Breast cancer cells reprogram macrophages to support lung metastases

Studies by German Cancer Research Center (DKFZ) and HI-STEM scientists have shown that metastatic breast cancer cells utilize macrophages, a type of immune cell, to promote the colonization of cancer metastases in the lungs. .. The results of the team’s experiments in mice transplanted with human breast cancer cells showed that reprogrammed macrophages stimulate vascular cells to secrete a cocktail of metastatic proteins that are part of the metastatic niche. The results of the study have allowed researchers to identify new targets and potential treatments for controlling breast cancer metastasis.

Dr. Thordur Oskarsson, Research Group Leader for DKFZ and HI-STEM, said: “The complexity of crosstalk between cancer cells, macrophages, and endothelial cells is striking. A new strategy for breast cancer metastasis by better understanding the many proteins and other factors involved in these metastatic interactions. We were able to identify various starting points for this. Early therapeutic concepts for this have already been developed and need to be validated in future studies. “

Oskarsson and his colleagues Nature Cancer“Perivascular tenascin C causes continuous activation of macrophages and endothelial cells, creating a metastasis-promoting vascular niche in the lungs.. In their dissertation, the team concluded: “The results show an important role in the ongoing metastatic vascular niche and underscore the role of extracellular matrix in its regulation. These interactions in metastatic nodules provide future treatments for metastatic diseases. It can serve as a useful target for development. “

Cancer spreads into the body as individual cells separate from the primary tumor and move to remote parts of the body through the bloodstream or lymphatic system. Before they grow into metastases at secondary sites, these cells need to communicate with the new environment through various molecular interactions. “To settle in this new hostile environment, cancer cells destroy the microenvironment and support its growth,” said Oskarsson, who is currently working at the H. Lee Moffitt Cancer Center and Laboratories. Researchers call this tumor cells that create a “metastatic niche.”

Blood vessels play a very special role in metastasis. Isolated tumor cells prefer to stay in the immediate vicinity. In particular, as many studies have already shown, the interaction of endothelial cells (ECs) that line blood vessels with cancer cells is important for metastasis. However, the details of this molecular exchange are still largely unknown. The authors further state that: “Recent findings show that blood vessels can go beyond the delivery of nutrients and have a substantial effect on the progression of metastases. Studies show that disseminated cancer cells are associated with the vasculature at the site of metastasis. It is related and suggests that adherence to EC and enhanced crosstalk regulate cancer cell phenotype and function in metastasis. “

Oskarsson et al. Investigated the interaction between cancer cells and EC in the lungs of mice during metastatic colonization of the lung by breast cancer cells. Researchers first observed that four genes in lung endothelial cells showed a particularly strong increase in activity 3 weeks after the onset of metastases. The gene encodes proteins, Inhbb, Lama1, Scgb3a1, and Opg, which are secreted into the microenvironment and promote the development of lung metastases individually and in combination. Inhbb (inhibin beta B) and Scgb3a1 (secretoglobin 3A1) give cancer cells stem cell properties, Opg (osteoprotegerin) prevents programmed cell death (apoptosis), and Lama1 (laminin subunit alpha 1) Supports cell survival through adhesion.

Importantly, high expression of the four newly identified niche factors was also found to correlate with a reduction in both recurrence-free survival and overall survival in breast cancer patients. “… We performed a Kaplan-Meier analysis using the expression of four vascular niche components in estrogen receptor (ER) -negative breast cancer samples to investigate their potential survival implications,” the team reported. .. “In these samples, expression of vascular niche factors is significantly associated with reduced recurrence-free survival and overall survival, indicating a potential role in breast cancer.”

But how do cancer cells produce a metastasis-promoting protein cocktail in the lung endothelium? To the surprise of scientists, cancer cells do not do this task directly, but utilize macrophages, a cell type of the innate immune system.

“These macrophages are often located near pulmonary blood vessels and are activated by tenascin, an extracellular matrix protein produced by breast cancer cells,” said the lead author of the study at HI-STEM’s postdoc. Dr. Hongu Tsunaki explained. .. Tenascin is involved in the progression of many cancer diseases. After activation with tenascin, macrophages produce a variety of factors that induce the production of protein cocktails that promote cancer in EC. The authors further commented: “Perivascular macrophages activated via tenascin C (TNC) stimulation of Toll-like receptors 4 (TLR4) are niche activated by secreting nitric oxide (NO) and tumor necrosis factor (TNF). In particular, this mechanism induces EC-mediated production of niche components, which are important regulators of EC behavior and angiogenesis, vascular endothelial growth factor (VEGF). It had nothing to do with. “

Researchers have used specific molecular agents to eliminate macrophages or their activity and show that these cells are important for the production of metastasis-promoting protein cocktails. “… By targeting both macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis, we have added the ability to suppress lung metastases in mice,” they write. “In summary, our results explain the distinct endothelial activation properties that macrophage-mediated inflammation induces the production of vascular niche proteins and VEGF signaling promotes EC proliferation.

The team concluded that their results provide new insights into the role of extracellular matrix in cancer metastasis and indicate potential therapeutic tools. “The results reveal significant crosstalk within the vascular niche and emphasize the importance of extracellular matrix proteins as regulators of the microenvironment in metastasis,” they write. “These results provide a rationale for exploring the combination of TLR4i and anti-VEGF therapy in suppressing vascular function in metastases.”