Cancer May Be Stopped In Its Tracks By MicroRNA Replacement Therapy

Main Category: Cancer / Oncology
Also Included In: Genetics;  Liver Disease / Hepatitis;  Lymphoma / Leukemia / Myeloma
Article Date: 13 Jun 2009 - 0:00 PDT

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A new study suggests that delivering small RNAs, known as microRNAs, to cancer cells could help to stop the disease in its tracks. microRNAs control gene expression and are commonly lost in cancerous tumors. Researchers have shown that replacement of a single microRNA in mice with an extremely aggressive form of liver cancer can be enough to halt their disease, according to a report in the June 12 issue of the journal Cell, a Cell Press publication.

They delivered the microRNA to the mice using a virus that has been applied in other forms of gene therapy. That so-called adeno-associated virus (AAV) is particularly good at targeting new genetic material to the liver.

"Mice given the control virus showed no change in the growth rate of their tumors and within three weeks, the cancer had taken over," said Joshua Mendell of Johns Hopkins University School of Medicine. "When we gave them the microRNA-carrying virus, some animals showed essentially complete regression of their tumors." In other cases, he said, the tumors were much smaller and far fewer.

Mendell said his team, which included his father Jerry Mendell at The Research Institute at Nationwide Children's Hospital, was hopeful the strategy would work based on previous evidence. Nonetheless, he added, "it is always surprising to see results this striking."

They were also amazed by how specifically the microRNA affected cancer cells, while leaving normal cells unscathed. "We found that the tumor cells are exquisitely sensitive [to microRNA replacement]--they not only stopped proliferating, but they actually died," he said. Meanwhile, the mice showed no evidence of any damage to their normal liver tissue.

MicroRNAs are important regulators of gene activity, the researchers explained, and a single microRNA can have far-reaching effects. That's because an individual microRNA can influence hundreds of gene transcripts to coordinate complex programs of gene expression and affect global changes in the physiology of a cell. A growing body of evidence shows that microRNAs are essential for normal development and to keep cells in balance. By the same token, when microRNAs get out of whack, they can lead to disease.

In the last five years, researchers have discovered a particularly important role for microRNAs in cancer. "Virtually all examined tumor types are characterized by globally abnormal microRNA expression patterns," Mendell said. Some microRNAs lead to cancer when they reach levels that are higher than normal. But in most instances, microRNA levels are found to decline in cancerous tumors compared to normal tissue.

Earlier studies have begun to suggest that methods to replace those lost microRNAs might hold particular promise for therapy. For one thing, reducing the level of microRNAs can actually drive the transformation of normal cells into cancerous ones. And, in the case of lymphoma, Mendell's group showed that a single microRNA could suppress the growth of cancer cells.

The new study is the first to show that the strategy might work in a living animal.

First, they showed that primary liver cancers, known as hepatocellular carcinomas (HCC), have a dramatic reduction in a specific microRNA designated as miR-26a. miR-26a is found at high levels in many tissues throughout the body. When they introduced the microRNA back into cancer cells, those cells stopped progressing through the cell cycle. Likewise, mice with the liver cancer that were given the virus-delivered microRNA therapy were protected from the disease as their cancer cells stopped proliferating and underwent a programmed cell death.

There is a dire need for new strategies to combat HCC, which the researchers said is the third leading cause of cancer deaths and the fifth most common malignancy worldwide. HCC is often diagnosed at an advanced and incurable stage. Even when it is caught earlier, other characteristics of the disease tend to make it a challenge to treat with currently available drugs.

The promising strategy for HCC is also likely to work in other cancers as well. The researchers chose mice with liver cancer as a test bed in part because the liver is readily targeted by AAV, but they said that they don't think there is anything special about liver cancer that makes it more sensitive to microRNA replacement therapy.

The barrier to applying this strategy to other tissues will rather be getting the microRNA into cancer cells, Mendell said. However, he noted, there are ways to deliver microRNA to other tissues using AAV and scientists are working on other vehicles for delivery -- synthetic nanoparticles, for instance -- that may just fit the bill.

The researchers include Janaiah Kota, The Research Institute at Nationwide Children's Hospital, Columbus, OH; Raghu R. Chivukula, Johns Hopkins University School of Medicine, Baltimore, MD; Kathryn A. O'Donnell, Johns Hopkins University School of Medicine, Baltimore, MD; Erik A. Wentzel, Johns Hopkins University School of Medicine, Baltimore, MD; Chrystal L. Montgomery, The Research Institute at Nationwide Children's Hospital, Columbus, OH; Hun-Way Hwang, Johns Hopkins University School of Medicine, Baltimore, MD; Tsung-Cheng Chang, Johns Hopkins University School of Medicine, Baltimore, MD; Perumal Vivekanandan, Johns Hopkins University School of Medicine, Baltimore, MD; Michael Torbenson, Johns Hopkins University School of Medicine, Baltimore, MD; K. Reed Clark, The Research Institute at Nationwide Children's Hospital, Columbus, OH, The Ohio State University, Columbus, OH; Jerry R. Mendell, The Research Institute at Nationwide Children's Hospital, Columbus, OH, The Ohio State University, Columbus, OH; and Joshua T. Mendell, Johns Hopkins University School of Medicine, Baltimore, MD.

Source:
Cathleen Genova
Cell Press