Unlocking the Mysteries of Metastasis

By Charles (Karl) Saxe, PhD

Something patients do not want to hear and physicians do not want to say is “your cancer has metastasized.”

Metastasis is the process whereby cancer cells spread from the site of the original tumor to one or more other places in the body. And with upwards of 90% of all cancer suffering and death associated with metastasis, it is the single most significant challenge to management of the disease.

It’s no wonder, then, that a major goal of cancer research is to understand what causes metastasis and how it happens. [more]

Why is metastasis so deadly?

Many different types of cancers can spread (metastasize), including blood cancers, but it is most often associated with solid tumors (like breast, prostate, or colon). Cancer cells can spread to many different parts of the body, though the most common sites are the lungs, liver, brain, and bones, and each kind of cancer tends to spread to specific sites.

Tumor cells spread through 3 major paths: through lymphatic vessels, through blood vessels, and along surfaces on the inside of the body cavity. Carcinomas typically begin their journey via the lymphatic route, then later spread via blood vessels to their final destination. In contrast, bone and soft tissue tumors, or sarcomas, usually metastasize directly by the blood vessel route. Only a small group of tumors (including mesotheliomas and ovarian carcinomas) spread through the body cavity.

So why are metastatic cancer cells so lethal? Often it is because metastatic cancer causes symptoms that are also common to other diseases. It is not unusual for a metastatic cancer to be discovered by tests being done for some other condition.

For example, doctors might find bone metastasis when checking on lower back pain, or lung metastasis because a patient has shortness of breath. Either of those symptoms could be caused by many things other than cancer so the metastatic tumor may get diagnosed only after it has grown significantly. It’s also possible, though not common, for a growing metastatic tumor to cause symptoms before the primary tumor is even found. When either of these things happen, it can be harder to treat the cancer successfully.

A complicated process

Remarkably, real progress in understanding the processes of metastasis has only happened in the last couple of decades, even though the concept was known in the 1800s.  For a long time metastasis was thought to be too complicated, too complex, to be understood.  It was thought there were no rules to how it happened.  It was not until the late 1970s and early 1980s that researchers showed that there were rules, that certain tumors metastasized to particular organs, and that you could manipulate them to understand why. 

Today we know that metastasis involves several steps, though we don’t know everything about each step.

  • First tumor cells must stop growing. Why some cancer cells stop growing and prepare to move while nearby tumor cells continue to grow out of control is an area of intense research. Part of the answer seems to involve signals they get from the normal cells surrounding the tumor. These can include immune cells that are recruited to the site of the tumor. But rather than help destroy the tumor, the cancer cells actually entice the immune cells to provide nutrition and guidance that helps the tumor cells to begin to metastasize.
  • Then the cancer cells must break away from the tumor. This process is more complicated than you might expect because cells tend to stick to each other. The cells not only have to escape from the tumor, but they must change from a cell that stays still into one that can crawl away from the tumor and move long distances throughout the body.
  • Next the cancer cells must move out of the tissue and into the blood or lymphatic system. We often think of them moving as single cells and arriving at their final destination the same way. But this is rarely the case. While they do sometimes move as individuals, recent research has shown that they often move as clusters or colonies. We’re not sure what this means.
  • Finally, the cancer cells move into a new location, where they begin to grow again.


The search for answers

One of the most intense areas of research is in understanding what happens in this new location.  This new environment is often called the “tumor microenvironment” or “metastatic niche.” There is evidence that it begins to form before the cancer cells even begin to spread. How does that happen?

And why is it that some cancer cells reach the metastatic niche and begin to grow and divide right away while others arrive at a niche and barely grow at all? The stalled cells are called micrometastases, and these small clusters of cells can remain in the new site, for decades, not growing, and not causing any problems.

Researchers hope a better understanding of the niche can provide new strategies for inhibiting the growth of metastatic cells.  If we can recreate the conditions that keep metastatic cells from growing beyond micrometastases, then even if we can not kill all of the cancer cells, maybe we can block their ability to grow and expand. For instance, we’re now uncovering how breast cancer cells metastasize to bone.

While the term metastasis was first coined in 1829, the history of metastasis is rather limited due, of course, to a lack of understanding of the processes involved. It’s just been in the past few decades that we’ve begun to uncover the mysteries and have found specific cancer genes associated with metastasis. Just as there are genes that promote tumor growth and genes that stop tumor growth, there are genes that both encourage and suppress metastasis. This last class of genes was a particular surprise and was controversial until quite recently. But it is this group of genes that has led the way in focusing on the importance of understanding the differences between tumors and the tumor microenvironment.

It is clear that to find better, less toxic therapies and save more lives from cancer, a major focus must be on understanding how metastasis occurs. The last decade or so has shown a dramatic increase in the amount of research being done, by American Cancer Society-funded researchers as well as others, to understand metastasis.

But as pointed out by ACS Scientific Council member Dan Welch, “Fewer than 8% percent of researchers mention the word ‘metastasis’ in their grant applications, in the context of actually working on the problem, …Figuring out how to prevent cancer – a key research focus today – would be the best approach, he agrees, but that’s of little help to patients who already have cancer. He further explains, “To prevent something, you have to know its cause. We have no idea why cancer cells spread, let alone what prompts them to disseminate throughout the body.”

But now we are beginning to, although the search goes on for answers on how to stop it.

Dr. Saxe is director of the American Cancer Society’s Society’s Program in Cancer Cell Biology and Metastasis.

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