Tiny gene poses huge problem for cancer cells

JOHNS HOPKINS (US)—Scientists have discovered a potential strategy for cancer therapy by focusing on what’s missing in tumors rather than what’s there.

Noticing the conspicuous absence of single-stranded genetic snippets called microRNAs in cancer cells, a team of researchers from Johns Hopkins and Nationwide Children’s Hospital delivered the genes to mice with liver cancer and found that tumor cells rapidly died while healthy cells remained unaffected.

This is one of the first demonstrations that microRNA replacement is an effective therapy in an animal model, the researchers say in a study published in Cell.

“This work suggests that microRNA replacement may be a highly effective and nontoxic treatment strategy for some cancers or even other diseases,” says Josh Mendell, an associate professor in the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University School of Medicine. “We set out to learn whether tumors in a mouse model of liver cancer had reduced levels of specific microRNAs and to determine the effects of restoring normal levels of these microRNAs to these cancer cells.


“We were very excited to see that the tumors were, in fact, very vulnerable to microRNA replacement.”

Mendall says the idea of replacing microRNAs expressed in high levels in normal tissues but lost in diseases is a novel approach. “Our work raises the possibility of a more general therapeutic approach that is based on restoring microRNAs to diseased tissues.”

The Johns Hopkins team was building on previous work (published January 2008 in Nature Genetics) showing that replacing microRNAs in lymphoma cells stopped the formation of tumors when the cells were injected into mice.

The new study involves animals that develop liver tumors closely resembling the human disease. Researchers chose to target the liver because, according to Mendell, it is a large organ whose function is detoxification and, therefore, is a relatively accessible target for the delivery of small molecules, compared to other tissues.

Using a “special delivery” virus that can deliver genes to tissues without causing them any disease or harm, the researchers intravenously injected a fluorescent microRNA-containing virus into one group of mice with aggressive liver cancer, and injected a control virus containing no microRNA into another group.

After three weeks, six of eight mice treated with the control virus experienced aggressive disease progression with the majority of their livers replaced by cancerous tissue. In contrast, eight of 10 of animals treated with the microRNA were dramatically protected, exhibiting only small tumors or a complete absence of tumors. Liver body weight ratios were significantly lower in the treated mice, further documenting cancer suppression.

“The livers of the mice that received the microRNA virus glowed fluorescent green, showing that the microRNA ended up where it was supposed to go, and the cancer was largely suppressed,” Mendell says. Equally intriguing, he says, is the fact that while the tumor cells rapidly died, normal liver cells were completely spared, demonstrating that the microRNA selectively kills cancer cells, without causing toxic effects on the normal liver or other tissues.

Mendell points out that the microRNA is normally present at high levels in non-diseased tissues, and especially in the liver. Mendell speculates that this is why healthy cells are tolerant to therapeutic delivery of even higher levels of the microRNA. However, the sensitivity of tumor cells to the microRNA suggests that loss of the molecule is a critical step as normal cells become cancer cells.

“Since we were able to demonstrate such dramatic therapeutic benefit in this extremely aggressive model of human liver cancer, we are hopeful that similar strategies will be effective for patients with this disease,” says Mendell.

The research was supported by the National Institutes of Health, the Sol Goldman Center for Pancreatic Cancer Research, and the Research Institute at Nationwide Children’s Hospital.

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