From Tumors to Therapy

Cancer-linked gene multiplies adult stem cells.

Tumors sprouting from mice may hold the secret to harvesting enough adult stem cells for medical treatment.

Researchers at MIT’s Whitehead Institute for Biomedical Research have found a gene that, when activated in mice, causes the production of so many adult stem cells that they aggregate into cancerous clumps. Activating and deactivating the same gene in stem cells that have been culled from humans may soon resolve one of the roadblocks to adult stem cell therapeutics: simply, how to grow enough of them to be useful for medical applications ranging from regrowing neurons to generating skin for burn victims.

Less than 1 percent of cells in any organ are adult stem cells, and it is extremely difficult to isolate these cells from the surrounding tissue. This means that researchers can get only a few at a time–not enough for therapeutic techniques, or even some experimental ones. Normally, researchers would just allow the cells to divide and thus multiply in a petri dish, but adult stem cells mature into their normal counterparts before this can happen.

“This is currently the biggest headache when it comes to using adult stem cells,” says Konrad Hochedlinger, a postdoctoral associate at Whitehead and the first author of the team’s paper, which was published in the May 6 issue of the journal Cell. Working with adult stem cells–even though they cannot form as many types of tissues as embryonic stem cells do–sidesteps the ethical issues of their embryonic analogues. However, it also means that the new methods of reproducing embryonic cells don’t apply.

A team led by Hochedlinger and biology professor Rudolf Jaenisch discovered that a gene called Oct-4 can stifle the adult stem cells’ maturation process. Oct-4 is normally active in embryonic cells, but eventually gets turned off to allow them to form into distinct organs. Also, misfired Oct-4 has been associated with some forms of testicular and ovarian cancer.

Putting two and two together, the team activated Oct-4 in a mouse and discovered that the resulting tumors in the rodent’s skin and intestines were actually the result of massive numbers of adult stem cells that wouldn’t stop dividing. Moreover, the team showed that Oct-4 could be turned off. When this happened, the adult cells quickly developed into normal cells and the tumors disappeared.

This probably won’t have cancer treatment applications, Hochedlinger says, because naturally occurring cancers involve much more complex reactions than simple Oct-4 activation does. However, the researchers are already beginning to use their knowledge to rapidly grow mouse adult stem cells in a petri dish.

Through this, they hope to understand the intricate expression of Oct-4 so that they can learn, among other things, how to activate Oct-4 for cell growth and then deactivate it so that the cells can be safely reinserted into the body, without the danger of tumor growth. The researchers expect to work with mice for another year or two before moving on to manipulating human cells. – By Stu Hutson

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