Notch and Cancer
IPO-LISBOA CIPM
Angiogenesis group
Francisco Caiado
Sérgio Dias
The Hallmarks of Cancer
(Hanahan and Weinberg)
Tissue
Invasion
and
Metastasis
Cancer Hallmarks and Notch signaling
Tissue
Invasion
and
Metastasis
Modulation of the Notch Signaling Pathway
Notch-Delta signaling pathway
• Regulates:
• establishment of patterns of gene
expression;
• cell differentiation;
• regulates binary cell fate choice;
• maintenance of stem cell populations;
• Function:
• Embryonic Development;
• Adult Self-Renewing Organs;
CANCER
Roca, C. and Adams, R. Genes & Dev. 2007 21: 2511-2524
Abnormal Notch signaling and
cancer
Oncogenic activity
of Notch
Maillard,I. and Pear, W. Cancer Cell 2003
Tumor supressor activity
of Notch
Abnormal Notch signaling and
cancer
Targeting Notch signaling:
• γ-secretase inhibitors (GSIs) are in
early clinical trials;
• mAbs targeting the ‘negative
regulatory region’ (NRR) of notch;
• mAbs that against DLL4 inhibit
Notch signaling in endothelial cells
and cause non-functional tumor
angiogenesis;
De la Pompa et al. Endocrine Reviews 28(3):339–363
Cancer Hallmarks and Notch signaling
Tissue
Invasion
and
Metastasis
Modulation of the Notch Signaling Pathway
Tumor Angiogenesis
Pro-angiogenic
factors:
• VEGF,
FGF,
Neuropillin, Ang-2,
MMPs…
Vessel
factors:
stabilizing
• Notch-Delta, PDGF1, Ang-1, ECMs…
Hashizume, H.l NCR 2000
Notch signaling and tumor
angiogenesis
Ridgway, J. et al Nature 2006
Thuston, G. et al NCR 2006
Post-natal vasculogenesis
Bone marrow (BM) derived progenitor
cells:
• recruited during physiological
“malignant” angiogenesis;
and
• BM mobilization; homing to angiogenic
sites (Integrins); invasion and migration;
• Induction of angiogenesis:
• Differentiation into endothelial cells;
• Activation of pre-existing
endothelial cells;
Notch signaling pathway?
Rafii, S. et al NCR 2002
1. Notch signaling regulates BMprogenitor endothelial differentation?
Markers:
CD133+CD34+KDR+
Lin- Sca-1+ Flk-1+
Igreja, C. et al Exp. Hematol. 2006
Caiado, F. et al Plos One 2008
Notch signaling inhibition impairs
adhesion and integrin expression
Caiado, F. et al Plos One 2008
2. BM-progenitor modulate endothelial
activation via Notch signaling?
Transplant of BMprogenitors control or
with reduced Dll4
Subcutaneous
injection of human or
mouse tumors
• Tumor growth;
• Tumor apoptosis;
• Vessel density;
Sub – lethal irrad.
NOD-SCID female
• Vessel stability;
BM progenitors with reduced Dll4 decrease
tumor proliferation and increase apoptosis
WT-EPC
Dll4-EPC
12
Apoptosis index
Tumor Volume (mm3)
C
10
8
6
4
2
0
0
Real, C Submited 2008
14
1
8
22
Days
26
**
60
50
40
30
20
10
0
*
Control
wtEPC
Dll4+/-EPC
BM progenitors with reduced Dll4 induce
increased but non-functional vascularization
Vessel
Density :
Pericyte
coverage :
Hypoxic index :
Real, C Submited 2009
Notch signaling modulates BM-progenitor
function during tumor angiogenesis
EPC
Activated endothelial cell
Endothelial cell
Apoptotic endothelial cell
Pericyte
Apoptotic pericyte
• Notch signaling regulates BM-progenitor cell endothelial differentiation;
• Dll4 expressed on BM-progenitor cells regulates endothelial stabilization
during tumor angiogenesis;
Acknowledgments:
S Dias
A. Gomes
A. Cachaco
Francisco
A. Costa
Cheila
Carla
Tânia
Cristina
Jacinta
Cristiana
Sara
•(2008/2009) Angiogenesis Lab members (Leonor Remédio Missing);
• Dr.Antonio Duarte (group members), Dr.Yadgita Hideo (group members);
• FCT, GlaxoSmithKline, Fundação Calouste Gulbenkian;