Discovery

Einstein scientists find crucial molecule involved in spread of breast cancer

Findings in the journal Nature suggest strategy for halting metastasis

Public release date: 8-Jun-2011
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Contact: Kim Newman
sciencenews@einstein.yu.edu
718-430-3101
Albert Einstein College of Medicine 

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June 8, 2011 — (Bronx, NY) — Researchers at Albert Einstein College of Medicine of Yeshiva University have identified a key player in the spread of breast cancer. The findings, published today in the online edition of Nature, identify a critical molecule that helps cancer spread beyond the primary tumor. The research highlights a potential new strategy against metastatic disease. The study's senior author is Jeffrey Pollard, Ph.D., professor of developmental and molecular biology and of obstetrics & gynecology and women's health at Einstein. He also holds the Louis Goldstein Swan Chair in Women's Cancer Research and is the deputy director of the Albert Einstein Cancer Center.

People rarely die from their primary (original) tumor. Instead, most cancer deaths occur because the cancer has spread, or metastasized, to other parts of the body. "By focusing on sites where cancer had spread, we were able to detect a molecule that stimulates metastasis," said Dr. Pollard. "This raises the possibility that metastasis could be kept from progressing – or even prevented – if the stimulating molecule could be blocked. This we achieved in mouse models of breast cancer."


Metastasis begins when cells break away from the primary tumor and gain the ability to move on their own. These cells invade nearby blood vessels (a process known as intravasation) and are carried by the bloodstream to other parts of the body. The bloodborne tumor cells then escape from vessels in a process known as extravasation. Once these tumor cells escape from the vessels, they seed new and deadly tumors that grow in these distant locations.


In previous studies, Dr. Pollard and his research team have shown that macrophages – immune system cells whose functions include fighting infections – actually promote the spread of cancer. His research has shown that macrophages not only assist tumor cells during both intravasation and extravasation but also help those wayward cells take root in their new locations and grow into metastatic tumors. In the current study, Dr. Pollard and colleagues investigated the process by which these macrophages are recruited to metastatic sites and subsequently promote tumor-cell extravasation, seeding and tumor growth.


Using models of human and mouse breast cancer, the researchers demonstrated that when breast tumor cells travel to the lung, these cells secrete CCL2, a chemokine molecule (i.e., one that attracts cells). CCL2 attracts immune cells called inflammatory monocytes -- in particular, those bearing receptors for CCL2, which then develop into macrophages. The monocytes and macrophages "invited" by CCL2 signaling then facilitate extravasation – the critical step in metastasis in which bloodborne tumor cells cross the vessel wall and implant in nearby tissue. One way monocytes help tumor cells escape from blood vessels and cause metastasis, the Einstein researchers found, is by secreting vascular endothelial growth factor, or VEGF, a substance that makes blood vessels leaky at the site where tumor cells exit from them.


Once the tumor cells are seeded, inflammatory monocytes continue to flock to the metastatic site – now attracted by CCL2 secreted not only by the tumor cells but also by nearby lung tissue that the tumor cells have targeted. In turn, these continuously recruited monocytes and the resultant macrophages promote the growth of the emerging metastatic tumor.
To confirm their findings, the researchers used anti-CCL2 antibodies to suppress CCL2 signaling in a mouse model of human metastasis – with striking results. In lungs challenged with metastatic tumor cells, the anti-CCL2 antibodies inhibited the influx of inflammatory monocotyes and macrophages to the metastatic sites, and the number of metastatic sites that developed in the lungs was markedly reduced. In addition, the mice lived much longer when CCL2 signaling was blocked.


"These findings have potential implications for therapy, since in human breast cancer we know that CCL2 expression and macrophage infiltration are associated with poor prognosis and metastatic disease," said Dr. Pollard. "If we can develop ways to inhibit these processes, we might be able to slow or stop breast cancer from spreading."

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Dr. Pollard's paper is titled "CCL2 recruits inflammatory monocytes to facilitate breast tumor metastasis." His coauthors include Bin-Zhi Qian, Ph.D.; Jiufeng Li; Hui Zhang; Takanori Kitamura, Ph.D.; and Jinghang Zhang, M.D., of Einstein and Liam R. Campion, M.S.; Elizabeth A. Kaiser; and Linda A. Snyder, Ph.D., of Ortho Biotech Oncology R&D, Radnor, PA. The research was funded by grants from the National Cancer Institute of the National Institutes of Health.
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About Albert Einstein College of Medicine of Yeshiva UniversityAlbert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. During the 2009-2010 academic year, Einstein is home to 722 M.D. students, 243 Ph.D.students, 128 students in the combined M.D./Ph.D. program, and approximately 350 postdoctoral research fellows. The College of Medicine has 2,775 fulltime faculty members located on the main campus and at its clinical affiliates. In 2009, Einstein received more than $155 million in support from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, 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. Through its extensive affiliation network involving five medical centers in the Bronx, Manhattan and Long Island - which includes Montefiore Medical Center, The University Hospital and Academic Medical Center for Einstein - the College of Medicine runs one of the largest post-graduate medical training programs in the United States, offering approximately 150 residency programs to more than 2,500 physicians in training. For more information, please visit www.einstein.yu.edu