Breast cancer spreads to brain by masquerading as neurons, study finds
Often, several years can pass between the time a breast cancer patient successfully goes into remission and a related brain tumor develops. During that time, the breast cancer cells somehow hide, escaping detection as they grow and develop. Now City of Hope researchers have found out how.
Breast cancer cells disguise themselves as neurons, becoming "cellular chameleons," the scientists found. This allows them to slip undetected into the brain and, from there, develop into tumors.
The discovery is being heralded as "a tremendous advance in breast cancer research."
Although breast cancer is a very curable disease – with more than 95 percent of women with early-stage disease surviving after five years – breast cancer that metastasizes to the brain is difficult to fight. In fact, only about 20 percent of patients survive a year after diagnosis.
"There remains a paucity of public awareness about cancer's relentless endgame," said Rahul Jandial, M.D., Ph.D., a City of Hope neurosurgeon who headed the breast-cancer-and-brain-tumor study, published online ahead of print this week in the Proceedings of the National Academy of Sciences.
"Cancer kills by spreading. In fact, 90 percent of all cancer mortality is from metastasis," Jandial said. "The most dreaded location for cancer to spread is the brain. As we have become better at keeping cancer at bay with drugs such as Herceptin, women are fortunately living longer. In this hard-fought life extension, brain metastases are being unmasked as the next battleground for extending the lives of women with breast cancer."
He added: "I have personally seen my neurosurgery clinic undergo a sharp rise in women with brain metastases years – and even decades – after their initial diagnosis."
Jandial and other City of Hope scientists wanted to explore how breast cancer cells cross the blood-brain barrier – a separation of the blood circulating in the body from fluid in the brain – without being destroyed by the immune system.
“If, by chance, a malignant breast cancer cell swimming in the bloodstream crossed into the brain, how would it survive in a completely new, foreign habitat?” said Jandial in a recent interview with New Scientist.
Jandial and his team's hypothesis: Given that the brain is rich in many brain-specific types of chemicals and proteins, perhaps breast cancer cells that could exploit these resources by assuming similar properties would be the most likely to flourish. These cancer cells could deceive the immune system by blending in with the neurons, neurotransmitters, other types of proteins, cells and chemicals.
Taking samples from brain tumors resulting from breast cancer, Jandial and his team found that the breast cancer cells were exploiting the brain's most abundant chemical as a fuel source. This chemical, GABA, is a neurotransmitter used for communication between neurons.
When compared to cells from nonmetastatic breast cancer, the metastasized cells expressed a receptor for GABA, as well as for a protein that draws the transmitter into cells. This allowed the cancer cells to essentially masquerade as neurons."Breast cancer cells can be cellular chameleons (or masquerade as neurons) and spread to the brain," Jandial said.
Jandial says that further study is required to better understand the mechanisms that allow the cancer cells to achieve this disguise. He hopes that ultimately, unmasking these disguised invaders will result in new therapies.
Other City of Hope researchers on the study were Josh Neman, Ph.D.; John Termini, Ph.D.; Sharon Wilczynski, M.D., Ph.D.; Nagarajan Vaidehi, Ph.D.; Cecilia Choy, Claudia M. Kowolik, Ph.D.; Huber Li; and Eugene Roberts, Ph.D.; and Amanda C. Hambrecht of University of Southern California.
This study is supported by National Institutes of Health grants 2K12CA001727-16A1, R01CA176611-01, R01-GM082896 and R01-GM097261, plus National Cancer Institute grant P30-CA033572.
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