notch and cancer

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

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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. - PowerPoint PPT Presentation

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  • Notch and CancerIPO-LISBOA CIPMAngiogenesis groupFrancisco CaiadoSrgio Dias

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

  • Cancer Hallmarks and Notch signalingTissue Invasion and MetastasisModulation of the Notch Signaling Pathway

  • Notch-Delta signaling pathwayRoca, 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 cancerOncogenic activity of NotchTumor supressor activity of NotchMaillard,I. and Pear, W. Cancer Cell 2003

  • De la Pompa et al. Endocrine Reviews 28(3):339363Abnormal Notch signaling and cancerTargeting Notch signaling:

    -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 signalingTissue Invasion and MetastasisModulation of the Notch Signaling Pathway

  • Tumor AngiogenesisHashizume, H.l NCR 2000Pro-angiogenic factors: VEGF, FGF, Neuropillin, Ang-2, MMPs

    Vessel stabilizing factors: Notch-Delta, PDGF-1, Ang-1, ECMs

  • Notch signaling and tumor angiogenesisRidgway, J. et al Nature 2006Thuston, G. et al NCR 2006

  • Post-natal vasculogenesisBone 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;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. 2006Caiado, F. et al Plos One 2008

  • Notch signaling inhibition impairs adhesion and integrin expressionCaiado, 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 Dll4Sub lethal irrad. NOD-SCID female Tumor growth; Tumor apoptosis; Vessel density; Vessel stability;

  • BM progenitors with reduced Dll4 decrease tumor proliferation and increase apoptosisReal, C Submited 2008

  • Vessel Density :BM progenitors with reduced Dll4 induce increased but non-functional vascularization Real, C Submited 2009

  • Notch signaling modulates BM-progenitor function during tumor angiogenesis 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 Remdio Missing); Dr.Antonio Duarte (group members), Dr.Yadgita Hideo (group members); FCT, GlaxoSmithKline, Fundao Calouste Gulbenkian;

    SaraCheilaA. GomesA. CachacoS DiasJacintaCristianaA. CostaCristinaCarlaTniaFranciscoAcknowledgments:

    *Genomic Instability: mechanism that allows higher mutations rates in pre-tumor cellsSelf-Sufficiency in growth signals: produce self growth factors; overexpress growth factor receptors; consitutively active growth factor receptors; downstream GF or integrin desregulation;Insensivity to anti-growth signals: induce a quiescent state (G0); induce post-mitotic differentiated state;Evading apoptosis: enhables mutations carrying cells to survive;Limitless replicative potencial: telomere maintenance; avoid senescence;Sustained angiogenesisTissue Invasion and Metastasis: epithelial to mesenchymal transition, integrin profile, protease profile

    Evolutionary conserved signaling pathway that envolves cell-cell interaction. Composed of receptors N1-4 and ligands Jagged 1,2 and Delta like-ligands 1,3,4. Receptors function as transcription factors upon ligand binding proteolitic cleavage of NICD wich translocates into the nucleus where it dislodges repressors(co-R) associated with the DNA-binding CSL transcription factor. NICD and CSL form a ternary complextogether with Mastermind (Mam) that recruits transcription factors activating target gene expression.

    Function (depends on cell/tissue context)Embryonic development: CNS, Somitogenesis, Cardiovascular, Endocrine Adult Self-Renewing organs: skin, intestine, bone-marrow*The result of altered Notch signaling depends on its normal function in a given tissue. Notch thus acts as an oncogene if its normal function is as a gatekeeper of stem cells or as a regulator of precursor cell fate; its tumor suppressor activityis detected in tissues in which Notch signaling initiates terminaldifferentiation events

    The oncogenic function of Notch is shown by the finding that truncated forms of all four Notch isoforms (Notch1- Notch 4), resulting in constitutively active Notch signaling, have transforming activity in vitro (203) an in various animal models (204 208);Furthermore, deregulated expression of wild-type Notch receptors, ligands, and targets is found in many human solid tumors (209, 210) and hematological malignancies;Notch alone may not be a very efficient oncogene, however, and it must associate with another oncoprotein to cause transformation; Although such partners have not yet been identified in naturally occurring tumors, transformation can be induced in vitro in various cell types by expressing NICD with certain oncoproteins.Available evidence thus suggests that, with the possible exception of some human epidermal malignancies, Notch signaling inhibition is a viable strategy for treatment of certain solid and hematopoietic tumors;mAbs that lock Notch receptors in an inactive conformation by binding to the negative regulatory region (NRR);GSI: good side cheap, oral availability, short activity (easy dosage); bad side low specificity, side effects (diarrhea caused by goblet cell metaplasia of the small intestine, The absence of myelotoxicity is welcome news in the setting of cancer chemotherapy. In mice, other adverse effects of systemic GSI treatment include reversible thymic suppression (Wong et al., 2004) and, in our hands, reversible hair depigmentation.

    Dll4 is expressed in tumor vessels;.Normal mice 3% of Lin- cells are Dll4 +, of these 10% are Sca1+ Flk-1+ and the remaining are sca flk negative.Hypoxic index: number of green cells;