Breast Cancer Cells Corrupt Macrophages to Promote Metastasis

Breast Cancer Cells Corrupt Macrophages to Promote Metastasis

Cancer can easily spread from the site of the primary tumor to distal regions of the body when cancer cells detach from the tumor. They travel to distal sites via the lymphatic system or bloodstream, and often lodge near vasculature in secondary organs. In order for the cells to grow in the new location, they must first communicate with the cells in the new environment, but relatively little is known about that process.

New research conducted by scientists at the German Cancer Research Center (DKFZ) and HI-STEM has shed light on the molecular interactions between cancer cells and the cells in the new environment that allow them to grow into a metastasis. The researchers found that metastatic breast cancer cells corrupt a type of immune cell – macrophages – to create a ‘metastatic niche’ at secondary sites, reprogramming the macrophages to stimulate the endothelial cells in the blood vessels to secrete several metastasis-promoting proteins. Once breast cancer metastasizes it cannot be cured. The 5-year survival is 22% and the median survival is three years. Each year, metastatic breast cancer claims around 40,000 lives. The discovery has led to the identification of new targets for hindering breast cancer metastasis.

“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,” said Thordur Oskarsson, PhD, research group leader at DKFZ and HI-STEM. “We have already developed initial therapeutic concepts for this, which we now need to validate in further studies.”

Interactions between cancer cells and endothelial cells are a key part of metastasis. Recent research suggests disseminated cancer cells associate with endothelial cells at metastatic sites and the enhanced adhesion and crosstalk regulate phenotype and the function of cancer cells in metastasis. The researchers studied these interactions in mice transplanted with human breast cancer cells and observed a strong increase in the activity of four genes three weeks after the onset of metastasis.

Those genes encode four proteins – Inhbb, Lama1, Scgb3a1, and Opg – which individually and collectively promote the development of lung metastases by conferring stem cell properties to the cancer cells, preventing cell death, and supporting adhesion-mediated cell survival. The researchers determined that high expression of these proteins was associated with poor relapse-free and overall survival, suggesting they played a role in breast cancer.

The researchers then explored how the cancer cells traveled to the endothelium of the lungs and created a metastatic niche and found that this was achieved through macrophages, which are activated by tenascin, an extracellular matrix protein. Tenascin is known to be involved in the progression of many cancers. Once activated by tenascin, the macrophages produce factors that induce the production of the cancer-promoting proteins in endothelial cells. “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,” explained the researchers in the paper.

The researchers then eliminated the macrophages and found that they were crucial to the secretion of the cocktail of metastasis-promoting proteins. “These results provide a rationale to explore the combination of TLR4i with anti-VEGF therapy in suppression of vascular functions in metastases,” concluded the researchers.

You can read more about the study in the paper – Perivascular tenascin C triggers sequential activation of macrophages and endothelial cells to generate a pro-metastatic vascular niche in the lungs – which was recently published in Nature Cancer. DOI: 10.1038/s43018-022-00353-6