Doctors have noticed for decades that people with Down Syndrome seldom develop cancers. Down Syndrome results from an extra copy of chromosome 21, leading scientists to wonder if something about that particular piece of the genome could protect against cancer. A few years ago, researchers at Johns Hopkins University tested that hypothesis. They added several different chromosome fragments from the mouse equivalent of human chromosome 21 to mice that are susceptible to colon tumors until they narrowed down its protective effect to just 33 genes– including one called Ets2.

Meanwhile, Dr. Robert Oshima and his team were already studying Ets2 and its role in breast cancer, where Ets2 does the opposite – it promotes tumor formation. Intrigued by the new and seemingly paradoxical findings in colon cancer, they started looking at mice bred to lack Ets2 only in intestinal cells.

“Our initial results were the complete opposite of what we expected,” says Dr. Jorge Múnera, former graduate student in the Oshima lab and now postdoctoral researcher in Dr. Hudson Freeze’s group. “Unlike what we saw in our breast cancer model, Ets2-deficient mice clearly had more colon tumors.”

It turns out that mice without intestinal Ets2 experienced a boost in cellular proliferation. They have more colon crypts (glands in the lower intestinal lining that aid digestion) and more cells dividing in the base of those crypts. The problem is that increased cell proliferation often means increased cancer risk. All this supports the hypothesis that Ets2 is needed to repress intestinal tumors. And it might help explain why people with more copies of the Ets2 gene – as in Down Syndrome – are more protected from colon cancer.

Drs. Oshima and Múnera attribute Ets2’s effect on cell proliferation to changes in stem cell number or behavior. Stem cells have two unique properties – they can either keep dividing to make more stem cells or specialize into a defined cell type. And since the intestinal lining constantly needs renewing, stem cells located at the crypt bottoms have the ability to specialize (differentiate) into new intestinal cells. Unfortunately, over-proliferation of these resident stem cells can also spark colon tumors.

In a paper published March 21 in the journal Stem Cells, Drs. Oshima and Múnera propose that Ets2 keeps colon stem cell proliferation in check, shifting the balance instead toward more differentiation. Dr. Oshima’s group is now beginning experiments to take a closer look at whether Ets2 acts directly on stem cells to influence their proliferation or function, or whether Ets2 works indirectly in another intestinal cell that in turn regulates stem cells.

Either way, Dr. Oshima sees this study as more supporting evidence for an unconventional type of cancer treatment called differentiation therapy. “If we can shift the balance to decrease stem cell proliferation and increase differentiation, we might be able to decrease tumor appearance or growth.”

New therapies for colon cancer would certainly be welcome – according to the National Cancer Institute, colorectal cancer is the third most common cancer and the third leading cause of cancer-related deaths in the United States.

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Original paper:
Múnera, J., Ceceña, G., Jedlicka, P., Wankell, M., & Oshima, R. (2011). Ets2 Regulates Colonic Stem Cells and Sensitivity to Tumorigenesis STEM CELLS, 29 (3), 430-439 DOI: 10.1002/stem.599