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.

Generation of a murine hepatic angiosarcoma cell line and reproducible mouse tumor model

“…24 Especially in endothelial cells the Notch pathway has been associated with tumor suppressor functions. [13][14][15] Chronic Dll4 blockade as well as loss of Notch1 heterozygosity induce vascular tumor formation. 14,15 In line with these findings, we have recently reported that Notch1 acts as a tumor suppressor gene in LSECs.…”

“…[13][14][15] Chronic Dll4 blockade as well as loss of Notch1 heterozygosity induce vascular tumor formation. 14,15 In line with these findings, we have recently reported that Notch1 acts as a tumor suppressor gene in LSECs. 13 In our Notch1 KO mouse model, AS development occurs spontaneously over time.…”

“…[13][14][15] Present literature only describes the occurrence of AS but detailed molecular characterization of this tumor is lacking. A major drawback of the AS models (inducible Notch1 deletion/loss of Notch1 heterozygosity/ chronic DLL4 blockade) is the difficulty to predict tumor presence in individual animals.…”

Vascular-targeted agents for the treatment of angiosarcoma

“…DNA abnormalities in the Notch signalling pathway have been identified in a small series of angiosarcoma patients [151]. Interestingly, pan inhibition of Notch signalling resulted in liver sinusoidal endothelial cell proliferation, intussusceptive angiogenesis, and the formation of hepatic vascular abnormalities, including angiosarcomas, in vivo [152,153].…”

“…Studies have shown inhibition of Notch1 in mouse models leads to the formation of vascular tumours, including hepatic angiosarcomas [152,153], and the importance of Notch in branching morphogenesis and in regulating endothelial cell expression of receptors such as VEGFR2 and NRP1 [30], identifies an area worth further study. The be assessed in cell viability and cell differentiation assays.…”