Cancer cells can stay hidden in the body for years before causing a relapse.

Treating breast cancer is challenging due to the fact that cancer cells can stay hidden in the body for years before causing a relapse. However, new research is now looking at how these dormant cells survive in the bone marrow, potentially leading to new treatments that can prevent cancer from returning. The study, led by Professor Anna Teti from the Department of Biotechnological and Applied Clinical Sciences at the University of L’Aquila in Italy and affiliated with Italy’s National Research Council, was carried out in collaboration with Ludwig Maximilian University of Munich and the University of Southern Denmark. Breast cancer relapse can occur even decades after successful treatment of a primary tumour. This is thought to happen when small numbers of cancer cells migrate to the bone marrow and enter a dormant state. While inactive, these cells can evade detection and treatment before eventually reactivating and spreading to the bones and other organs. While scientists have long recognised the bone marrow as a sanctuary for dormant cancer cells, exactly how these cells survive undetected for so long has remained a mystery. Cancer cells mimic healthy stem cells Bone marrow contains specialised microenvironments known as niches, which help regulate stem cell behaviour. One of these areas, the endosteal niche, is located near the bone surface and contains bone-forming cells known as osteoblasts. The research team discovered that breast cancer cells appear to imitate some of the characteristics of healthy stem cells in order to survive within these protective environments. Bone marrow contains specialised microenvironments known as niches, which help regulate stem cell behaviour “We discovered that breast cancer cells can exploit the same protective systems that normally maintain healthy stem cells in bone marrow,” said Professor Teti. “This allows cancer cells to remain hidden and potentially reactivate years later.” To investigate further, researchers focused on two signalling proteins, Notch1 and Notch2, which help cells communicate with their surroundings and regulate important functions. Using imaging techniques, gene expression analysis and laboratory experiments, the team found that Notch2 plays a much more significant role in dormancy than Notch1. Breast cancer cells with high levels of Notch2 divided more slowly when interacting with osteoblasts in the endosteal niche, an indicator of cellular dormancy. Key genes linked to dormancy identified The researchers also carried out RNA sequencing to examine gene activity. They found that Notch2-rich cancer cells showed reduced activity in genes associated with growth and division while activating genes commonly linked to blood-forming stem cells in bone marrow. In particular, dormant cancer cells expressed high levels of CXCR4, CD34 and TIE2, genes that help stem cells survive within the bone marrow niche. Experiments in mice revealed that cells with elevated CXCR4 or TIE2 levels produced fewer and smaller bone tumours, pointing towards a reduced capacity for cancer spread. In particular, dormant cancer cells expressed high levels of CXCR4, CD34 and TIE2, genes that help stem cells survive within the bone marrow niche “This was a particularly interesting finding because it suggests that cancer cells can acquire stem cell-like properties to evade treatment and survive in the body for very long periods,” remarks Professor Teti. The study also found that Notch2-rich cells activated stress-response pathways known as the unfolded protein response, enabling them to survive under difficult conditions. These cells displayed increased levels of PERK, ATF4, CHOP and a newly identified marker associated with dormant breast cancer cells, called CD177. Researchers observed that CD177-high cells also had elevated Notch2 and CXCR4 expression, lower rates of proliferation and were linked to improved patient survival outcomes. What next? The findings provide new insight into how breast cancer cells can remain dormant in bone marrow for years before reactivating. The identification of Notch2, CXCR4, CD177 and stress-response pathways as key regulators of dormancy could support the development of therapies designed to eliminate dormant cancer cells or prevent their reawakening, potentially reducing the risk of breast cancer relapse.

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