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, 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" 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.
INFORMATION:
About Breast Cancer
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.
About Montefiore Health System
Montefiore is a premier academic health system and the University Hospital for Albert Einstein College of Medicine. Combining nationally-recognized clinical excellence with a population health perspective that focuses on the comprehensive needs of the communities it serves, Montefiore delivers coordinated, compassionate, science-driven care where, when and how patients need it most. Montefiore consists of eight hospitals and an extended care facility with a total of 2,747 beds, a School of Nursing, and state-of-the-art primary and specialty care provided through a network of more than 150 locations across the region, including the largest school health program in the nation and a home health program. The Children's Hospital at Montefiore is consistently named in U.S. News' "America's Best Children's Hospitals." Montefiore's partnership with Einstein advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. The health system derives its inspiration for excellence from its patients and community, and continues to be on the frontlines of developing innovative approaches to care. For more information please visit http://www.montefiore.org. Follow us on Twitter; like us on Facebook; view us on YouTube.
Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. During the 2013-2014 academic year, Einstein is home to 743 M.D. students, 275 Ph.D. students, 103 students in the combined M.D./Ph.D. program, and 313 postdoctoral research fellows. The College of Medicine has more than 2,000 full-time faculty members located on the main campus and at its clinical affiliates. In 2013, Einstein received more than $150 million in awards from the National Institutes of Health (NIH). This includes the funding of major research centers at Einstein in aging, intellectual development disorders, diabetes, cancer, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore Medical Center, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Through its extensive affiliation network involving Montefiore, Jacobi Medical Center -- Einstein's founding hospital, and three other hospital systems in the Bronx, Brooklyn and on Long Island, Einstein runs one of the largest residency and fellowship training programs in the medical and dental professions in the United States. For more information, please visit www.einstein.yu.edu, read our blog, follow us on Twitter, like us on Facebook, and view us on YouTube.
