Microenvironment and Tumor Cells Interact To Allow Brain Metastases

Dihua Yu, M.D., Ph.D. Professor and Deputy Chair Dept. of Molecular and Cellular Oncology Hubert L. and Olive Stringer Distinguished Chair in Basic Science University Distinguished Teaching Professor Co-Director, Center of Biological Pathways Univ. of TX MD Anderson Cancer Center Houston, TX 77030

Dr. Dihua Yu

MedicalResearch.com Interview with:
Dihua Yu, M.D., Ph.D
.
Professor and Deputy Chair
Dept.  of Molecular and Cellular Oncology
Hubert L. and Olive Stringer Distinguished Chair in Basic Science
University Distinguished Teaching Professor
Co-Director, Center of Biological Pathways
Univ. of TX MD Anderson Cancer Center
Houston, TX 77030

Medical Research: What is the background for this study? What are the main findings?

Dr. Yu: Metastasis is the number one cause of cancer-related mortality. Despite the continuous advancement of modern medicine in better controlling primary cancer progress, brain metastasis incidence constantly and steadily increases. Major neoplastic diseases such as melanoma, lung, breast, and colon cancers have high incidences of brain metastases. One-year survival after diagnosis of brain metastasis is less than 20%.

Cancer cells dynamically interacts with specific organ microenvironments to establish metastasis as depicted by the “seed and soil” hypothesis. Many research have focused on how tumor cells modulate the metastatic microenvironment, but the reciprocal effect of the organ microenvironment on tumor cells has been overlooked. The brain tissue is very distinct from primary tumor environment for metastatic cancer cells. Brain metastasis frequently manifests in the late stages of cancer, and a long period of dormancy often precedes relapse. This implies that additional regulations imposed by the brain microenvironment are essential for metastatic colonization and outgrowth. Yet it is unclear when and how disseminated tumor cells acquire the essential traits from the brain microenvironment that primes their subsequent metastatic outgrowth.

Medical Research: What are the main findings?

Dr. Yu: Here we found that primary tumor cells with normal PTEN expression lose PTEN after dissemination to the brain, but not to other organs. Metastatic brain tumor cells that have experienced PTEN loss have PTEN levels restored once they leave the brain. This brain microenvironment-dependent, reversible PTEN mRNA and protein down-regulation is epigenetically regulated by microRNAs (miRNAs) from astrocyte-derived exosomes. This adaptive PTEN loss in brain metastatic tumor cells leads to an increased secretion of cytokine chemokine (C-C motif) ligand 2 (CCL2), which recruits Iba1+ myeloid cells that reciprocally enhance outgrowth of brain metastatic tumor cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth.

Medical Research: What should clinicians and patients take away from your report?

Dr. Yu: As the above findings have been validated in patients primary and brain metastatic tissues, the findings provide insights on prevention or treatment of brain metastasis. For example, CCL2 inhibitors have been used in clinical trials and our data showed that stable ablation of CCL2 inhibits brain metastasis in vivo, demonstrating the potential of CCL2-targeting for therapeutic intervention of life-threatening brain metastases. Furthermore, astrocyte-derived exosomes and their specific molecular contents (e.g. miR-19a) have the potential as a useful biomarker for early detection of brain metastasis.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Yu: Our findings highlighted an important plastic and tissue-dependent nature of metastatic tumor cells and a bi-directional co-evolutionary view of “seed and soil” hypothesis. It represents one important mechanism by which activated astrocytes and other brain stromal cells promote brain metastatic outgrowth. Further research in cancer metastasis should consider the bi-directional effect on microenvironment and tumor cells. Specifically, we will study how metastatic cancer cells induce gliosis or whether production of astrocyte exosomes is influenced by cancer cells. We are also exploring other mechanisms by which activated astrocytes and other brain stromal cells promote brain metastasis. A comprehensive understanding of the novel bi-directional effects on microenvironment and tumor cells will provide unprecedented opportunities to tackle the daunting challenge of metastasis.

 Citation:

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

Lin Zhang, Siyuan Zhang, Jun Yao, Frank J. Lowery, Qingling Zhang, Wen-Chien Huang,Ping Li, Min Li, Xiao Wang, Chenyu Zhang, Hai Wang, Kenneth Ellis, Mujeeburahiman Cheerathodi, Joseph H. McCarty, Diane Palmieri, Jodi Saunus, Sunil Lakhani, Suyun Huang, Aysegul A. Sahin, Kenneth D. Aldape,Patricia S. Steeg & Dihua Yu

Nature (2015) doi:10.1038/nature15376

 

Dihua Yu, M.D., Ph.D. (2015). Microenvironment and Tumor Cells Interact To Allow Brain Metastases 

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