can nodes kill you?

Before a tumor spreads from its original location to other parts of the body, it typically invades nearby lymph nodes. For more than a century, researchers have debated whether this invasion of lymph nodes helps the cancer spread (or metastasize) to other organs.

A new study in mice suggests that it is an important step for cancer metastasis, and details how that happens.

Lymph nodes are bean-shaped organs that filter viruses, bacteria, and cancer cells out of the body. When you’re sick and the doctor feels the sides of your neck, they’re checking to see if your lymph nodes are swollen with immune cells fighting off an infection.

The study, partially funded by NCI’s Cancer Systems Biology Consortium, showed that cancer cells in the lymph nodes of mice encourage immune cells to protect tumors rather than attack them. As a result, the initial tumor essentially gains a pass to spread to the rest of the body.

The findings were published May 6 in Cell.

Cancer cells “not only avoid attack in the lymph nodes, but they actually turn things completely around and somehow convince the immune system to help the tumor spread,” explained the study’s senior scientist, Edgar Engleman, M.D., of Stanford Medicine.

Many studies have looked at the interplay of immune cells and cancer cells inside tumors, but these findings highlight “action happening somewhere else, outside of the metastatic and primary tumors,” said Hannah Dueck, Ph.D., of NCI’s Division of Cancer Biology. It highlights the role of the lymph nodes in the overall immune response to cancer, she said.

With some exceptions, the study was mostly carried out in mice implanted with melanoma, so additional studies are needed to see if the same phenomenon happens in people and with other kinds of cancer, Dr. Dueck noted.

“Lymph nodes are the heart and soul of the immune system,” Dr. Engleman said. But they haven’t gotten as much attention as they deserve, he added.

Lymph, a watery mixture of immune cells and fluid, flows through our bodies via a network of veinlike pipes. Hundreds of lymph nodes are dotted along this network.

Lymph nodes are like sophisticated training centers. Inside, immune cells learn how to fight infections and cancer. Once fully trained, the immune cells leave the lymph nodes to monitor the body for intruders.

To metastasize, cancer cells break off from the primary tumor and travel through the blood or lymph to other organs. If someone is found to have cancer in their lymph nodes, it’s usually a bad sign that the cancer has or will soon spread to other parts of the body. Most cancer deaths are caused by metastatic cancer.

But it’s never been clear what cancer cells are actually doing in the lymph nodes.

“One of the theories is that, in the lymph node, [cancer cells] gain traits that make them metastatic. And then, from there, they go to the distant organ,” Dr. Dueck explained.

“There is another theory that some cells from the tumor go to the lymph nodes, and some go to the distant organ,” she said. With this view, the lymph nodes don’t play a critical role in metastasis, she added.

With the necessary models and tools at their disposal, Dr. Engleman’s team set out to address the long-standing debate about these two theories.

The researchers first asked whether cancer in the lymph nodes of mice helps tumors metastasize to the lungs, one of the most common places cancer spreads to.

They implanted groups of melanoma cells under the skin of mice and let them form tumors. In some mice, the cancer spread to the lymph nodes, and in other mice, it didn’t. After several weeks, the researchers injected melanoma cells that don’t spread to lymph nodes into the veins of the mice and then checked their lungs for cancer.

There were far more tumors in the lungs of mice that had cancer in their lymph nodes than in mice that didn’t, they found.

So, it appears that spreading to lymph nodes helps cancer metastasize to the lungs, Dr. Engleman said.

Next, the researchers asked what gives some melanoma cells the ability to spread to the lymph nodes.

They found that cancer cells that had spread to the lymph nodes had higher levels of certain proteins, including PD-L1 and MHC-I, than melanoma cells that didn’t spread. High levels of PD-L1 and MHC-I send signals that tell cancer-fighting immune cells not to attack.

Further studies confirmed that higher levels of PD-L1 and MHC-I shielded melanoma cells from attack by immune cells. More specifically, immune cells called NK cells killed fewer melanoma cells that spread to the lymph nodes than melanoma cells that didn’t spread.

“It’s quite remarkable what [cancer cells have] to dodge on the way to the lymph nodes. There is lots of immune attack,” Dr. Engleman explained.

The researchers also explored what happens once cancer gets to the lymph nodes. Similar to what other studies have found, it appears that when cancer cells arrive, they shift the amounts and types of immune cells in the lymph nodes.

In mice, for example, there were fewer cancer-killing immune cells in lymph nodes that were invaded by melanoma than in lymph nodes that were cancer-free, the researchers found.

There were also more immune cells called T-regulatory cells (T-regs) in lymph nodes that were invaded by melanoma cells.

And in tissue samples from people with head and neck cancer, there were more T-regs in lymph nodes where cancer had invaded than in lymph nodes that were cancer-free.

The main role of T-regs is to protect healthy cells from attack by other immune cells that have gone off the rails. By doing so, T-regs help prevent autoimmune diseases and chronic inflammation. But T-regs can sometimes get mixed up, protecting unhealthy cells that should be eliminated, like cancer cells.

That’s exactly what the researchers appeared to see in their mouse studies: In mice that were bred to lack T-regs, melanoma tumors were less able to spread to the lungs.

The scientists then removed T-regs from the lymph nodes of mice where melanoma had or hadn’t invaded. They transferred the T-regs into other mice with melanoma that hadn’t invaded the lymph nodes. Only the T-regs from lymph nodes with cancer helped melanoma cells spread to the lungs, the researchers found.

Like other kinds of T cells, T-regs have special receptors that let them “recognize” the cells they protect. In mice with melanoma that invaded into lymph nodes, the researchers found T-regs that recognized the cancer cells.

In the near future, the team plans to examine exactly how cancer cells in the lymph nodes coax T-regs to protect them.

In the lymph nodes, immune cells learn what to attack (such as infected cells) and what to protect (such as healthy cells).

But this study suggests that, in lymph nodes invaded by cancer, immune cells learn to protect the cancer cells rather than attack them, Dr. Engleman said. This phenomenon is called immune tolerance.

The research team suspects that “those specialized [T-reg] cells—once they’re educated by the tumor—leave the lymph node, go all over the body, and instruct the immune system not to attack” other cancer cells, he explained.

If that’s the case, it would make distant organs more hospitable to the cancer, he said.

“Thus, we propose a new model of metastasis we call ‘Metastatic Tolerance,’” tweeted the study’s lead scientist, Nathan Reticker-Flynn, Ph.D., of Stanford University.

Lymph fluid would build up and cause swelling if it were not drained in some way. Lymph vessels draw up the lymph fluid from around the cells to send it towards the chest. There, lymph fluid collects into a large vessel that drains into a blood vessel near the heart.

Lymph vessels send lymph fluid through nodes throughout the body. Lymph nodes are small structures that work as filters for foreign substances, such as cancer cells and infections. They contain immune cells that can help fight infection by attacking and destroying germs that are carried in through the lymph fluid. Lymph nodes are located in many parts of the body, including the neck, armpit, chest, abdomen (belly), and groin. They contain immune cells that can help fight infection by attacking and destroying germs that are carried in through the lymph fluid.

There are hundreds of lymph nodes throughout the body. Each lymph node filters the fluid and substances picked up by the vessels that lead to it. Lymph fluid from the fingers, for instance, works its way toward the chest, joining fluid from the arm. This fluid may filter through lymph nodes at the elbow, or those under the arm. Fluid from the head, scalp, and face flows down through lymph nodes in the neck. Some lymph nodes are deep inside the body, such as between the lungs or around the bowel, to filter fluid in those areas.

When there’s a problem, such as infection, injury, or cancer, lymph nodes in that area may swell or enlarge as they work to filter out the “bad” cells. Swollen lymph nodes (lymphadenopathy) tell you that something is not right, but other symptoms help pinpoint the problem. For instance, ear pain, fever, and enlarged lymph nodes near your ear are clues that you may have an ear infection or cold.

Some areas where lymph nodes commonly swell are in the neck, groin, and underarms. In most cases, only one area of nodes swells at a time. When more than one area of lymph nodes is swollen it’s called generalized lymphadenopathy. Some infections (such as strep throat and chicken pox), certain medicines, immune system diseases, and cancers like lymphoma and leukemia can cause this kind of swelling. Your health care provider will look for more information to figure out the cause of the swelling. Lymph node swelling is often caused by something other than cancer.

Cancer can appear in the lymph nodes in 2 ways: it can either start there or it can spread there from somewhere else.

Cancer that starts in the lymph nodes is called lymphoma. You can read more about lymphoma in Hodgkin Lymphoma and Non-Hodgkin Lymphoma.

More often, cancer starts somewhere else and then spreads to lymph nodes. That is the focus of this section.

Cancer can spread from where it started (the primary site) to other parts of the body.

When cancer cells break away from a tumor, they can travel to other areas through either the bloodstream or the lymph system. If they travel through the lymph system, the cancer cells may end up in lymph nodes. Most of the escaped cancer cells die or are killed before they can start growing somewhere else. But one or two might settle in a new area, begin to grow, and form new tumors. This spread of cancer to a new part of the body is called metastasis.

In order for cancer cells to spread to new parts of the body, they have to go through several changes. They must become able to break away from the original tumor and attach to the outside wall of a lymph or blood vessel. Then they must move through the vessel wall to flow with the blood or lymph to a new organ or lymph node.

When cancer does spread to lymph nodes, it usually spreads to nodes near the tumor itself. These are the nodes that have been doing most of the work to filter out or kill the cancer cells.

Normal lymph nodes are tiny and can be hard to find, but when there’s infection, inflammation, or cancer, the nodes can get larger. Those near the body’s surface often get big enough to feel with your fingers, and some can even be seen. But if there are only a few cancer cells in a lymph node, it may look and feel normal. Lymph nodes deep in the body cannot be felt or seen. So doctors may use scans or other imaging tests to look for enlarged nodes that are deep in the body. Often, enlarged lymph nodes near a cancer are assumed to contain cancer.

The only way to know whether there is cancer in a lymph node is to do a biopsy. Doctors may remove lymph nodes or take samples of one or more nodes using needles. The tissue that’s removed is looked at under the microscope by a pathologist (a doctor who diagnoses illness using tissue samples) to find out if there are cancer cells in it. The pathologist prepares a report, which details what was found. If a node has cancer in it, the report describes what it looks like and how much was seen.

When a surgeon operates to remove a primary cancer, they may remove one or more of the nearby (regional) lymph nodes as well. Removal of one lymph node is considered a biopsy, but when many lymph nodes are removed, it’s called lymph node dissection. When cancer has spread to lymph nodes, there’s a higher risk that the cancer might come back after surgery. This information helps the doctor decide whether more treatment, like chemo, immunotherapy, targeted therapy or radiation, might be needed after surgery.

If cancer is found in one or more lymph nodes, it could mean that more tests are needed to know how far the cancer has spread. This information is used to determine the stage of your cancer and the best treatment options.

For more information on staging, see Cancer Staging, or find your cancer type for more detailed information.

When lymph nodes are removed, it can leave the affected area without a way to drain off the lymph fluid. Many of the lymph vessels now run into a dead end where the node used to be, and fluid can back up. This is called lymphedema, which can become a life-long problem. The more lymph nodes that are removed, the more likely it is to occur. To learn more about what to look for, ways reduce your risk, and how to manage this side effect, see Lymphedema.