Duke researchers are making strides in understanding how breast cancer cells can evade treatment by hiding in bone marrow tissue.
In a study published last Wednesday in the journal Science Translational Medicine, Dorothy Sipkins, associate professor in the division of hematological malignancies and cellular therapy, led a team that was able to observe the movement of breast cancer cells (BCCs) in and out of bone marrow tissue. The research sheds light on how cancers can often return again in patients whose earlier treatments showed success.
“Our focus grew out of work I did as a postdoctoral fellow that defined for the first time how very unique blood vessels in regions of the bone marrow provide a portal of entry for metastasizing leukemic cells,” Sipkins wrote in an email. “Since then, we’ve been trying to understand how different types of malignant cells utilize this ‘gateway’, and how their subsequent interactions with these blood vessels and with other molecules and cells in the bone marrow determines their fate.”
During their experiments, the researchers tagged molecular proteins associated with BCC migration and found that the protein E-selectin played a role in bringing BCCs into bone marrow tissue while the protein pair CXCR4 and SDF-1 could control whether BCCs stayed dormant in the bone marrow or were pushed back into the bloodstream.
Trevor Price, a postdoctoral associate in the Sipkins lab and first author of the study, wrote in an email that the researchers now plan to investigate the fate of BCCs once they have exited from dormancy in the bone marrow. The scientists hope to one day use their findings to help stop cancers from returning by using inhibitor molecules, which were shown in this study to block the function of E-selectin and CXCR4.
In an interview with ScienceDaily, Sipkins explained that breast cancer relapses can often occur several years after the cancer is thought to be in remission and that dormant BCCs are frequently observed to be hiding in bone marrow tissue.
She noted in an email that the bone marrow appears to be the most important “depot” for dormant BCCs in patients with estrogen-receptor positive breast cancer, the type affecting approximately 80 percent of breast cancer patients, according to breastcancer.org.
“In ER+ breast cancer, the bone is a very common site of cancer relapse,” Price said. “Migration can occur very early during the disease and primary tumour resection may not prevent relapse occurring."
He added that chemotherapy cannot effectively target these cells.
In order to track the migration of BCCs in their study, the team injected female mice with human BCCs.
The team then followed the cells' movement through video-rate fluorescence microscopy. In this approach, a laser frequently scans across a tissue that has been tagged with fluorescent markers, ultimately producing a large set of images that can collectively form a video.
“The unique facility in employing this technique is that it gives us single-cell resolution of the location, interactions and movement of cancer cells within the bone marrow niche, in vivo and in real time,” Price wrote. “Coupling this with a variety of fluorescent based tools allows us literally see where cancer cells metastasize and what stromal factors they interact with. Understanding how they interact with the niche can point to how we stop metastasis from getting there.”
During the study, the researchers discovered that the proteins E-selectin, SDF-1 and CXCR4 served in varying degrees as gatekeepers for BCC migration, with the first facilitating entry into the bone marrow and the latter two involved in the adherence of dormant BCCs to the walls of bone marrow tissue "niches."
Price wrote that once initial discoveries were made regarding the roles of E-selectin and SDF-1 in BCC homing, the team contacted GlycoMimetics, a pharmaceutical company that is currently sponsoring clinical trials for a study on their specific E-selectin inhibitor, GMI-1271.
He noted that this inhibitor was used to test whether disrupting the interaction between BCCs and E-selectin would affect and inhibit homing [of BCCs].
Going forward, Sipkins wrote that she and other investigators are beginning to focus on other steps of mechanisms governing BCC dormancy in bone marrow.
“We are very focused on understanding the fate of mobilized BCCs in our preclinical model; in particular, how they may undergo programmed cell death or become sensitive to other therapies,” Sipkins wrote. “We also hope to test whether similar approaches cause BCCs to mobilize in patients with metastatic bone disease."
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