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LOST MOLECULE IS LETHAL FOR LIVER CANCER CELLS IN MICE
-MicroRNA kills tumor cells, lets healthy cells live
June 11, 2009- Scientists at Johns Hopkins have discovered a potential strategy for cancer therapy by focusing on what’s missing in tumors.
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 these tiny regulators of genes to mice with liver cancer and found that tumor cells rapidly died while healthy cells remained unaffected.
Publishing results of the study June 12 in Cell, the researchers say they have provided one of the first demonstrations that microRNA replacement provides an effective therapy in an animal model of human disease.
On the left are two mouse livers that were treated with
the control virus; notice they are engulfed in tumors.
On the right are two mouse livers treated with the microRNA
virus; they show no tumors or significantly reduced tumors.
* click on image for higher resolution
“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, M.D., Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, 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.”
His team had considered the possibility that the replacement of a single small RNA might have little if any effect, especially in the setting of all the complex changes that drive the aberrant behavior of a cancer cell. But the tumor cells in the mouse were indeed sensitive to the restoration of the microRNA—so much so that they died, rapidly.
“This concept of replacing microRNAs that are expressed in high levels in normal tissues but lost in diseases hasn’t been explored before,” Mendell says. “Our work raises the possibility of a more general therapeutic approach that is based on restoring microRNAs to diseased tissues.”
The Hopkins team was building on precedent-setting research (published January 2008 in Nature Genetics) showing that in a Petri dish, 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.
The red dots in these photos indicate cancer cells
that are dying. The image on the left shows the
amount of cell death in a control-treated tumor and,
on the right, in a microRNA-treated tumor. Tumor
sections were stained with TUNEL, a marker for cells
undergoing programmed cell death.
* click on the image for high resolution
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. The viral delivery system was developed by Mendell’s father, Jerry Mendell, M.D., director of the Center for Gene Therapy at The Research Institute at Nationwide Children’s Hospital in Columbus, and K. Reed Clark, Ph.D., associate professor and director of the Viral Vector Core Facility at Nationwide Children’s Hospital.
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 said.
Equally intriguing, he reported, “The tumor cells that received the microRNA were rapidly dying while the normal liver cells were completely spared. These findings, as well as the results of specific tests for liver damage, demonstrated that the microRNA selectively kills the cancer cells without causing any detectable 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 very tolerant to therapeutic delivery of even higher levels of this microRNA. However, the sensitivity of tumor cells to this microRNA suggests that loss of this 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.
In addition to Joshua Mendell, authors of the paper are Jerry Mendell, K. Reed Clark, Janaiah Kota and Chrystal L. Montgomery, of The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio; and Raghu R. Chivukula, Kathryn A. O’Donnell, Erik A. Wentzel, Hun-Way Hwang, Tsung-Cheng Chang, Perumal Vivekanandan, and Michael Torbenson, all of Johns Hopkins University School of Medicine.
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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