Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice
Zhenyi Liu, … , David R. Piwnica-Worms, Raphael Kopan
Zhenyi Liu, … , David R. Piwnica-Worms, Raphael Kopan
Published January 25, 2011
Citation Information: J Clin Invest. 2011;121(2):800-808. https://doi.org/10.1172/JCI43114.
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Research Article

Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice

Abstract

The role of the Notch signaling pathway in tumor development is complex, with Notch1 functioning either as an oncogene or as a tumor suppressor in a context-dependent manner. To further define the role of Notch1 in tumor development, we systematically surveyed for tumor suppressor activity of Notch1 in vivo. We combined the previously described Notch1 intramembrane proteolysis–Cre (Nip1::Cre) allele with a floxed Notch1 allele to create a mouse model for sporadic, low-frequency loss of Notch1 heterozygosity. Through this approach, we determined the cell types most affected by Notch1 loss. We report that the loss of Notch1 caused widespread vascular tumors and organism lethality secondary to massive hemorrhage. These findings reflected a cell-autonomous role for Notch1 in suppressing neoplasia in the vascular system and provide a model by which to explore the mechanism of neoplastic transformation of endothelial cells. Importantly, these results raise concerns regarding the safety of chronic application of drugs targeting the Notch pathway, specifically those targeting Notch1, because of mechanism-based toxicity in the endothelium. Our strategy also can be broadly applied to induce sporadic in vivo loss of heterozygosity of any conditional alleles in progenitors that experience Notch1 activation.

Authors

Zhenyi Liu, Ahu Turkoz, Erin N. Jackson, Joseph C. Corbo, John A. Engelbach, Joel R. Garbow, David R. Piwnica-Worms, Raphael Kopan

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Figure 2

N1::Crelo/fl mice developed vascular tumors.

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N1::Crelo/fl mice developed vascular tumors. (A) Kaplan-Meier survi...
(A) Kaplan-Meier survival analysis of 41 mutant and 45 control animals. Animals euthanized or alive at the time of analysis were censored (44 control and 26 mutant). (B) Summary of the major pathological findings from a comprehensive analysis of 13 pairs of control and mutant animals. Some animals developed hemangiomas in multiple tissues, making the tumor count greater than 13. The distribution of hemangiomas in different organs is further dissected (see Supplemental Table 1). (C–F) Representative images of spleen (C) and liver from N1::Crelo/+ (D) and N1::Crelo/fl animals (E and F). (E) Liver from a naturally deceased animal. (F) Liver from a euthanized N1::Crelo/fl animal, in which the tumors were still intact and filled with blood. (G–I) H&E liver sections from N1::Crelo/+ (G) and N1::Crelo/fl animals (H and I). See Results for details. (J–L) Immunostaining of liver tumor for PECAM (J), vWF (K), and PECAM and Ki67 (L). Inset in L shows the enlarged view of boxed area. Representative vascular tumors in other organs are shown in M (skin; H&E) and N (ovary; vWF). Scale bars: 50 μm; 10 μm (L, inset).