MicroRNA controls tissue-specific PTEN expression in brain cancer

Scientists at The University of Texas MD Anderson Cancer Center have found that primary tumor cells with otherwise normal expression of a tumor suppressor--PTEN--lose PTEN expression specifically in the brain but not in other organs.

The group, led by Dihua Yu, deputy chair of the Department of Molecular and Cellular Oncology, published its work last week in the journal Nature. The findings could be significant for the development of a novel antimetastasis therapy that targets advanced-stage brain cancer.

"Development of life-threatening cancer metastasis requires that tumor cells adapt to and evolve within drastically difference microenvironments of metastatic sites," said Yu. "Yet it is unclear when and how tumor cells acquire the essential traits in a foreign organ's microenvironment that lead to successful metastasis. Our study showed that primary tumor cells with normal PTEN expression lose PTEN expression when they reach the brain, but not in other organs."

They determined that the loss of PTEN expression in the brain was occurring because of microRNAs (miRNAs) that are released from exosomes secreted from astrocytes--star-shaped glial cells that are critical for nervous tissue function. MiRNAs are regulatory noncoding RNAs that influence gene expression and these are thought to control PTEN expression in the brain.

Muted expression of a tumor suppressor like PTEN is by no means a good thing, but what the group also showed was that a cytokine called CCL2 was secreted in parallel to a reduction in PTEN expression. This shows the detrimental effects of lowering PTEN expression since CCL2 is known to recruit microglial cells to the aggressive tumor cells, enhancing the tumor's likelihood of survival.

"Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumor cells in response to different organ environments, underpinning an essential role of co-evolution between the tumor cells and their microenvironment," said Yu. "This signifies the dynamic and reciprocal 'cross talk' between tumor cells and the metastatic environment. It may provide new opportunities for effective anti-metastasis therapies, particularly for advanced-stage brain cancer patients."

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