Researchers demonstrate how breast cancer cells invade bone marrow where they escape chemotherapy and hormonal therapies that would otherwise eliminate the cancer cells using a mouse model. This research has revealed not only a way to prevent breast cancer cells from invading bone marrow but also a mechanism to purge the cancer cells from the marrow into the blood, where the cancer can be treated.1
“Clinical studies have found that breast cancer can be caught early and treated, and patients can have no signs of disease,” said Dorothy A. Sipkins, MD, PhD, associate professor in the division of hematological malignancies and cellular therapy at Duke University, Durham, North Carolina, and senior author of the study.
“And then 5, 10, or even 15 years later, a patient can relapse. Most often, the site of the metastasized cancer is in the bone.”
This study described how cancer cells from hormone receptor-positive breast cancer can circulate through the blood until they encounter blood vessels in bone marrow that contain a molecule called E-selectin. The cancer cells bind to E-selectin and enter the spongy, inner tissue of bones, forming what the researchers dubbed micrometastases. These micrometastases can remain dormant for years.
If these dormant cells become active again, they can cause metastatic cancer relapse, for which there is no cure. Micrometastases can form even at very early stages of breast cancer.
Inhibiting E-selectin with GMI-1271, a drug currently in clinical trials, prevented cancer cells from invading the bone marrow in mice. To purge cancer cells from the marrow, researchers administered plerixafor, a drug given to human bone marrow donors to push stem cells into the bloodstream for harvesting.
Administration of plerixafor in mice forced dormant breast cancer cells from the bone marrow into the bloodstream. Researchers are hopeful that this could allow the cancer cells to be killed by the immune system, chemotherapy, or hormonal therapy.
“Now we know how they are getting in,” Sipkins said. “We also identified an important mechanism that allows them to remain anchored in the bone marrow. In the mouse, our findings could offer new strategies to intervene at the molecular level before dormant cells can take hold and cause relapse.”
These results offer a possible explanation as to why some breast cancers return after what was thought to be complete remission. The researchers plan to replicate the tests in additional animal experiments and in humans, hoping that they will find new therapies for treating breast cancer.
“We are hopeful that by understanding how these breast cancer cells migrate through the body and what their life cycle is, we can discover ways to make them more vulnerable and treatable,” Sipkins said.
“Our hope is to move forward with additional studies in mice to better understand our approach before moving on to studies in humans.”
1. Price TT, Burness ML, Sivan A, et al. Dormant breast cancer micrometastases reside in specific bone marrow niches that regulate their transit to and from bone [published online May 25, 2016]. Sci Transl Med. doi:10.1126/scitranslmed.aad4059.