405
J Pathol. 2005 Jan;205(2):181-93
15641017
Glia. 2003 Jul;43(1):62-9
12761868
J Clin Invest. 2002 Sep;110(6):851-60
12235117
Cancer Res. 2009 Nov 1;69(21):8429-37
19843846
Oncogene. 1988 Aug;3(2):179-85
2842714
Cancer Cell. 2008 Jan;13(1):58-68
18167340
Cancer Cell. 2003 May;3(5):411-3
12781356
Trends Immunol. 2007 Nov;28(11):491-6
17964217
Nat Rev Genet. 2007 Jan;8(1):58-69
17173058
Cancer Res. 2006 Apr 1;66(7):3355-8, discussion 3358-9
16585152
Am J Hum Genet. 2005 Jul;77(1):1-15
15931593
Science. 2002 Sep 20;297(5589):2051-3
12242442
Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13212-7
16141338
EMBO J. 1989 Jan;8(1):133-6
2653809
Cell. 1997 Nov 14;91(4):501-10
9390559
Nat Rev Drug Discov. 2006 Sep;5(9):741-54
16915232
Semin Cancer Biol. 2007 Feb;17(1):19-30
17174104
Cancer Cell. 2002 Aug;2(2):149-55
12204535
Oncogene. 2002 Dec 9;21(56):8568-76
12476303
Nature. 2003 May 15;423(6937):255-60
12714970
Nat Protoc. 2009;4(7):1064-72
19561589
Cell. 1999 Oct 29;99(3):247-57
10555141
J Nucl Med. 2008 Jun;49 Suppl 2:164S-79S
18523072
Nat Genet. 1997 Sep;17(1):88-91
9288104
J Pathol. 2005 Jan;205(2):194-205
15641018
Science. 2003 Apr 18;300(5618):489-92
12702876
Cell. 1999 May 14;97(4):527-38
10338216
Circ Res. 2005 Jan 7;96(1):27-42
15637305
J Virol. 1995 Nov;69(11):7138-46
7474134
Cell. 1990 Jun 1;61(5):759-67
2188735
Cancer Res. 2006 May 1;66(9):4591-601
16651409
Cell. 2002 May 3;109(3):321-34
12015982
Adv Cancer Res. 2008;101:277-348
19055947
Nat Genet. 1997 Aug;16(4):397-401
9241281
Cold Spring Harb Symp Quant Biol. 2005;70:435-44
16869781
Medicine (Baltimore). 1993 Nov;72(6):393-406
8231788
Cell. 2007 Feb 23;128(4):683-92
17320506
J Clin Invest. 2004 Sep;114(5):623-33
15343380
Cancer Res. 1995 Nov 15;55(22):5184-6
7585570
Cell. 2005 Aug 12;122(3):473-83
16096065
Nat Rev Cancer. 2007 Sep;7(9):645-58
17687385
J Pathol. 1999 Jan;187(1):43-60
10341706
Biochim Biophys Acta. 1990 Dec 11;1032(2-3):213-35
2261495
Science. 1999 Feb 26;283(5406):1321-5
10037601
Cell. 1996 Jul 12;86(1):159-71
8689683
Cancer Res. 2002 Nov 15;62(22):6362-6
12438215
Expert Rev Anticancer Ther. 2008 Jun;8(6):853-64
18533795
Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5947-52
16585505
Cytogenet Genome Res. 2004;104(1-4):116-22
15162024
Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2002-7
8700875
Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547-51
1319065
Nature. 2005 Jul 14;436(7048):272-6
16015333
Dev Cell. 2004 Jan;6(1):7-28
14723844
Cell. 2008 Oct 31;135(3):437-48
18984156
Mol Cell Biol. 2004 Oct;24(20):8862-71
15456861
Nat Genet. 2007 Jul;39(7):914-21
17572676
Carcinogenesis. 2005 Mar;26(3):513-23
15358632
Environ Mol Mutagen. 1991;18(4):316-21
1836179
Science. 2003 Apr 18;300(5618):455
12702868
Cell. 2008 May 16;133(4):727-41
18485879
Genes Dev. 2006 Sep 15;20(18):2527-38
16980582
Clin Cancer Res. 2008 Jan 1;14(1):249-58
18172277
Pathol Int. 2008 Sep;58(9):544-58
18801069
Science. 1977 Aug 26;197(4306):893-5
887927
Cell Tissue Res. 2009 Jan;335(1):261-9
18766380
Curr Opin Biotechnol. 2005 Dec;16(6):681-6
16263256
Nature. 2003 May 15;423(6937):302-5
12714971
Mutat Res. 2005 Aug 25;576(1-2):4-21
16038709
Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1118-23
11158604
Nat Rev Genet. 2003 Sep;4(9):721-34
12951573
Mutat Res. 2000 Nov 20;455(1-2):191-215
11113476
Brief Funct Genomic Proteomic. 2007 Sep;6(3):180-5
17967808
Nat Rev Genet. 2005 Jun;6(6):507-12
15931173
Biotechniques. 2005 Aug;39(2):215-24
16116795
Breast Cancer Res. 2000;2(6):400-7
11250733
Cancer Res. 2006 Jan 1;66(1):62-8
16397217
Nat Genet. 2000 Sep;26(1):109-13
10973261
Cell. 1988 Sep 9;54(6):831-40
2842066
Development. 2000 Apr;127(8):1671-9
10725243
Oncogene. 2006 Sep 25;25(43):5885-97
16998503
Cancer Chemother Pharmacol. 2001 Aug;48 Suppl 1:S35-40
11587364
Trends Pharmacol Sci. 2004 Jun;25(6):337-42
15165750
Genetics. 2006 Mar;172(3):1783-97
16361245
EMBO J. 2006 Jul 26;25(14):3422-31
16858412
Semin Cell Dev Biol. 2002 Apr;13(2):143-9
12240599
Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13895-900
18779577
Nat Rev Cancer. 2006 Jan;6(1):24-37
16397525
Nat Genet. 1999 Jan;21(1):70-1
9916792
EMBO Rep. 2000 Aug;1(2):133-9
11265752
Nucleic Acids Res. 1997 Jul 15;25(14):2723-9
9207017
Methods Mol Biol. 2006;337:185-205
16929948
Leukemia. 2008 Aug;22(8):1503-18
18548105
Genes Dev. 1991 Sep;5(9):1513-23
1653172
Methods Mol Biol. 2009;530:49-77
19266329
Development. 2000 Apr;127(8):1607-16
10725237
Methods Mol Biol. 2004;256:183-98
15024167
Cell. 2002 Jan 25;108(2):135-44
11832204
Development. 2007 Feb;134(4):635-46
17215298
Proc Natl Acad Sci U S A. 2005 May 17;102(20):7221-6
15870191
Adv Cancer Res. 2002;85:13-50
12374284
Genome Res. 2006 Sep;16(9):1075-83
16899657
Proc Natl Acad Sci U S A. 1989 Oct;86(20):7971-5
2530578
Cell. 2004 Dec 17;119(6):861-72
15607981
Crit Rev Oncol Hematol. 2008 Mar;65(3):200-11
18389522
Cancer Cell. 2005 Aug;8(2):119-30
16098465
Toxicol Pathol. 2009 Jan;37(1):114-22
19098118
Methods. 2001 May;24(1):71-80
11327805
Clin Cancer Res. 2008 Dec 15;14(24):8027-41
19088019
Science. 1999 Dec 10;286(5447):2172-6
10591652
Cell. 1991 May 31;65(5):737-52
1904008
Brain Pathol. 2009 Jan;19(1):132-43
19076778
Am J Pathol. 1999 Feb;154(2):581-90
10027415
Mutat Res. 2008 Jul-Aug;659(1-2):15-30
18485806
Ann N Y Acad Sci. 1999;887:150-63
10668471
Stem Cell Rev. 2008 Sep;4(3):203-10
18595010
Proc Natl Acad Sci U S A. 2004 May 11;101(19):7347-51
15123829
Am J Pathol. 1996 Dec;149(6):1899-917
8952526
Genes Dev. 2001 Dec 15;15(24):3243-8
11751630
Trends Mol Med. 2002 Jul;8(7):346-53
12114115
Epigenetics. 2009 May 16;4(4):255-64
19550145
Nat Genet. 2004 Jun;36(6):543-4
15167922
Cancer Res. 2007 Aug 1;67(15):7059-61
17671171
Nat Rev Cancer. 2009 Jun;9(6):389-99
19461666
Adv Drug Deliv Rev. 2006 Aug 7;58(5-6):723-34
16876287
Nat Genet. 2000 Dec;26(4):424-9
11101838
Genetics. 2005 Feb;169(2):1133-46
15545647
Cancer Res. 1978 Mar;38(3):485-93
203382
Cell. 2006 Jun 30;125(7):1269-81
16814714
Mol Cell. 2004 Dec 22;16(6):861-5
15610730
Carcinogenesis. 2006 Oct;27(10):2133-9
16782971
J Cell Biol. 1992 Mar;116(6):1517-26
1541640
Hum Gene Ther. 2003 Aug 10;14(12):1193-206
12908970
Nature. 2007 Jun 21;447(7147):966-71
17515920
Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3346-51
8622939
N Engl J Med. 2005 Nov 10;353(19):2012-24
16282176
Genes Dev. 2008 Jun 15;22(12):1607-16
18559477
Cell. 1993 Nov 19;75(4):631-9
8242739
Eur J Cancer. 2004 Apr;40(6):852-7
15120041
Nat Rev Cancer. 2003 Jun;3(6):401-10
12778130
Proc Natl Acad Sci U S A. 2009 Oct 6;106(40):17169-74
19805158
Nature. 2004 Sep 23;431(7007):461-6
15329734
Int J Cancer. 1998 Aug 12;77(4):640-4
9679770
Development. 1996 Oct;122(10):3195-205
8898232
Cell. 2006 Jun 30;125(7):1253-67
16814713
EMBO Rep. 2000 Aug;1(2):127-32
11265751
Nat Med. 2009 Jan;15(1):110-6
19122659
J Neurooncol. 2000 Oct-Nov;50(1-2):89-98
11245284
J Clin Invest. 2009 Apr;119(4):964-75
19307726
Genetics. 1996 Dec;144(4):1769-76
8978062
Nat Protoc. 2009;4(2):206-23
19180090
J Virol. 1994 Jul;68(7):4358-68
7515971
Cancer Res. 2006 Apr 1;66(7):3351-4, discussion 3354
16585151
Clin Cancer Res. 2006 Sep 15;12(18):5305-11
17000663
Oncogene. 2005 Nov 21;24(52):7656-72
16299527
J Natl Cancer Inst. 2008 Dec 3;100(23):1672-94
19033571
Dis Model Mech. 2008 Sep-Oct;1(2-3):78-82
19048064
Contrib Microbiol. 2006;13:118-137
16627962
Cancer Res. 2003 Jun 15;63(12):3011-8
12810618
Clin Exp Metastasis. 2009;26(4):345-55
18787963
Nature. 2004 Sep 16;431(7006):343-9
15372041
Nature. 1998 Apr 9;392(6676):569-74
9560153
Science. 2009 Mar 27;323(5922):1747-50
19251594
Cold Spring Harb Symp Quant Biol. 2005;70:275-82
16869763
Nat Genet. 2008 May;40(5):650-5
18408720