August 12, 2015—(BRONX, NY)—Using real-time, high-resolution imaging, scientists have identified how a “doorway” in the blood vessel wall allows cancer cells to spread from breast tumors to other parts of the body. The findings lend support to emerging tests that better predict whether breast cancer will spread, which could spare women from invasive and unnecessary treatments, and could lead to new anti-cancer therapies. The research, conducted by investigators at the NCI-designated Albert Einstein Cancer Center (AECC) and Montefiore Einstein Center for Cancer Care, utilized a mouse model of human breast cancer and mice implanted with human breast tissue. The study was published today in the online edition of Cancer Discovery.
John Condeelis, Ph.D.The Einstein-Montefiore researchers previously found that breast cancer spreads when three specific cells are in direct contact: an endothelial cell (a type of cell that lines the blood vessels), a perivascular macrophage (a type of immune cell found near blood vessels), and a tumor cell that produces high levels of Mena, a protein that enhances a cancer cell’s ability to invade. The site where these three cells come in direct and stable contact––called a tumor microenvironment of metastasis, or TMEM––is where tumor cells enter blood vessels.
“It has been known for some time that blood vessels in tumors are abnormally permeable. But what regulates that permeability hasn’t been clear. Based on our latest imaging studies, we can now say that this phenomenon is regulated by TMEM macrophages,” said lead author Allison Harney, Ph.D., Bridge Postdoctoral Fellow in the Integrated Imaging Program at Albert Einstein College of Medicine.
This new research indicates that the TMEM macrophage releases a protein called vascular endothelial growth factor, or VEGF, which causes a local increase in blood vessel permeability. The effect is temporary but can last long enough to allow cancer cells to enter the blood stream—escaping the primary tumor and traveling to distant metastatic sites.
The researchers also observed for the first time that transient blood vessel permeability and tumor cell entry into the bloodstream occur simultaneously and exclusively at TMEM sites. The discovery was made using intravital high-resolution two-photon microscopy to image primary breast cancer tumors in mice and human xenografts (human breast cancer tissue grafted into mice).
“The discovery of a unique doorway that allows tumor cells into the blood stream opens new opportunities for the development of anti-metastasis therapeutics.”– John Condeelis, Ph.D.
“The discovery of a unique doorway that allows tumor cells into the blood stream opens new opportunities for the development of anti-metastasis therapeutics” said study leader John Condeelis, Ph.D., professor and co-chair of anatomy and structural biology, co-director of the Gruss Lipper Biophotonics Center and the Integrated Imaging Program, and the Judith and Burton P. Resnick Chair in Translational Research at Einstein and leader of the Tumor Microenvironment and Metastasis Program at AECC.
More than 232,000 American women developed breast cancer last year and nearly 40,000 women died from the disease, according to the National Cancer Institute. It is the most common cancer among women in the United States. Most breast cancer deaths occur because the cancer has spread, or metastasized, meaning that cells in the primary tumor have invaded blood vessels and traveled via the bloodstream to form tumors elsewhere in the body.
The paper is titled “Real-time imaging reveals local, transient vascular permeability and tumor cell intravasation stimulated by Tie2Hi macrophage-derived VEGFA.” The other Einstein contributors are: Esther N. Arwert, Ph.D., (also at London Research Institute, London), David Entenberg, M.Sc., Yarong Wang, M.S., Peng Guo, Ph.D., Bin-Zhi Qian, Ph.D. (and at University of Edinburgh, UK), Maja H. Oktay, M.D. (and at Montefiore), Jeffrey W. Pollard, Ph.D., (and at University of Edinburgh), and Joan G. Jones, M.D. (and at Montefiore).
The study was supported by grants from the Department of Defense Breast Cancer Research Program (W81XWH-13-1-0010) and the National Institutes of Health (CA100324). Support was also provided by Einstein’s Integrated Imaging Program.
The following researchers report financial relationships in companies involved in the technologies studied: Drs. Jones and Condeelis are consultants and stockholders of MetaStat, Inc., Boston, MA; Dr. Oktay and Entenberg are consultants of MetaStat; Dr. Condeelis is a consultant of Deciphera Pharmaceuticals, LLC, Cambridge, MA; and Drs. Harney and Wang have a sponsored research agreement with Deciphera. Neither MetaStat nor Deciphera contributed financial resources or reagents to the study. The other authors disclose no potential conflicts of interest.