Metastasizing tumor cells lose expression of the tumor suppressor PTEN at a much higher rate when they enter the brain compared to other organs, suggesting that the brain's unique microenvironment may prime metastatic cells for aggressive growth, a recent study reports. The findings may have implications for developing targeted therapies for brain metastases.
Metastasizing tumor cells lose expression of the tumor suppressor PTEN at a much higher rate when they enter the brain compared to other organs, suggesting that the brain's unique microenvironment may prime metastatic cells for aggressive growth, a recent study reports. The findings may have implications for developing targeted therapies to treat brain metastasis.
Researchers analyzed PTEN expression in primary tumors and in metastatic lesions isolated from different organs and found that the rate of PTEN loss was markedly higher in brain metastases. Subsequent studies in animal models and human cancer cell lines revealed that PTEN expression significantly decreases after metastasis to the brain but is restored when those cells leave the brain, indicating that PTEN expression changes in response to specific organ microenvironments. The findings are published in Nature.
“This is the first study to show this organ-specific, nongenetic, reversible PTEN loss in the brain, as opposed to other organs or in primary tumors,” says the study's lead author Dihua Yu, MD, PhD, deputy chair of the Department of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center in Houston. “Our study describes a brain-specific process that allows metastatic tumor cells to adjust to the brain's environment for outgrowth.”
Yu's team demonstrated that PTEN loss is regulated by brain astrocytes that secrete exosomes containing PTEN-targeting microRNAs. In animal studies, they reported that “astrocyte-deprived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumor cells” and that blocking astrocyte exosome secretion restores PTEN expression and suppresses brain metastasis.
Notably, investigators found that tumor cells with low PTEN expression secrete higher levels of the chemokine CCL2 than tumor cells with normal PTEN expression. Reducing CCL2 expression in mouse models of brain metastases significantly extended survival compared to controls.
Several CCL2 inhibitors and antibodies are currently being developed for treatment of cancer and other diseases. For example, a phase Ib trial is evaluating the small-molecule inhibitor CCX872 (ChemoCentryx) in patients with nonresectable pancreatic cancer.
“Although clinical application of CCL2 inhibition for metastasis treatment is far different from the genetic approach we used in our study, our data demonstrate the potential of CCL2 targeting for therapeutic intervention in life-threatening brain metastases,” says Yu. “We will collaborate with pharmaceutical companies on inhibiting brain metastases in animals and hope to translate our findings to the clinic to benefit patients.”
- ©2015 American Association for Cancer Research.