Immune System Defending Neutrophils Can Surprisingly Aid in Cancer Metastasis

    Researchers at Cold Spring Harbor Laboratory (CSHL) published a study (“Cancer Cells Induce Metastasis-Supporting Neutrophil Extracellular DNA Traps”) in Science Translational Medicine that reveals how neutrophils, the most common type of white blood cell and enemy of bacteria and other invaders, can be “hijacked” by cancer cells and used as an aid in metastasis. The study also shows a possible way of preventing this.

    Mikala Egeblad, Ph.D., and her team demonstrate, using live-imaging technology, that a remarkable weapon sometimes deployed by neutrophils against invaders like bacteria and yeast can aid metastasis in a mouse model of triple-negative breast cancer, one of the most aggressive subtypes and known to be prone to spread and relapse in people.

    This astonishing weapon appropriated by cancer cells is a lattice of DNA that is ejected from an activated neutrophil when the neutrophil detects a threat. Such nets—appropriately dubbed neutrophil extracellular traps or NETs—form dense spider web-like structures outside the neutrophil. The DNA that forms the backbone of the web is studded with tiny toxic enzymes that can degrade and digest invaders.

    “The remarkable thing we witnessed in live imaging was the ability of cancer cells to induce nearby neutrophils to eject their NETs, even when no infection or invader was present,” says Dr. Egeblad. “Our experiments showed that the NETs, in such situations, can promote metastasis.”

    Although the precise mechanism is still being explored, Dr. Egeblad thinks NETs help cancer cells by literally eating through the proteins that form a tissue’s scaffolding—thus opening up small holes and crevices that cancer cells can occupy. This can be a first step in forming a cancer colony at a site distant from the primary tumor.

    Is it possible to prevent neutrophils from deploying their NETs? Doing so throughout the body would be an awful idea, since we depend on their killing action every day. But, says Dr. Egeblad, “you don’t have to prevent it. You can degrade and digest the NETs as they are being formed.”

    The team was inspired by a treatment used in cystic fibrosis, a disease in which the lungs cannot clear infections. Patients with cystic fibrosis are burdened, among other things, by innumerable deployed NETs that are ejected from neutrophils trying to fight the persistent infections often occupying the patients’ lungs. Patients can inhale a drug employing the enzyme DNase, which cuts right through the NETs. As its name implies, DNase will cut into anything made of DNA, as are the NETs sent out by neutrophils.

    “We are incredibly lucky to have the help of Dr. Michael Goldberg and his team at the Dana-Farber Cancer Institute,” notes Dr. Egeblad. “We were explaining our discovery at a conference and mentioned that we were lacking a way to get DNase to work inside tissues and Dr. Goldberg said he might be able to help.” His team had developed a way to stabilize enzymes such as DNase by “gluing” them to extremely tiny drug-delivery devices called nanoparticles that can be injected into humans. In this case, nanoparticles were not used as containers for a drug, but instead, as minuscule spherical objects coated with the drug, DNase, so that its cutting effect would begin on contact with the NETs.

    Dr. Egeblad’s team successfully tested the method in mice modeling triple-negative breast cancer, markedly reducing, and for some mice even preventing, metastases to the lung, the most common site of metastasis in this animal model.

    Since these experiments used the same formulation of DNase that is used in an FDA-approved cystic fibrosis treatment, the way is clear to optimization of the system devised by Drs. Egeblad and Goldberg’s teams. It will be important to determine which breast cancer patients are most likely to benefit from such a treatment—presumably including those who have recently had an infection or who have undergone surgery and thus are at heightened infection risk. The optimal timing of drug delivery is also under study.

    Dr. Egeblad stresses that the work is also pertinent to current cancer treatments, since a neutrophil-boosting growth factor, called granulocyte colony-stimulating factor (G-CSF), is given to many cancer patients during chemotherapy. That is because chemo is quick to kill white blood cells, a loss that can expose a patient to potentially lethal infections. On the basis of what they now know about the impact of neutrophils on metastasis, “it will be important to evaluate if this practice may actually be dangerous in some cases,” Dr. Egeblad observes. Her team is studying this problem while it works on optimizing DNase treatment to counter neutrophils when metastatic risk is high.