ScienceDaily (May 7, 2009) — New research led by investigators at
Memorial Sloan-Kettering Cancer Center (MSKCC) identifies three genes that
specifically mediate the metastasis, or spread, of breast cancer to the brain
and illuminates the mechanisms by which this spread occurs.
According to the study, COX2 and HB-EGF — genes that induce cancer cell mobility
and invasiveness — were found to be genetic mediators in the spread of breast
cancer to the brain. A third gene, ST6GALNAC5, was shown to provide cancer cells
with the capability of exiting the blood circulation and passing through the
blood-brain barrier to enter the brain tissue.
"Our research sheds light on the role these genes play in determining how breast
tumor cells break free and, once mobile, how they decide where to attack," said
Joan Massagué, PhD, Chair of the Cancer Biology and Genetics Program at MSKCC
and a Howard Hughes Medical Institute investigator.
Breast cancer metastasis to the brain typically occurs years after removal of a
breast tumor, suggesting that disseminated cancer cells initially lack the
specialized functions needed to overtake the dense network of capillaries that
constitute the blood-brain barrier. This barrier prevents the entry of
circulating cells and regulates the transport of molecules into the brain
tissue. To generate brain metastasis, circulating cancer cells must, therefore,
be able to pass through the blood-brain barrier and interact with the brain
microenvironment.
In
the study, Dr. Massagué and his colleagues isolated cancer cells that
preferentially targeted the brain from patients with advanced disease. By
combining this approach with gene expression profiling, additional testing in
mouse model systems, and analysis of a body of clinical data, the investigators
identified certain genes and functions that selectively mediate cancer cell
passage through the blood-brain barrier.
The authors observed that ST6GALNAC5, an enzyme that is normally active only in
brain tissue, causes a chemical reaction that creates a coating on the surface
of breast cancer cells that enhances their ability to breach the blood-brain
barrier. Their findings show that breast cancer cells use this brain-specific
cell-coating enzyme as a means of infiltrating the brain.
"Our results draw attention to the role of the cell surface coating as a
previously unrecognized participant in brain metastasis, and to the possibility
of using drugs to disrupt its interactions," said Dr. Massagué. "Further study
is necessary to explore the role of these genes in brain metastasis and their
interest as therapeutic targets."
The study authors also noted that COX2 and HB-EGF, which prime breast cancer
cells for entrance into the brain, had previously been found to be involved in
breast cancer's spread to the lung. This suggests a partial sharing of genetic
mediators of metastasis to both the brain and lung and may explain the
association of brain and lung relapse in women with breast cancer.
Metastasis is responsible for the majority of all cancer deaths and occurs when
tumor cells acquire the ability to escape their original location and invade
healthy tissue and organs elsewhere in the body. According to the National
Cancer Institute, 170,000 new cases of cancer metastasis to the brain are
diagnosed each year in the United States alone. The incidence of brain
metastases is rising as a result of their resistance to treatments that are
effective against cancer spread to other sites.
Researchers from the University of Chicago and the following institutions in The
Netherlands contributed to this research: Academic Medical Center, Amsterdam;
Erasmus Medical College, Rotterdam; Josephine Nefkens Institute, Rotterdam; and
Cancer Genomics Centre, Rotterdam.
The work was supported by grants from the National Institutes of Health, the
Kleberg Foundation, the Hearst Foundation, and the Netherlands Genomics
Initiative/Netherlands Organization for Scientific Research.
