Anemia in Bone Metastasis Results When Cancer Cells Hijack Iron-Recycling Macrophages

Cancer specialists have long known that anemia, caused by a lack of healthy red blood cells, can arise when cancer metastasizes to the bone, but it’s been unclear why. A research team led by Princeton University scientists Yibin Kang, PhD, and Yujiao Han, PhD, has uncovered that in metastatic breast cancer, this process involves a type of cellular hijacking.

Reporting in Cell on their latest preclinical work, Kang, Han, and team describe how they discovered that cancer cells effectively commandeer specialized erythroblast island (EBI) macrophages that normally recycle iron in the bone. This hijacking deprives red blood cells of necessary iron, and also helps the tumor continue to grow in the bone.

The team’s research ultimately aims to help uncover how to slow down bone metastasis. “The hope is to slow down or treat bone metastasis and, at the same time, alleviate the complications of anemia,” said Han, an associate research scholar in the Department of Molecular Biology at Princeton. Han is lead author of the team’s published paper, titled “Tumors hijack macrophages for iron supply to promote bone metastasis and anemia,” in which the researchers concluded, “Our findings reveal a molecular mechanism linking bone metastasis with hematologic complications such as anemia … These findings provide potential therapeutic implications for both bone metastasis and cancer-associated anemia.”

Bone marrow is both a primary site for hematopoiesis and what the authors call “a fertile niche for metastasis.” Metastatic cancer—cancer that has spread to other parts of the body beyond the original tumor site—is one of the deadliest forms of cancer. Of patients who die from breast and prostate cancer, 70% have bone metastasis.

Patients with bone metastasis commonly develop severe local and systemic complications, including anemia, the authors pointed out. “Anemia profoundly affects cancer patients’ quality of life and survival and is a common clinical presentation in breast cancer patients with bone metastasis.” However, they continued, “The mechanism of the common occurrence of anemia among patients with bone metastasis remains poorly understood.”

According to Kang, the team’s discovery reported in Cell represents a new research direction for his lab—one that shifts the attention from the “seeds” of cancer to the “soil” in which it grows within a metastatic organ site. This concept, known as the “seed and soil hypothesis,” was first proposed more than a century ago by British surgeon Stephen Paget. For much of the past two decades, Kang, who is a Warner-Lambert/Parke-Davis Professor of Molecular Biology at Princeton, and many others in the cancer biology field have focused primarily on the tumor cells themselves (the “seeds”) and how they adapt to spread and grow in bone. But to truly understand metastasis, Kang said, it is just as important to study the soil—the surrounding environment that nurtures or restrains the cancer.

Until recently, however, the “soil” of the bone marrow remained largely uncharted. “It has been a big black hole,” Kang said, who is also a founding member of the Princeton Branch of the Ludwig Institute for Cancer Research. “We did not have a comprehensive understanding of what the soil is made of.”

That has begun to change with the advent of advanced cell-labeling and single-cell sequencing technologies. For their newly reported studies, the investigators combined in vivo niche labeling in mouse models with high-resolution single-cell RNA sequencing (scRNA-seq) to systematically characterize hematopoietic cells within the bone marrow niche. Using these technologies, Kang’s team was able to map the bone marrow in unprecedented detail.

Kang, Han, and colleagues were able to identify and visualize clusters of specialized macrophages gathering around the tumor. These Vcam1+Cd163+Ccr3+ macrophages were enriched in the bone metastatic niche in the mouse tumor models. The specialized cells should have been supporting red blood cell production, but instead, were diverted to serve the cancer. “We identified a distinct macrophage population enriched in the metastatic niche,” they wrote. “These specialized macrophages typically maintain iron homeostasis and support red blood cell (RBC) production in the erythroblastic islands (EBIs) of healthy bone marrow.”

Under healthy conditions, these macrophages act as “nurse cells,” feeding iron to developing red blood cells so they can mature and carry oxygen. But in the presence of bone metastases, the tumor lures these macrophages to its side using signaling molecules, then diverts their iron away from red blood cells. In addition, the disruption goes beyond iron loss alone. Kang and Han found that the tumor-exploited macrophages also fail to support the final maturation step of red blood cells—the expulsion of their nuclei—further stalling red blood cell development and worsening anemia.

This starves the bone marrow of the iron needed for healthy red blood cell production and locks red blood cells in their immature state, leaving patients anemic. “Tumor cells hijack these macrophages for iron supply, reducing iron availability for erythroblasts, impairing erythropoiesis, and contributing to anemia,” the team reported. At the same time, the cancer cells put the stolen iron to their own use. They adapt by mimicking red blood cells themselves. Under the guidance of a blood-cell transcription factor called GATA1, tumor cells begin producing hemoglobin, the same oxygen-transporting protein that fills red blood cells.

This “red blood cell mimicry” allows the tumor to thrive in the bone’s oxygen-poor environment, protecting the cancer cells from stress and helping them survive. “Tumor cells adopt erythroblast-like features in response to hypoxia, facilitating further adaptation,” the scientists noted. In short, the tumor creates a vicious cycle: it co-opts the bone’s iron-recycling system to feed itself, while simultaneously sabotaging the body’s ability to make new red blood cells.

“It’s essentially a wolf disguising itself as a sheep by eating similar food to what sheep eat, and that helps them survive better in the environment,” said Kang, who is also an associate director of Rutgers Cancer Institute of New Jersey.

Although the current study focused on metastatic breast cancer, the findings have been extended to other major cancer types and carry broad implications. The investigators, in addition, identified macrophages with similar iron-transporting features in human bone metastases and showed that elevated HBB expression correlates with increased risk of bone metastasis. “Notably, similar iron metabolism features were observed in a subset of macrophages in human bone metastases across multiple cancer types,” they wrote.

By revealing how tumors manipulate their surroundings, the work opens new avenues for therapies designed not only to slow or stop bone metastasis but also to alleviate the debilitating anemia that so often accompanies it. “Understanding the mechanisms driving cancer-associated anemia and developing targeted treatments are crucial for improving both life quality and survival,” the authors stated. “Our research suggests that preventing their tumor-driven rerouting or restoring EBI macrophage function could offer an effective therapeutic strategy to alleviate anemia and inhibit tumor progression in bone metastasis.”