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The newspaper of The Johns Hopkins University February 25, 2008 | Vol. 37 No. 23
In the Lab: Keeping At-Risk Cells From Developing Cancer

By Audrey Huang
Johns Hopkins Medicine

Researchers at Johns Hopkins have discovered that cancers arising from epigenetic changes — in this case, the inappropriate activation of a normally silent gene — develop by becoming addicted to certain growth factors.

Reporting online in the Dec. 11 Early Edition of the Proceedings of the National Academies of Sciences, the team shows that blocking this "addiction" can greatly prevent cancer growth.

"If this is translatable to people, it could be really exciting," said Andrew Feinberg, professor of medicine, oncology and molecular biology and genetics and director of the Epigenetics Center at Johns Hopkins. "It means we might be able to do something about at-risk cells before cancer develops, and treat these cells biochemically and specifically rather than using current drugs that are nonspecific and kill everything in their path."

The gene for growth factor IGF-II (insulin-like growth factor two) is one of several in the human genome that is controlled by imprinting — where one of the two copies of the gene is turned off, depending on which parent it came from. Normally, the IGF-II gene from your father is turned on and the one from your mother is turned off. Loss of this imprinting causes the activation of the maternal copy, leading to activation of both copies of the IGF-II gene, which has been associated with a fivefold increased frequency of intestinal tumors in people.

The Johns Hopkins team tested mouse cells with imprinting intact, meaning that they have only one copy of IGF-II activated, and compared them to cells that had lost imprinting and have both copies of IGF-II activated. They found that normally imprinted cells respond to normal doses of growth factor and recover within 90 minutes. However, cells that had lost imprinting were activated by the smallest doses and continued to stay activated for more than 120 minutes.

Andre Levchenko, an assistant professor of biomedical engineering at Johns Hopkins and co- director of the study, said, "It's like they were on a hair trigger, which was totally counterintuitive to what we might have predicted. You would expect in cells that have lost imprinting — and therefore have twice the amount of gene product — that it would take higher doses to activate the cell. In fact, the cell becomes hypersensitized while having too much IGF-II around."

The researchers then wondered if blocking the cells' response to IGF-II could block cancer growth in animals. Mice that develop colon cancer were given a drug that specifically blocks a cell's ability to respond to IGF-II. These mice developed 70 percent fewer precancerous lesions than mice without treatment.

"Finding the molecular mechanism behind cancer development allowed us to use a specific drug to actually take care of these risky cells before the animal developed cancer," Feinberg said. "It's making us think about cancer prevention in a whole new way."

The research was funded by the National Institutes of Health and the Swedish Cancer Research Foundation.

Authors on the paper are Atsushi Kaneda, Chiaochun Wang, Raymond Cheong, Winston Timp, Patrick Onyango, Bo Wen, Christine Iacobuzio-Donahue, Levchenko and Feinberg, all of Johns Hopkins; Rolf Ohlsson, of Uppsala University, Uppsala, Sweden; Rita Andraos and Mark Pearson, of Novartis Institute of Biomedical Research, Basel, Switzerland; and Alexei Sharov, Dan Longo and Minoru Ko, of the National Institute on Aging, Baltimore.


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