New Surprising Discovery of Cancer Metastasis: 'Reversible' Tumor Suppressor Loss

It is no surprise that people prefer to be in a warm place like Hawaii other than suffering harsh environments in Antarctica. Similarly, the PTEN, a tumor suppressor gene, is also influenced by the microenvironment of certain body organs to which it travels.

Recently, scientists at the University of Texas MD Anderson Cancer Center have discovered that PTEN is regulated by different organs, which is not good for patients with brain metastases, as PTEN in cells is shut off in the brain. Surprisingly, PTEN will recover once the cells migrate to other organs.

Their study results were published in the journal of Nature, which may be quite important for the development of new and effective anti-metastasis therapies particularly for patients with advanced-stage brain cancer.

"Development of life-threatening cancer metastasis requires that tumor cells adapt to and evolve within drastically different microenvironments of metastatic sites," said Dr. Dihua Yu, deputy director of the Molecular and Cellular Oncology Department. "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 uncovered that metastatic brain tumor cells that have experienced PTEN loss have restored the PTEN levels once they leave the brain. They identified that the "reversibility" of PTEN loss is induced by micro RNAs (miRNAs) from astrocytes generated in brain and spinal cord.

Exosomes, secreted by astrocytes, contain PTEN targeting miRNAs and transmits these PTEN-targeting miRNAs to PTEN tumor cells by exosomes between cells. Exosomes are some tiny, virus-sized particles. MiRNAs are non-coding molecules known to play an important in the regulation of gene expression.

The team also found that the PTEN loss of brain cells can result in an increase in cytokine CCL2 secretion, which recruits microglia to the metastatic tumor cells. This  promotes tumor cell growth and protects tumor cells from cell death, leading to a fatal brain metastasis.

Reference:

Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth, Nature.