Emily B. Harrison, Ph.D.
Every year more than one million women are diagnosed with breast cancer. Tumors are most often discovered through screening techniques like self-checks, breast exams, or mammograms. Immediately, plans are made to extract the tumor either by removing a small area around the tumor, a lumpectomy, or the entire breast in a mastectomy. Unfortunately, even once the tumor has been removed, cancer cells can still seed tumors in distant sites, called metastases. In fact, the rates of metastasis spike a year following surgery. While this post focuses on breast cancer, patients with many types of cancer face the same problem. Like the mythical Hydra, removing one tumor leads to the growth of others, leaving cancer patients and doctors in an epic struggle against this terrifying beast.
A mysterious pattern
What causes this increase in metastasis one year after surgery, and more importantly, how can we prevent it? One explanation is that surgery dislodges cells while the tumor is being removed. This is possible, but this phenomenon occurs even when the entire breast is removed and a scalpel blade doesn’t come anywhere near the tumor. Perhaps the cancer cells left the tumor before the surgery occurred, but weren’t detected? This is likely, but doesn’t explain why the one-year window is so critical. It is as if the cells sit dormant until the surgery, when something stirs them, awakening them to grow and divide.
A group of scientists centered out of Boston set out to answer these questions and the results were published earlier this year in Science Translational Medicine. Of course, testing whether or not removing a tumor causes metastases to grow is not possible in people; these life-saving surgeries need to be done. Therefore, scientists studied tumors growing in mice and devised an elegant system to test the effect of surgery on metastasis.
Could inflammation be the culprit?
The researchers speculated that the increase in metastasis was caused by the body responding to injury. Surgery, like any injury to the body, causes inflammation: redness, heat, and swelling. Inflammation also recruits immune cells to fight any bacteria or viruses that have entered the body and to clear away debris. When clean-up is finished, inflammation helps regrow new tissue and blood vessels to replace what was damaged. In a healthy person, this allows wounds to heal, but there are decades of research studying how cancer cells hijack inflammation to their own ends, to grow and feed tumors instead of repair wounds. In conditions where inflammation lasts years and even decades, it can even lead to cancer.
In previous OncoBites posts we have told you how we can use the body’s immune system to fight cancer with therapies like immune checkpoint inhibitors, CART cells, and cancer vaccines. These therapies help the adaptive immune system to fight cancer by creating and empowering trained assassins that hunt and destroy their target, namely, T cells. While the immune system is indeed a powerful tool in the war on cancer, there is a more sinister side too.
How to dissect a complex system
To study how the immune system could awaken dormant tumors, the researchers genetically engineered cancer cells that could easily be controlled by the mouse immune system. By expressing a foreign protein, green fluorescent protein, or GFP, the immune system could easily recognize the GFP-labeled cancer cells and the T cells could keep the tumors in check. Next, the authors created a way to mimic surgery in a consistent way, by implanting a small spongy material under the skin. As expected, this injury caused immune cells to home to the site, cells to grow into the empty space, and blood vessels to sprout.
When the engineered GFP cells and the wound mimicking sponge were implanted together, it made the cancer cells grow large tumors that could not be thwarted by the T cells. But more surprisingly, when GFP cells and the sponge were implanted on opposite sides of the mouse, far away from one another, the tumors also grew unchecked. This effect happened even if the sponge was implanted one week after the cancer cells, or if just a cut was made in the skin, without a sponge. It even happened in other types of cancer, such as melanoma. This implies that any major wound-healing process supports metastasis, even if the wound is not near the tumor. This connection between wound-healing immune responses and cancer progression has been seen before in the context of the tumor environment, but not systemically.
In the blood of wounded mice, there were many more immune cells than controls, specifically neutrophils and monocytes, classical first-responders to injury and part of the innate immune system. In the tumors there were more secreted molecules that draw these cells into the tumor, called cytokines. In addition, there were higher levels of molecules that inhibit T-cells, like PD-L1. These results indicate that the system-wide immune response can fuel tumor growth. Similar links between monocytes and metastases have been published by other research groups, including the group I work with. In our study, blocking the key cytokine responsible for recruiting monocytes effectively prevented metastasis in lung cancer models.
Dampening inflammation might be the key
The final experiment in the Science Translational Medicine paper sought to stop inflammation, to prevent tumors from growing after a surgery. Fortunately, there are already good drugs that inhibit inflammation. Perhaps right now you have a bottle of Ibuprofen in your medicine cabinet. Drugs like Ibuprofen belong to a class called non-steroidal anti-inflammatory drugs, or NSAIDs. In this study, NSAIDs were able to reduce inflammation and prevent it from fueling tumor growth. In fact, patients who are given NSAIDs after surgery are less likely to develop metastatic tumors than those given other pain medications.
As we learn about the relationship between our immune system and cancer, we realize how complicated it truly is. But as our understanding grows, we can design better therapies capable of orchestrating an immune response that will eliminate rather than promote cancer. In the end, to fight a many-headed beast we will likely need multiple weapons.
Krall, J. A., Reinhardt, F., Mercury, O. A., Pattabiraman, D. R., Brooks, M. W., Dougan, M., … & Weinberg, R. A. (2018). The systemic response to surgery triggers the outgrowth of distant immune-controlled tumors in mouse models of dormancy. Science translational medicine, 10(436).
Porrello, A., Leslie, P. L., Harrison, E. B., Gorentla, B. K., Kattula, S., Ghosh, S. K., … & Waugh, T. A. (2018). Factor XIIIA—expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking. Nature communications, 9(1), 1988.
Hercules slaying the Lernaean Hydra II by kajojak on Flickr