By generating tumors in laboratory mice that mimic human liver cancer and by comparing the DNA of mouse and human tumors, researchers at Cold Spring Harbor Laboratory have identified two genes that are likely to play a role in the third leading cause of human cancer deaths. The study also establishes an efficient and adaptable method for exploring the biology of liver cancer, for validating potential therapeutic targets, and for testing new treatments. The findings are reported in the June 30 issue of the journal Cell.
Liver cancer ("hepatocellular carcinoma" or HCC) is the fifth most frequent neoplasm worldwide. However, owing to the lack of effective treatment options, it is the third leading cause of cancer deaths.
To gain a better understanding of the molecular causes of HCC, the researchers--led by Scott Lowe of Cold Spring Harbor Laboratory--devised a strategy for genetically engineering liver stem cells, harvested from mouse embryos, and subsequently transplanting the cells into adult mice. Following transplantation (by injection into the spleen), the cells can become part of the recipient mouse's liver.
Depending on the initial, genetically engineered makeup of the liver stem cells, and on genetic alterations that occur spontaneously after they are transplanted, the cells can have a high probability of forming tumors. Scanning the DNA of such tumors has the potential to uncover the relevant spontaneous genetic alterations and reveal the corresponding genes that, when altered, contribute to liver cancer.
In parallel with their analysis of the mouse liver tumors, the researchers scanned the DNA of human liver and other tumors. Remarkably, they found that a region of human chromosome 11 that is evolutionarily related to the segment of mouse chromosome 9 was amplified in several of the human tumors.
Additional experiments revealed that two genes--Yap and cIAP1--were both consistently overexpressed in both the mouse and human tumors. Thus, when produced at abnormally high levels, proteins encoded by the Yap and cIAP1 genes are likely to contribute significantly to human liver and other cancers.
The study also revealed that whereas producing either the Yap or the cIAP1 protein at an abnormally high level triggers tumor formation in mice, simultaneously overproducing both proteins dramatically accelerates tumor formation. Therefore, these proteins and others in the biochemical pathways they control are attractive candidates for the development of novel cancer therapies.
Illustrations: Available on request
Message posted by: Rashmi Nemade
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