Reading time: 4 mins
“I lit up like a Christmas tree, Hazel Grace.”
This line, from John Green’s bestselling novel The Fault in Our Stars, hits hard. A young teenage survivor of cancer has had a widespread relapse picked up in one of his many routine scans since going into remission years earlier. Unfortunately, his cancer returned, with a vengeance. He doesn’t make it.*
This is not an unfamiliar turn of events; once a patient gets an initial diagnosis of cancer, they often spend the rest of their lives dreading a recurrence, even after going into remission. It’s why we say “in remission” and not “cured,” after all; for many people, the cancer is only hiding, hibernating in different tissues before it one day bursts back into life. The reason why remains a mystery, but a recent study of white blood cells shed some light on one way cancer cells evade detection for so many years and then, suddenly, are triggered to grow.
In a study conducted by researchers from Cold Spring Harbor, Harvard, UC Davis, and Cambridge University, a connection was found between a type of white blood cells, called neutrophils, and cancer recurrence. Neutrophils are one of the first lines of defense in bacterial infections, which they fight in a variety of ways, including by releasing webs called NETs that function as traps for bacteria. These NETs kill infections, but also inflame the tissue in which they reside, which is known to be cancerous. In fact, NETs have been linked with metastasis (or invasion of cancer into other organs) in the past. Previously, population studies have shown that chronic lung inflammation, stemming from causes like infection or smoking, are associated with higher risk of lung tumors recurring in patients that originally presented with breast cancer. In fact, smoking doubled the risk of recurrence and death in breast cancer patients.
This study sought to definitively link inflammation with cancer cell “awakening” by studying dormant cancer cells in mice. They found that hibernating breast cancer cells in the lungs remained dormant after short-term exposure to a molecule known to cause inflammation, but grew and metastasized when exposed for periods of time associated with prolonged infections. They observed that neutrophils were more abundant in mouse lungs that had dormant cancer cells than in those that did not, and that if mice were depleted of neutrophils before treatment, the hibernating cancer cells remained dormant and did not metastasize. When researchers treated mice with NET-neutralizing drugs, like enzymes that break down the material that composes the NETs, they found that cancer invasion and inflammation were both significantly reduced, indicating that NETs are the culprit behind metastasis and that they are further triggering more inflammation. When inflammation was the result of cigarette extract, rather than the bacterial molecules from the initial experiments, the result was much the same, indicating that smoking can also provide lung irritation sufficient to induce cancer cell awakening when paired with neutrophils.
Through very careful and thorough experimentation, researchers found that NETs are able to wake up cancer cells because the enzymes they produce, neutrophil elastase and matrix metalloproteinase 9, break down and change the structure of a protein that supports lung cells (among others) called laminin. This broken-down laminin is able to bind to cancer cells and stimulate a cell growth and metastasis pathway. By taking the time to understand the mechanism behind their observations, they were also able to develop a therapy to stop the breakdown of the laminin and thereby prevent awakening and metastasis. They found that by giving mice an antibody that binds specifically to this broken-down laminin and blocks it from interacting with cancer cell receptors, they were able to disrupt the interaction between NETs and cancer cells and keep cancer cells dormant, thereby keeping mice in remission.
The data presented in this paper, while elaborate and precise, is still not available for human patients, as it was only shown in mouse models of disease, which often lack the complicated interaction of various factors that characterize naturally occurring human diseases. However, if laminin is also shown to be restructured in human patients, and if it holds true for other types of cancer cells lying dormant in other types of tissue, an antibody that binds cancer-awakening proteins could be a huge step forward in stopping the recurrence of cancer in patients in remission, particularly smokers or those prone to infection or other inflammatory events. Much work remains on how to effectively use a tool like this in humans for long periods of time, but we’ve taken a step in understanding the mechanisms of cancer through this work, and that is, in itself, deeply valuable.
Albrengues, J., Shields, M. A., Ng, D., Park, C. G., Ambrico, A., Poindexter, M. E., … & Bružas, E. (2018). Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science, 361(6409), eaao4227.
* Yeah, that was a spoiler, but both the book and the movie have been out for years. Don’t worry, even knowing what will happen won’t save you from crying when it does.