Berkeley Lab Researchers Discover How and Where Breast Tumor Cells Become Dormant and What Causes Them to Become Metastatic

The long-standing mystery behind dormant disseminated breast tumor cells and what activates them after years and even decades of latency may have been solved. Researchers with the U.S. Department of Energy (DOE)’s Lawrence Berkeley National Laboratory (Berkeley Lab) have identified the microenvironment surrounding microvasculature – the small blood vessels that transport blood within tissues – as a niche where dormant cancer cells reside. 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 where they may remain in a dormant state, clinically undetected, for an extended period of time, before suddenly becoming 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,” says cell biologist Mina Bissell, in whose laboratory this work was done. “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.”

Bissell, Distinguished Scientist with Berkeley Lab’s Life Sciences Division ranks among the world’s foremost breast cancer researchers. She is one of two corresponding authors – the other is Cyrus Ghajar a bioengineer and member of Bissell’s research group – of a paper describing this study in the journal Nature Cell Biology. The paper is titled “The perivascular niche regulates breast tumor dormancy.”

“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.”

Previous research by Bissell and her group showed that the basement membrane, the thin layer of extracellular matrix proteins surrounding breast and other epithelial tissue, provides a microenvironment that induces quiescence in normal epithelial cells and dormant tumor cells alike. Given that breast cancer cells traveling through the bloodstream on their way to secondary sites where breast tumors metastasize most often – lung, bone marrow, brain and liver – must first pass through the basement membrane microvasculature, Ghajar and Bissell suspected that the basement membrane could be a major component of the dormant niche in distant organs.