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Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias.

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Presentation on theme: "Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias."— Presentation transcript:

1 Notch and Cancer IPO-LISBOA CIPM Angiogenesis group Francisco Caiado Sérgio Dias

2 The Hallmarks of Cancer (Hanahan and Weinberg) Tissue Invasion and Metastasis

3 Cancer Hallmarks and Notch signaling Tissue Invasion and Metastasis Modulation of the Notch Signaling Pathway

4 Notch-Delta signaling pathway Roca, C. and Adams, R. Genes & Dev : 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

5 Abnormal Notch signaling and cancer Oncogenic activity of Notch Tumor supressor activity of Notch Maillard,I. and Pear, W. Cancer Cell 2003

6 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;

7 Cancer Hallmarks and Notch signaling Tissue Invasion and Metastasis Modulation of the Notch Signaling Pathway

8 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…

9 Notch signaling and tumor angiogenesis Ridgway, J. et al Nature 2006Thuston, G. et al NCR 2006

10 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

11 1. Notch signaling regulates BM- progenitor endothelial differentation? Markers: CD133+CD34+KDR+ Lin- Sca-1+ Flk-1+ Igreja, C. et al Exp. Hematol. 2006Caiado, F. et al Plos One 2008

12 Notch signaling inhibition impairs adhesion and integrin expression Caiado, F. et al Plos One 2008

13 2. BM-progenitor modulate endothelial activation via Notch signaling? Subcutaneous injection of human or mouse tumors Transplant of BM- progenitors control or with reduced Dll4 Sub – lethal irrad. NOD-SCID female Tumor growth; Tumor apoptosis; Vessel density; Vessel stability;

14 BM progenitors with reduced Dll4 decrease tumor proliferation and increase apoptosis C WT-EPC Dll4-EPC Days Tumor Volume (mm3) ControlwtEPCDll4+/-EPC Apoptosis index * ** Real, C Submited 2008

15 Vessel Density : Pericyte coverage : Hypoxic index : BM progenitors with reduced Dll4 induce increased but non-functional vascularization Real, C Submited 2009

16 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;

17 (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. Gomes A. Cachaco S Dias Jacinta Cristiana A. Costa Cristina Carla Tânia Francisco Acknowledgments:


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