In the new research, Kopan and his colleagues engineered mice to develop random but progressive disruptions in the Notch1 gene in cells that depend on its signal. This model mimics a scenario that may occur in cancer patients receiving anti-Notch therapies for extended time periods.
Then, the researchers monitored the mice for any potential negative consequences and compared the outcomes of 41 mutant mice to 45 normal "control" mice.
Within several months, the experimental mice developed opaque corneas, which were already known to be associated with a loss of Notch1 signaling.
Otherwise, for more than a year, the genetically engineered mice appeared to grow and develop normally. Then, for no apparent reason, they started dying suddenly.
The researchers conducted autopsies on 13 pairs of experimental and control mice. They noted vascular tumors and/or abnormal collections of blood vessels called hemangiomas in 85 percent (11/13) of the mutant mice, primarily in the liver. Some of the mice developed additional tumors in the uterus, colon, lymph nodes, skin, ovary and testis.
None of the control animals developed vascular tumors or hemangiomas. On average, the experimental mice lived 420 days compared with 600 days for the control mice.
"It is highly unlikely that mice in the experimental group would randomly die so soon," Kopan explains. "When we examined the mice, we found evidence of ruptured blood vessels and pooling of blood in their body cavities along with an odd-looking liver pathology."
The investigators then conducted MRI scans on living experimental mice. They noted that their livers had holes that looked "like a big Swiss cheese instead of having a dense, reddish, featureless landscape," Kopan says. "This is highly abnormal."
All the evidence pointed to abnormalities in the endothelial
|Contact: Caroline Arbanas|
Washington University School of Medicine