notch and cancer ipo-lisboa cipm angiogenesis group francisco caiado sérgio dias
TRANSCRIPT
![Page 1: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/1.jpg)
Notch and Cancer
IPO-LISBOA CIPM
Angiogenesis group
Francisco Caiado
Sérgio Dias
![Page 2: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/2.jpg)
The Hallmarks of Cancer (Hanahan and Weinberg)
Tissue Invasion
and Metasta
sis
![Page 3: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/3.jpg)
Cancer Hallmarks and Notch signaling
Tissue Invasion
and Metasta
sis
Modulation of the Notch Signaling Pathway
![Page 4: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/4.jpg)
Notch-Delta signaling pathway
Roca, C. and Adams, R. Genes & Dev. 2007 21: 2511-2524
• 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
![Page 5: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/5.jpg)
Abnormal Notch signaling and cancer
Oncogenic activity of Notch
Tumor supressor activity of Notch
Maillard,I. and Pear, W. Cancer Cell 2003
![Page 6: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/6.jpg)
De la Pompa et al. Endocrine Reviews 28(3):339–363
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;
![Page 7: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/7.jpg)
Cancer Hallmarks and Notch signaling
Tissue Invasion
and Metasta
sis
Modulation of the Notch Signaling Pathway
![Page 8: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/8.jpg)
Tumor Angiogenesis
Hashizume, H.l NCR 2000
Pro-angiogenic factors:
• VEGF, FGF, Neuropillin, Ang-2, MMPs…
Vessel stabilizing factors:
• Notch-Delta, PDGF-1, Ang-1, ECMs…
![Page 9: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/9.jpg)
Notch signaling and tumor angiogenesis
Ridgway, J. et al Nature 2006 Thuston, G. et al NCR 2006
![Page 10: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/10.jpg)
Post-natal vasculogenesis
Bone marrow (BM) derived progenitor cells:
• recruited during physiological and “malignant” angiogenesis;
• 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
![Page 11: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/11.jpg)
1. Notch signaling regulates BM-progenitor 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
![Page 12: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/12.jpg)
Notch signaling inhibition impairs adhesion and integrin expression
Caiado, F. et al Plos One 2008
![Page 13: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/13.jpg)
2. BM-progenitor modulate endothelial activation via Notch signaling?
Subcutaneous injection of human or mouse tumorsTransplant of BM-
progenitors control or with reduced Dll4
Sub – lethal irrad. NOD-SCID female
• Tumor growth;
• Tumor apoptosis;
• Vessel density;
• Vessel stability;
![Page 14: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/14.jpg)
BM progenitors with reduced Dll4 decrease tumor proliferation and increase apoptosis
C
WT-EPC
Dll4-EPC
0
2
4
6
8
10
12
0 14 18
22 26
Days
Tu
mo
r V
olu
me
(mm
3)
0102030405060
Control wtEPC Dll4+/-EPC
Ap
op
tosi
s in
dex *
**
Real, C Submited 2008
![Page 15: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/15.jpg)
Vessel
Density :
Pericyte coverage :
Hypoxic index :
BM progenitors with reduced Dll4 induce increased but non-functional vascularization
Real, C Submited 2009
![Page 16: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/16.jpg)
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;
![Page 17: Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias](https://reader030.vdocuments.mx/reader030/viewer/2022013011/56649cc25503460f9498ae37/html5/thumbnails/17.jpg)
•(2008/2009) Angiogenesis Lab members (Leonor Remédio Missing);• Dr.Antonio Duarte (group members), Dr.Yadgita Hideo (group members);• FCT, GlaxoSmithKline, Fundação Calouste Gulbenkian;
Sara
Cheila
A. GomesA. Cachaco
S Dias
Jacinta
Cristiana
A. Costa
Cristina
Carla Tânia
Francisco
Acknowledgments: