Metastatic Breast Cancer Cells Activate Stem Cell Genes
Magnified stem cells
One cancerous cell breaks off from a tumor, slips into the bloodstream, and lodges elsewhere in the body in only seconds. These colonizers may bloom into deadly metastatic cancer right away or lie dormant for years, only to trigger a recurrence decades after the primary tumor is removed.
Metastases cause the vast majority of cancer deaths, but their tiny seeds are so difficult to track that few researchers have managed to study them. Now, in Nature (2015; doi:10.1038/nature15260), scientists described capturing and studying individual metastatic cells from human breast cancer tumors implanted into mice as the cells escaped into the blood stream and began to form tumors elsewhere in the body.
The researchers discovered that genetic programs expressed in these cells were quite distinct from the primary tumors in which they originated and included genes typically expressed in mammary stem cells. The findings could change the way researchers think about how cancer spreads and suggest new drugs to track down and disable its deadly seeds.
For the most part, modern cancer drugs ignore differences between primary and metastatic tumors, said Zena Werb, PhD, professor and vice-chair of anatomy at University of California San Francisco, and a senior author on the new study.
"We test drugs for their ability to make primary tumors shrink, but most just don't work on metastases, and this leaves patients open to recurrence," Werb said. "Patients have their original tumor treated or removed, but then the cancer comes back 20, 30, 40 years later because there were just a few metastatic cells sitting around."
Because metastasis is difficult to study, no one really knows how dormant metastatic cells can survive incognito for decades. As a result, only approximately 7% of all breast cancer funding goes to studying metastatic cancer, despite the fact that it causes virtually all breast cancer deaths.
In the new paper, the researchers used a technique called patient derived xenograft (PDX), which involves transplanting human tumor cells into mice. Against the backdrop of healthy mouse tissue, rogue metastatic cells from the human tumor stick out like flares. The researchers developed a new method using flow cytometry that let them capture individual human metastatic cancer cells traveling through the mouse's blood or lodged elsewhere in its body, then used newly developed microfluidic technology to characterize the active genes in these rare cells.
"We were able to look at gene expression at a whole new level of resolution," Lawson said. "We could pull 12 metastatic cells out of the brain and tell you what is special about those 12 cells. Or the two cells we found in the blood. And we discovered there's something really unique about metastatic cells as they arrive in distant tissues."
The team compared patterns of gene expression in human cancer cells lodged in different organs of the PDX mice and found stark differences between early stage and more advanced metastatic colonies. The genetic program that makes a cell metastatic did not depend on the genetics of its tumor of origin. This suggests that new techniques might allow researchers to find and specifically target these cells throughout the body in a variety of patient populations.