Breast cancer is notorious for its ability to relapse after many years, long after a patient had completed treatment. A major site of disease dissemination and relapse is bone, although the critical signals that allow circulating breast cancer cells to identify bone microvasculature, enter tissue, and tether to the microenvironment are poorly understood. Now, a study from researchers at the Duke Cancer Institute identifies a molecular key that breast cancer cells use to invade bone marrow in mice, where they may be protected from chemotherapy or hormonal therapies that could otherwise eradicate them. The team state through years of experiments in mice, they have found ways to outmaneuver this stealth tactic by preventing breast cancer cells from entering the bone marrow and flushing cancer cells out into the blood stream where they could be targeted for destruction. The opensource study is published in the journal Science Translational Medicine.
Previous studies show that patients diagnosed with localized breast cancer, even when treated with adjuvant therapy, remain at risk for late metastatic relapse, most commonly in bone. Clinically silent bone marrow micrometastases can be detected in 30% of breast cancer patients with stage I to III disease and predict the likelihood of disease relapse. These data suggest that the bone marrow is a particularly attractive location for micrometastases and that characteristics of its microenvironment can maintain tumour dormancy for extended periods. However, despite growing understanding of breast cancer cell microenvironment interactions, it is unknown how metastatic breast cancer cells enter the bone. The current study identifies the mechanism that enables breast cancer cells to remain anchored in the bone marrow and offers new strategies to intervene at the molecular level before dormant cells can take hold and cause relapse.
The current study used real-time fluorescence microscopy to track breast cancer cell migration in mouse xenograft models of human breast cancer cell metastasis. Results show that by combining constitutively expressed fluorescent protein labels with cell membrane dyes, the lab were able to discriminate the precise anatomic location and movement of dormant versus proliferative metastases.
Data findings show that dormant and proliferating breast cancer cells occupy distinct areas, with dormant breast cancer cells predominantly found in E-selectin and stromal cell–derived factor 1 (SDF-1)–rich perisinusoidal vascular regions. The team used highly specific inhibitors of E-selectin and CXCR4, an SDF-1 receptor, to demonstrate that E-selectin and SDF-1 orchestrate opposing roles in BCC trafficking. Results show that E-selectin interactions are critical for allowing breast cancer cell entry into the bone marrow, however, the SDF-1/CXCR4 interaction anchors breast cancer cells to the microenvironment, and its inhibition induces mobilization of dormant micrometastases into circulation.
In further studies the researchers gave the mice plerixafor, an agent used in human bone marrow donors to push stem cells into the bloodstream for harvesting. It was observed that the drug was able to force dormant breast cancer cells out of the bone tissue into the bloodstream. The lab conclude that flushing these dormant cancer cells back into the bloodstream might give the immune system, chemotherapy or hormonal therapy another opportunity at killing them off.
The team surmise that their findings provide insight into one of the most devastating tendencies of some breast cancers, namely, the ability to return after seemingly being vanquished. For the future, the researchers hope the findings, if replicated in additional animal and human tests, could eventually lead to new therapies for treating breast cancer.
Source: The Duke Cancer Institute