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Neutrophil 'traps' help tumor cells metastasize

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By Anette Breindl
Senior Science Editor

Researchers have identified "a new way that cancer cells are hijacking innate immune cells to promote metastasis," Mikala Egeblad told BioWorld Today.

Egeblad is an associate professor at Cold Spring Harbor Laboratory and the senior author of the paper describing the findings, which appeared in the Oct. 19, 2016, issue of Science Translational Medicine.

It's another battlefield in the multifront war between cancer and the immune system, where immune cells try to kill tumor cells, and tumor cells try to escape, inhibit or co-opt immune cells.

Neutrophils are the most common type of white blood cells and, as such, act as the infantrymen of the innate immune system. One of their weapons is the formation of neutrophil extracellular traps (NETs) – sticky packages of DNA, histones and proteases that are meant to catch and digest bacterial invaders.

Egeblad and her colleagues identified the role of NETs in metastasis because in previous work on metastatic breast cancer, they had "noticed that these metastatic breast cancer cells were attracting a lot of neutrophils," she said.

Other researchers had reported that, in contrast, neutrophils, under certain circumstances, appeared to promote tumor metastasis, so Egeblad was curious about exactly how neutrophils and metastases interacted. "I thought that was an interesting question, given that this is our most prevalent white blood cell," she said.

In their experiments, the authors showed that in mouse models, xenografted breast cancer cells that reached the lung tended to have NETs around them. The team also analyzed tissues from human cancer patients, and they showed that metastases of triple-negative breast tumors contained NETs.

In cell culture, NETs stimulated tumor cells to move, and inhibiting NET formation, or digesting the NETs with a nanoparticle, could inhibit that migration.

Exactly how the NETs help the tumor cells is "one of the things we weren't able to address in this first story – we are working hard on that," Egeblad said.

"Our data suggest that it's not really helping them get into the tissue, but it's helping them take off" and grow into larger metastases once they have managed to set up shop in the lungs.

Her theory is that the NETs are acting as a scaffold that is leading to high concentrations of proteases that act on the extracellular matrix, preparing a microenvironment that enables metastatic seeds to grow.

In the work now published in Science Translational Medicine, Egeblad and her team focused on breast cancer metastases to the lung. But Egeblad's hunch is that the relationship between NETs and mets is more general.

Other groups have shown that neutrophils may be helpmates in the metastasis of pancreatic cancer and sarcoma in experiments with human tissues, and neutrophils have been implicated in metastasis in yet other mouse models of different tumor types.

Different kinds of cancer may use NETs to varying degrees. Breast cancer cells were able to induce neutrophils, which may not be the case for other cancer types. "Some of the cancer cells may piggyback onto NETs formed physiologically by infection," Egeblad said.

Likewise, metastases in other sites than the lung may be aided by NETs. In mouse models of breast cancer, the lung is the biggest site of metastasis. In humans, breast cancer also often metastasizes to the bones and to the brain, and Egeblad and her colleagues are working to develop models of those sites.

They are also testing different ways to prevent neutrophils from making NETs, to ultimately test whether preventing NET formation could prevent breast cancer recurrence. Whether the nanoparticles they have described in their current paper "are ultimately going to be the best way, we don't know yet. . . . We are trying out different ways," Egeblad said. "The nanoparticle would be an intravenous treatment, and the patients are really not happy with that, for obvious reasons."

The findings also provide a more immediate warning with respect to current treatment strategies.

Chemotherapy can be "very toxic to neutrophils," she said, and neutropenia, the large-scale death of neutrophils, can itself be life-threatening as patients become unable to fight infections. Recombinant granulocyte colony-stimulating factor (G-CSF) is used to limit neutropenia – but in their paper, Egeblad and her colleagues identified G-CSF as a factor that helped tumor cells promote NET formation.

Those findings, Egeblad said, "point to whether one should think about that practice, and whether there is a way to get a balance" between preventing neutropenia and promoting metastasis.