Notch and Cancer

IPO-LISBOA CIPM

Angiogenesis group

Francisco Caiado

Sérgio Dias

The Hallmarks of Cancer (Hanahan and Weinberg)

Tissue Invasion

and Metasta

sis

Cancer Hallmarks and Notch signaling

Tissue Invasion

and Metasta

sis

Modulation of the Notch Signaling Pathway

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

Abnormal Notch signaling and cancer

Oncogenic activity of Notch

Tumor supressor activity of Notch

Maillard,I. and Pear, W. Cancer Cell 2003

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;

Cancer Hallmarks and Notch signaling

Tissue Invasion

and Metasta

sis

Modulation of the Notch Signaling Pathway

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…

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 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

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

Notch signaling inhibition impairs adhesion and integrin expression

Caiado, F. et al Plos One 2008

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;

BM progenitors with reduced Dll4 decrease tumor proliferation and increase apoptosis

C

WT-EPC

Dll4-EPC

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0 14 18

22 26

Days

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Control wtEPC Dll4+/-EPC

Ap

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Real, C Submited 2008

Vessel

Density :

Pericyte coverage :

Hypoxic index :

BM progenitors with reduced Dll4 induce increased but non-functional vascularization

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;

•(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: