How dormant breast cancer tumor cells become metastatic

The long-standing mystery about what activates dormant disseminated breast cancer tumor cells after years and even decades of latency may have been solved. Dormant cancer cells have been found to reside in the microenvironment surrounding microvasculature, which are the small blood vessels that transport blood within tissues. When these blood vessels begin to sprout, the new tips produce molecules that transform dormant cancer cells into metastatic tumors.

In a small but significant number of breast cancer patients, cancerous cells can move through the bloodstream from breast tissue to secondary sites in other parts of the body. There, they may remain in a dormant state that is clinically undetected for an extended period of time before they suddenly become metastatic. It has been difficult if not impossible to predict if and when metastases will occur.

“Our study reveals that a stable microvasculature constitutes a dormant niche, whereas a sprouting neovasculature sparks micrometastatic outgrowth,” said cell biologist and lead investigator Mina Bissell, PhD, of Lawrence Berkeley National Laboratory in California. “Sprouting is meant to coincide with tissue growth, but if a tumor cell happens to be in the wrong place at the wrong time, then it comes under the influence of the factors deposited by tip cells and it starts growing.”

“Some patients may experience metastatic relapse within months, other patients may go several years or even decades without distant recurrence,” Bissell says. “The recent discovery of tumor-promoting milieus, referred to as metastatic niches, that are established at distant sites prior to or upon the arrival of disseminated tumor cells could explain cancer cells that relapse early, but in late relapsing populations, what tumor cells do from the time of dissemination to the time they become clinically detectable has been a big question.”

The research team discovered that the protein thrombospondin-1, which is prevalent in stable microvasculature, creates a dormant niche by suppressing the growth of breast cancer cells. When the tips of blood cells begin to sprout, the thrombospondin-1 proteins give way to tumor necrosis factor-beta 1 and periostin proteins in the neovasculature. This turns it into a metastatic niche that both permits and accelerates the growth of breast cancer cells.

The identification of dormant niches in basement membrane microvasculature and how those niches become metastatic in the neovasculature holds important implications for future breast cancer therapies. These research findings, published in Nature Cell Biology (2013; doi:10.1038/ncb2767), will support future models that will allow therapies to be screened that impact tumor dormancy and metastasis.
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