Research: preventing metastases

If a tumor has already formed daughter tumors, a cure is often not possible. Researchers are looking for ways to prevent scattering

Preferred organs: Skin cancer often metastasizes to the liver and lungs

© W & B / Dr. Ulrike Möhle

A cancer diagnosis is often no longer a death sentence. But there is one piece of news that, despite all the progress, has lost little of its horror: the cancer has metastasized, i.e. further tumors in other organs. Nine out of ten patients today do not die from the primary tumor, as experts call the original cancerous tumor, but from its spread. Even if they cannot be identified at the time of diagnosis, patients are not sure. The worry that cancer will return hangs over them like a sword of Damocles for many years.

Pathways of cancer cells

Although cancer often only becomes an incurable disease through its daughter tumors, research here is still in its infancy. "In the past few decades, the examinations have concentrated on the primary tumor," confirms Professor Andreas Fischer from the German Cancer Research Center in Heidelberg. With great success.

90 percent of patients who die of cancer do not die from a primary tumor, but from metastases

For several years now, researchers have been looking at the next big questions: What causes cancer cells to travel in the body? How do they manage to grow in the unfamiliar environment of distant organs?

In general, cancer cells move through the body in two ways: via the blood and the lymphatic system. To get to remote organs, they have to overcome some hurdles. Even detaching oneself from the tumor cell structure requires special skills. To get into the blood, they have to penetrate tissue, then survive in a hostile environment teeming with immune cells, and finally adapt to a foreign organ. Impossible for healthy cells. But more than 99.9 percent of migrating cancer cells also die, even with highly aggressive tumors.

Tumor clusters floating through the body

"Metastasis is an extremely inefficient process," says Fischer. Researchers around the world want to find out how individual cells still manage to survive. Scientists have already tracked down a cause that makes cancer cells mobile. "Mobility is primary in human nature," explains Professor Klaus Pantel, Head of the Institute for Tumor Biology at the University Medical Center Hamburg-Eppendorf.

Via the blood to distant organs

© W & B / Dr. Ulrike Möhle

TO THE PICTURE GALLERY

© W & B / Dr. Ulrike Möhle

Initially, the tumor has no contact with the bloodstream

© W & B / Dr. Ulrike Möhle

Over time, skin cancer penetrates deeper layers

© W & B / Dr. Ulrike Möhle

Individual cancer cells travel with the bloodstream

© W & B / Dr. Ulrike Möhle

Some cells succeed in docking in an organ

© W & B / Dr. Ulrike Möhle

The new tumor needs blood vessels to grow

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Cancer does not become a fatal disease until it forms deposits in distant organs. Black skin cancer (malignant melanoma) usually only becomes threatening when it spreads. This often happens very early in this type of cancer

When an embryo develops, the cells initially migrate through the body. At the destination, they transform into different cell types and thus form the organs. Later on, genetic programs suppress the original joy of movement. Cancer cells manage to switch them off again. Especially when oxygen is scarce, they regress into a kind of stem cell and become mobile.

At the University Hospital Basel, Professor Nicola Aceto and his team are working on using this knowledge therapeutically. Once a tumor has started to spread, there are not only individual cancer cells in the blood, but also small clumps of cells, so-called tumor clusters, which then drift through the body. Research indicates that these are particularly dangerous. "They seem to play a major role, especially in breast cancer," says Aceto.

Heart medication for metastases?

With his team, he tested almost 2500 active ingredients that have already been approved. Some remedies that have been used to date for heart disease have succeeded in breaking up the dangerous clusters. In the process, the cells lost their stem cell properties. In laboratory tests, the formation of metastases could be significantly reduced. As a next step, the researchers want to test for which patients the drugs are suitable in clinical studies.

Professor Christoph Klein holds the Chair of Experimental Medicine at the University of Regensburg

© W & B / Jens Wegener

Cancer cells do not only become mobile at a late stage of the disease. "With a thickness of half a millimeter, for example, half of the melanomas that are capable of forming metastases have already spread," says Professor Christoph Klein, holder of the chair for experimental medicine and therapeutic methods at the University of Regensburg. In breast cancer, too, cancer cells are found in the bone marrow at an extremely early stage.

No metastases without scattering. But it doesn't mean that all cells start to grow. The larger the tumor, the more likely it is that metastases will occur as a result - this finding still applies. But why?

Metastatic niches in the organs

"For the body, the tumor represents something like a wound that never heals," says Fischer. This has effects on the whole organism. "The tumor prepares the bed for the metastases, so to speak." It sends out substances that inhibit the immune system or stimulate the growth of new blood vessels. Small cell vesicles with proteins, DNA fragments and other substances from the tumor, called exosomes, also travel through the body.

Organs such as the liver, lungs, and bone marrow that best accommodate them are also a preferred site of metastasis. So-called metastatic niches form in the organs, which are prepared by the primary tumor for colonization with tumor cells. They also succeed in changing adjacent, healthy tissue in such a way that it supports the growth of daughter tumors.

"The formation of metastases is incredibly complex," says cancer researcher Klein. New technologies make it possible to understand not just the individual cell, but the entire system. "Here I see opportunities for a completely different understanding of medicine."

New approaches in cancer therapy

The better understanding leads researchers to new points of attack: One promising approach comes from Spanish scientists at the Barcelona Institute of Science and Technology. They discovered a certain fatty acid receptor that occurs in large numbers on some particularly aggressive tumor cells. If they blocked this with antibodies, the cancer formed much less often secondary tumors, as the researchers in Nature to report.

Such approaches could be interesting for a situation in which many cancer patients find themselves: the tumor was recognized early and completely removed. No metastases can be seen. Still, there is a risk of relapse. Because in different organs there are most likely already isolated cancer cells.

In order to destroy this, some patients are given chemotherapy today. Most of the toxins used work by interfering with the cell's reproductive cycle. However, many of the cancer cells that have spread do not divide at first, or divide only slowly. According to Klein, other drugs that act on metastases often have no effect either.

"There is a big gap here," says the researcher. With his team, he develops models for drug tests in order to prevent the colonization of foreign organs in a more targeted manner. "The hope of finding drugs that work better and are perhaps only half as toxic is quite realistic," says Klein.

Euthanize cancer cells

New opportunities could also arise from a better understanding of dormant tumor cells. Many of the migrating cells fall into a kind of sleep after dispersing.

Research into these sleeper cells is one of Professor Klaus Pantel's specialties. "There is great therapeutic potential here," he says. Apparently the body manages to keep the resting cells under control, sometimes for years. Until they become active again at some point. That this is the case can already be measured with the help of blood tests developed by Pantel's team.

The researchers are working on a method to treat the awakened cells in good time before the metastases have grown. "We only see this when there are billions of cells," he says. Then healing is usually impossible.

On the trail of cancer with registers

Another goal would be to keep the cells quiet. But you would have to know what wakes them up. "Research is still completely in the dark here," says Pantel. The cancer expert is intensifying the search. He is already in contact with major epidemiological centers.

The plan: to use large cancer registries to search for events in the lives of cancer patients that could provide information about what arouses the cancer - and thus perhaps develop means that will let them sleep for a lifetime.