Studies by scientists at the German Cancer Research Center (DKFZ) and HI-STEM have found that metastatic breast cancer cells exploit macrophages, a type of immune cell, to promote the settlement of cancer metastases in the lungs. Results from the team’s experiments in mice transplanted with human breast cancer cells showed that reprogrammed macrophages stimulate blood vessel cells to secrete a cocktail of metastasis-promoting proteins that are part of the metastatic niche. The study findings led the researchers to identify new targets and potential therapeutic avenues for restraining breast cancer metastasis.

Thordur Oskarsson, PhD, research group leader, DKFZ and HI-STEM, said, “The complexity of the crosstalk between cancer cells, macrophages, and endothelial cells is striking. With a better understanding of the numerous proteins and other factors involved in these metastatic interactions, we were able to identify a variety of starting points for new strategies against breast cancer metastasis. We have already developed initial therapeutic concepts for this, which we now need to validate in further studies.”

Oskarsson and colleagues reported on their findings in Nature Cancer, in a paper titled, “Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs.” In their paper, the team concluded, “The results show a crucial role for the vascular niche during metastatic progression, and emphasize the role of the extracellular matrix in its regulation. These interactions in metastatic nodules may serve as useful targets when developing future therapies against metastatic disease.”

Cancer spreads within the body as individual cells detach from the primary tumor and travel to distant body regions via the bloodstream or lymphatic system. Before they can grow into a metastasis at a secondary site, these cells must communicate with their new environment through a variety of molecular interactions. “In order to settle in this new, hostile milieu, the cancer cells corrupt the microenvironment to support their growth,” said Oskarsson, who now works at H. Lee Moffitt Cancer Center and Research Institute. Researchers refer to this as the tumor cells creating a “metastatic niche.”

Blood vessels play a very special role in metastasis. Detached tumor cells prefer to stay in their immediate vicinity. In particular, the interactions of cancer cells with the endothelial cells (ECs) lining the inside of the vessels are crucial for metastasis, as many studies have already shown. However, the details of this molecular exchange are still largely unknown. The authors further noted, “Recent findings indicate that blood vessels can have substantial impact on metastatic progression that extends beyond nutrient delivery. Studies have shown that disseminated cancer cells associate with vasculature at metastatic sites, and suggest that enhanced adhesion and crosstalk with ECs regulate phenotype and function of cancer cells in metastasis.”

Oskarsson and colleagues investigated interactions between cancer cells and ECs in the lungs of experimental mice during metastatic colonization of the lung by breast cancer cells. The researchers first observed that four genes in the lung endothelial cells showed a particularly strong increase in activity three weeks after the onset of metastasis. The genes encode the proteins, Inhbb, Lama1, Scgb3a1, and Opg, which are secreted into the microenvironment, and which both individually and in combination promote the development of lung metastases. Inhbb (inhibin beta B) and Scgb3a1 (secretoglobin 3A1) confer stem cell properties to cancer cells, Opg (osteoprotegerin) prevents programmed cell death—apoptosis—and Lama1 (laminin subunit alpha 1) supports adhesion-mediated cell survival.

Importantly, high expression of the four newly identified niche factors was also found to correlate with shortened duration of both relapse-free survival and overall survival of breast cancer patients. “ … we performed Kaplan–Meier analyses using expression of the four vascular niche components in estrogen receptor (ER)-negative breast cancer samples and investigated a potential link to survival,” the team reported. “In these samples, expression of the vascular niche factors was significantly associated with poor relapse-free and overall survival, indicating a potential role in breast cancer.”

But how do cancer cells get the lung endothelium to produce the metastasis-promoting protein cocktail? To the surprise of the scientists, the cancer cells do not do this job directly themselves, but instead harness macrophages, a cell type of the innate immune system.

“These macrophages, which often reside in the vicinity of the lung blood vessels, are activated by tenascin, an extracellular matrix protein produced by breast cancer cells,” explained Tsunaki Hongu, PhD, postdoc at HI-STEM and the first author of the study. Tenascin is involved in disease progression in many cancers. After activation by tenascin, macrophages produce various factors that induce the production of the cancer-promoting protein cocktail in ECs. The authors further commented, “Perivascular macrophages, activated via tenascin C (TNC) stimulation of Toll-like receptor 4 (TLR4), were shown to be crucial in niche activation by secreting nitric oxide (NO) and tumor necrosis factor (TNF) to induce EC-mediated production of niche components. Notably, this mechanism was independent of vascular endothelial growth factor (VEGF), a key regulator of EC behavior and angiogenesis.”

The investigators eliminated macrophages or their activity, using specific molecular agents, to show that these cells were crucial to the production of the metastasis-promoting protein cocktail. “… targeting both macrophage-mediated vascular niche activation and VEGF-regulated angiogenesis resulted in added potency to curb lung metastasis in mice,” they wrote. “Together, our results describe distinct endothelial activation properties where 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 the extracellular matrix in cancer metastasis, and point to potential therapeutic avenues. “The results reveal a critical crosstalk within vascular niches, and underscore the importance of extracellular matrix proteins as regulators of the microenvironment in metastasis,” they wrote. “These results provide a rationale to explore the combination of TLR4i with anti-VEGF therapy in suppression of vascular functions in metastases.”

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