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Astrocyte-Derived Exosomal miRNA Induces Loss of PTEN Gene Expression in Brain & Primes Brain Tumor Metastasis; More Evidence for Dynamic and Reciprocal Cross-Talk Between Tumor Cells and Metastatic Environment

It’s no surprise that people enjoy warm places like Hawaii, but may suffer in hostile locales such as Antarctica. A tumor suppressor gene called PTEN is similar in that it is affected by the microenvironments of certain bodily organs in which it finds itself. Scientists at The University of Texas MD Anderson Cancer Center, together with colleagues, have found that PTEN is regulated by different organs. For patients with brain metastases, this is not good, as PTEN in cells is shut off in the brain. Surprisingly, PTEN is restored once cells migrate to other organs. It’s a discovery that may be important for developing effective new anti-metastasis therapies of particular importance for advanced-stage brain cancer patients. The study findings were published in the October 19, 2015 issue of Nature. The article is titled “Microenvironment-Induced PTEN Loss by Exosomal microRNA Primes Brain Metastasis Outgrowth.” “Development of life-threatening cancer metastasis requires that tumor cells adapt to and evolve within drastically different microenvironments of metastatic sites,” said Dihua Yu (photo), M.D., Ph.D., Deputy Chair of the Department of Molecular and Cellular Oncology at MD Anderson. “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.” The study of Dr. Yu and colleagues found that metastatic brain tumor cells that have experienced PTEN loss have PTEN levels restored once they leave the brain. The researchers determined that the “reversible” PTEN loss is induced by microRNAs (miRNAs) from astrocytes located in the brain and spinal cord. Astrocytes, so called for their star-like shape, secrete exosomes that contain PTEN-targeting miRNAs and transfer PTEN-targeting miRNAs inter-cellularly to tumor cells via exosomes. Exosomes are tiny, virus-sized vesicles that can carry a wide variety of informational and other molecules. MicroRNAs are short, non-coding RNA molecules known to play a role in the regulation of gene expression.

The research team also found that the PTEN loss in brain tumor cells led to an increased secretion of a cytokine known as CCL2, which recruits brain cells known as microglial cells to metastatic tumors. This enhances tumor cell growth and protects tumor cells from cell death, which can lead to life-threatening brain metastases.

“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 Dr. 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.”

MD Anderson team participants included Lin Zhang, Siyuan Zhang, M.D., Ph.D., Jun Yao, Ph.D., Frank Lowery, Qingling Zhang, M.D., Wen-Chien Huang, M.D., Ping Li, Min Li, Ph.D., Xiao Wang, Ph.D., Chenyu Zhang, Ph.D., Hai Wang, M.D., and Kenneth Ellis, all of the Department of Molecular and Cellular Oncology; Mujeeburahiman Cheerathodi, Ph.D., Suyun Huang, M.D., Ph.D., and Joseph McCarty, Ph.D., Neurosurgery; and Aysegul Sahin, Ph.D. and Kenneth Aldape, M.D., Pathology.

Other institutions involved in the work included the University of Notre Dame, South Bend, Indiana, the Woman’s Malignancies Branch, National Cancer Institute, Bethesda, Maryland, the University of Queensland Centre for Clinical Research, Herston, Queensland, Australia, and China Medical University, Taichung, Taiwan.

[Press release] [Nature abstract] [ interview with Dr. Yu]