u c s f comprehensive cancer center normal tissue tumor induction carcinogen gemm genetic background...
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UCSFComprehensive
Cancer Center
NormalTissue
Tumor inductionCarcinogenGEMM
GENETIC BACKGROUND
Heterogeneous mousepopulation
BenignTumor
InvasiveTumor
Metastasis Therapy Relapse
Exposure toCarcinogens, promoters
Modelling Human Cancer in the Mouse
Angiogenesis, stromal cellsImmune systemInflammation
Somatic mutations
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Cancer Center
Chemical carcinogen models
Radiation models
Lifestyle models
Susceptibility
Summary
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Cancer Center
Initiation
Promotion
Epidermal Cell
Initiated Cell
Benign Tumor
MetastaticTumor
MalignantTumor
Progression
DMBA TPA papilloma
Multistage skin carcinogenesis
Hras mutMutant Ras amplificationLoss of wt Ras
Invasion
Epithelial-mesenchymalTransition (EMT)
Metastasis
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HRAS NRAS KRAS
Breast 1/200 (~0%) 0/147 (0%) 11/270 (4%)
Large Intestine 2/501 (~0%) 11/404 (3%) 4283/13564 (32%)
Lung 7/1355 (1%) 21/1868 (1%) 1568/8427 (19%)
Melanoma 89/1585 (6%) 491/2702 (18%) 31/1288 (2%)
Pancreas 0/191 (0%) 4/215 (2%) 2637/4388 (60%)
Salivary Gland 22/111 (20%) 0/30 (0%) 1/45 (2%)
Ovary 0/94 (0%) 4/109 (4%) 209/1234 (17%)
Haematopoietic and lymphoid tissue
8/2345 (~0%) 756/6077 (12%) 204/3913 (8%)
Endometrium 4/293 (1%) 1/277 (~0%) 224/1548 (14%)
Ras Mutations in Human Cancer
Sanger Center COSMIC database (www.sanger.ac.uk/genetics/CGP/cosmic/)
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p c c c c c c c
normal
mutant
H-ras
CARCINOGEN-INDUCED H-RAS MUTATIONS IN SKIN TUMORS
Quintanilla et al
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H-ras and skin cancer
1. Skin tumors induced by the same carcinogen carry the same oncogene: H-ras
2. Skin tumors induced by DMBA have the same activating mutation in H-ras
3. Mutations occur early – at time of initiation
4. Amplification of mutant ras or loss of wild type ras occurs during progression
(circa 1982- 1986)
5. Tumours from F1 hybrid mice show preferential mutation of one parental allele
6. Some mouse strains are resistant to ras-initiated tumours.
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UrethaneDMBA
Lung Adenomas
90% K-ras mutations
Tissue-specific Ras mutations
Conclusions: H-ras is required for skin, and K-ras for lung tumors
Skin papillomas/carcinomas
90% H-ras mutations
TPA
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ATMAtaxia telangiectasia
BRCA1Familial breast and
ovarian cancerp53
Li-Fraumeni syndrome
NBS1-MRE11-RAD50Nijmegen breakage syndrome
Ataxia-telangiectasia-like disorderCDS1/CHK2
Li-Fraumeni syndrome
Cell-cycle checkpoints DNA repair
Double-stranded breaks in DNARadiation
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Mouse genetic models for radiation-induced cancers
4Gy
NO tumors
Kemp et al, p53 deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nature Genetics, 8(1):66-69 (1994)
P53+/-
LymphomasSarcomas
4Gy
Delta P p53m/m
Solid tumors
OR
Fbxw7+/-
4Gy
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0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 10 20 30 40 50 60 70 80 90 100
Age (weeks)
Pro
po
rtio
n o
f S
urv
ivin
g
Spon 129/Sv (52)
Rad 129/Sv (73)
p53+/- mice are extremely susceptible to radiation-induced tumorigenesis
Kemp et al, Nat.Genet, 1994
UCSFComprehensive
Cancer Center
0
0.2
0.4
0.6
0.8
1
0 10 20 30 40 50 60
Age (weeks)
Pro
port
ion
of T
umor
-Fre
e
(Spretus x 129/Sv)F1 (70)
(B6 x 129/Sv)F1(95)
129/Sv (73)
Genetic background affects radiation-induced lymphoma susceptibility
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Gct4
Genetic changes in radiation-induced tumors
0
10
20
30
40
70
50
60
80
90
7 8 9 10 11 121 2 3 4 5 6 13 14 15 16 17 18 19
PctmHcf2Hcs7Pas8
Pas6
Sluc3
Pas1
Sluc4
Par1
Lts1
Par2
Pas3
Sluc1
Hcs4
Hcr1Hcs5
Hcs1Skts1
Skts2
Skts3
Skts5
Skts11
Skts10
Hcs2
Hcr2
Hcs3
Hcs6
Scc3
Scc1
Scc2
Ccs1 Scc4
Scc5
Ssic1Mom1
Ter
Tli1
Tlag1
Tlsr2
Tlsm1
Foc1
Esl1
Msmr1
Esl1
Fv1
Rmcf
Fv2
Fv4
Rfv3Rfv1,2
Ril3
Rvil1
Lyr1
Ril1
Rmv1,2,3
Pctr1
Pctr2
Pctr1
Rrs
Sluc6
Sluc7
Sluc8
Sluc9
Sluc10
Skts6Pas6
Sluc11Sluc12
Sluc13
Hcf1Sluc14
Msmr2
Papg1
Par4
Liver
Liver
Ots1
Rgv1
Lyr2
Psl1
Skts8
Skts7
Skts12
Skts9
Scc7Ccs2
Pas9
Gct1
Skts4
Scc8Pas4
Scc9
Pas5b(Pas5)
Par3
Gct2
Scc6
Pgct1
Pas7
Tgct1
X
Skts13
Gct3
Foc1
Lyr3
Rfv3
Ikaros
STK15: Mitotic checkpoint
Fbxw7/Cdc4
Notch1
Myc
P53-dependent
HipK2 P53-independent
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The Circadian Clock
Fu and Lee, Nature Reviews Cancer, 2003
Clock genes and cancer?
Female shift workers have increasedRisk of breast and/or colon cancer
Mouse knockouts of Per2Have increased colon tumors andlymphoma
A polymorphism in human PER3 isAssociated with breast cancer
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Cancer Center
Ko, C. H. et al. Hum. Mol. Genet. 2006 15:R271-277R; doi:10.1093/hmg/ddl207
Control of the Mammalian Circadian Clock
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“GOOD PROGNOSIS” Breast cancer
Van’t Veer et al, 2002
NETWORK ANALYSIS OF HUMAN BREAST CANCER
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Aurora-A
Aurora-B
CyclinB
Blooms
Mitotic spindleprotein
Never-in mitosisGene a
cytokinesis
Mitotic spindle checkpoint
Anaphase spindleElongation 1
Mitotic-specificUbiquitin-conjugating
Spc25Kinetochore protein
UBE2T(Fanc)
PER3
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Per3Per3
Tumor suppressor genes on human 1p36 (mouse chr.4)
Chd5 Bagchi et alCell 2007Kif1b- Schlisio et al
Genes Dev. 2008
UCSFComprehensive
Cancer Center
0 5 10 15 200.0
0.2
0.4
0.6
0.8
1.0
Time (Years)
Dis
ea
se
Fre
e S
urv
iva
l
p= 0.0009
DFS at 10 years ± SE (%) 69 ± 3 vs. 56 ± 5
ALL PATIENTSN= 413
122
PER3 LOW
291
PER3 NORMAL/HIGH
39% RECURRENCE 27% RECURRENCE
P=0.013
LOW EXPRESSION OF PER3 IS ASSOCIATED WITHPOOR PROGNOSIS
Van de Vijver et al, NEJM 2002Chin et al Cancer Cell 2006
UCSFComprehensive
Cancer Center
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20
Time (Years)
Pro
bab
ility
of
Dis
ease
Fre
e S
urv
iva
l
p= 0.0003
74 ± 3 vs. 54 ± 5
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20
Time (Years)
Pro
bab
ility
of
Dis
ease
Fre
e S
urv
iva
l
p= 0.9
56 ± 5 vs. 57 ± 6
BUT ONLY IN ER-POSITIVE TUMORS
ER+ ER-
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Per3 null mice are susceptible to breast cancer
5 10 15 20 250.0
0.2
0.4
0.6
0.8
1.0
0
Time (Months)
Pro
babi
lity
of T
umor
Fre
e S
urvi
val
p= 0.003
B
0%
MMTV-neu per3
Genotype
05
10152025303540
WT (n=17) Het (n=33) Null (n=28)B
reas
t ca
nce
r in
cid
ence
(%
)
A
12%
36%p= 0.005
DMBA gavage
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