glioblastoma multiforme - columbia university · 2015-10-05 · glioblastoma multiforme" 3! 6!...
Post on 05-Jun-2020
1 Views
Preview:
TRANSCRIPT
Highly malignant, invasive, difficult-to-treat primary brain tumor""Frequency: 9,000 cases/year (peak age, 55–65 years)""Recurrence: rapid growth; size may double every 10 days""Median survival: ~ 1 year"
Glioblastoma Multiforme!
Kaplan-Meier Survival Curves!
100!90!80!70!60!50!40!30!20!10!0!
Months from Surgery!0!
Surv
ival
% !
Survival of adult patients with glioblastoma multiforme"
3! 6! 9! 12! 15! 18! 21! 24! 28! 32! 36! 40! 44!
Pediatric Brain Tumors"
Frequency : 3000 cases/year"
Pediatric brainstem glioma"
• Brainstem location represents 8-15% of all brain tumors in the pediatric population"
• Usually inoperable tumors because of the particular location in the brain "
Survival for Children with Diffuse Pontine Gliomas (CCG 9941)"
J Clin Oncol 20:3431-3437, 2002!
Tumor cells multiply which results in growth"
Normal growth is controlled"
Why do tumor cells grow?"
Tumor cells receive the instructions to grow but a r e i n s e n s i t i v e t o instructions to stop"
Blue: nucleus"
Green: nestin"Nestin: marker of stem cells"
Propagation of neural stem cells"
Differentiation of neural stem cells "in neurons and glia"
Blue: nucleus"
Green: GFAP"astrocytes"
Red: β-IIITub"neurons"
?"
?"
Brain development requires a controlled switch from proliferation to differentiation!
Stem Cells! Differentiated "neurons!
"
Disruption of pathways essential for neurogenesis have been implicated in childhood and adult brain cancers, for which immature progenitor cells have been proposed as cells-of-origin"
Neurogenesis and Brain tumors!
Undifferentiated state!
High growth potential!High amounts of Id proteins!
Differentiated state!
Low growth potential!Low amounts of Id proteins!
Id proteins: inhibitors of differentiation"
Iavarone and Lasorella, 2003
! No Id proteins!
CANNTG!E-box!
bHLH heterodimer!
Activation of" transcription"
and differentiation!
! Id proteins in functional excess!
E-box!
Inhibition of" transcription and"
block of differentiation!
Id2 !Id2 !
CANNTG!
Id proteins are antagonists "of transcription factors!
Id2 ! Id2 !
Rb! Id2!
IGF EWS-Ets
Myc
bHLH
S!
G2!M!
G1! p57Kip2!
The Rb-Id2-bHLH pathway in pediatric tumors!
Normal cells Cancer cells Cancer cells invade normal tissues
Id2 Rb!
Wild type Rb Id2 inactive
Rb! Id2!
Mutant Rb Id2 hyperactive
Id2-/-;Rb+/-!Rb+/-!
Microfil-orange "Latex perfusion "
Pecam-1"
Id2 loss impairs tumor growth and "angiogenesis in tumors from Rb+/- mice"
Id1" Id2" HIF1α#
Id proteins are coexpressed with HIF1α in human glioblastoma"
Time (months after diagnosis)!
Id2" positive, n=29"
Id2" negative, n=18"
P!=0.0046!
Overall study population!
0" 20" 40" 60" 80" 100" 120"0"
20"
40"
60"
80"
100"
Id2 overexpression in neuroblastoma" is associated with reduced survival!
Surv
ival
(per
cent
age)!
Id proteins involved in all processes associated with development of neural tumors!
Id
VEGF Signaling
Integrins, MMP2
Lineage Specific bHLH Rb, bHLH, Ets, Pax
Metalloproteinases
Id
Angiogenesis
Anaplasia Proliferation
Tissue Invasion
THE FUTURE : Anti Id2 therapeutics"
Differentiation!
Growth arrest!
Inhibition of angiogenesis!
Increased cell death!
Id2!Id2!Id2!
Id2!Id2!
Id2! Id2!
Id2!Id2!
Developmental lineages derived from the neural crest and the genesis of neuroblastoma"
?"
?"
Underlying challenge: how to control stem cells!
N-Myc!
Huwe1!
N-Myc!
Stem cell!
Glia!
Neuron!
Control brain tumor/neural stem cell behavior!
Huwe1F/Y! Huwe1F/YNes!Pax6/DAPI!Pax6/DAPI!
SVZ"
IZ"
SVZ"
IZ"
Loss of Huwe1 expands "the neural stem cell population"
βIII-tubulin/DAPI" βIII-tubulin/DAPI"
Nestin/DAPI" Nestin/DAPI"
50 µm!
Huwe1F/Y! Huwe1F/YNes!
Loss of Huwe1 impairs"neural stem cell differentiation"
Focal deletions and decreased expression of Huwe1 in GBM!
Normal brain !n=23!
GBM!n=77!!
P-value: 9.3E-10!
TCGA!
Oncomine!
Expression of Huwe1 is lost in primary neuroblastomas displaying accumulation
of N-Myc protein"
Huwe1!
#3524!
#3629!
N-Myc!
Lineage commitment Differentiation
Cell cycle arrest
Neural stem cell
Growth arrest Maturation
Tumor growth
Tumor stem cell
N-Myc N-Myc
N-Myc N-Myc
Huwe1
Growth factors
Huwe1
p27 CD2
Growth factors
Malignant gliomas invade the normal brain
The mesenchymal signature of high-grade glioma"Unsupervised clustering of 76 high grade tumors by expression of 108 genes
that are positively or negatively associated with survival reveals 3 tumors classes - Proneural (PN), Mesenchymal (Mes) and Proliferative (Prolif)."
Malignant(gliomas(belonging(to(the(mesenchymal(sub2class(express(genes(linked(to(the(most(aggressive(proper9es(of(glioblastoma((migra9on,(invasion(and(
angiogenesis)(and(mark(the(worst(clinical(outcome.(
The mesenchymal network of six major hubs "of transcription factors in high-grade gliomas"
Mesenchymal genes(Activator"Repressor"
Tau( SMA(
Vector"
Stat3C/CEBPβ
Stat3C/CEBPβ
Tau/SMA/Dapi"
βIIITubulin"
βactin"
Olig2!
Ctgf"
FN1"E" 10"5" E" 5" 10"
Vector" Stat3C/CEBPβ
STAT3 and C/EBPβ inhibit neuronal differentiation and induce mesenchymal
transformation in neural stem cells"
Vector"
Stat3C/CEBPβ"
Untreated" 20 days"
shCtr" shStat3" shC/EBPβ# shStat3+shC/EBPβ#
Knockdown of Stat3 and C/EBPβ cooperates to inhibit tumor cell invasion and angiogenesis"
shCtr"Vimen9n( Vimen9n(
10000(µm(
CD31( CD31(
T!
B!
T!
B!
shStat3+shC/EBPβ#
Human glioma-shStat3+shC/EBPβ#Human glioma-shCtr"100"
Cum
ulat
ive S
urviv
al"
Days post-injection"
80"
60"
40"
20"
0"120"80"60"40" 100"
**!
Loss of Stat3 and C/EBPβ in human glioma cells inhibits tumorigenesis in the mouse brain"
shCtr"
shStat3+shC/EBPβ#
The combined expression of Stat3 and C/EBPβ correlates with the poorest outcome of glioma patients"
Positive Stat3 + C/EBPβ "
Negative Stat3 + C/EBPβ "
STAT3
FOSL2
CEBPB
bHLH-B2
RUNX1
Stat3 and C/EBPβ are Master Regulators
ARACNe Regulatory Network Mesenchymal Signature Of High
Grade Glioma
Stat3 and C/EBPβ are Transforming Oncogenes of Neural Stem Cells
Stat3 and C/EBPβ are Predictors of Negative Clinical Outcome
Glioblastoma From systems biology to prognosis to personalized therapy"
top related