American Association for Cancer Research

The Tumor Microenvironment

Invasion: The three steps required for a tumor to become invasive and metastasize

Let’s think back to the skin. On the outside of the skin are the epithelial cells. Underneath that is the connective tissue cells, the matrix, that provides a structure. So, how would a tumor arising in the epithelial cells become invasive and penetrate the matrix? Well, there are actually three steps that have to happen. First, the epithelial cells that have become cancerous have to attach to this matrix. Then they have to bulldoze a way through the matrix barrier. Then they have to be able to move. So, those are the three separate steps. The reason that we're talking about this is that if we can understand precisely what happens in each step, what specific molecules are involved in each step, then we can figure out how to stop it.
Matrisian slide3
Step one is matrix attachment. We know that the matrix is made up of very special structural proteins, that it looks like chicken wire, and that it holds everything together. It has sugars hanging off of it, and it has different proteins that link things together. Think of it as how you build a building, like when you play with Legos. You put all these pieces together and that’s what creates the structure.

The cell has to attach to this matrix, and it attaches through some very specific proteins on the cell surface. We call these proteins integrins because they integrate—or link—the cell and the underlying matrix. And once we understand protein molecules at this level, we can start to think about how to block them.

Step two of invasion happens through the action of proteases, enzymes that degrade proteins by cutting them like a big pair of scissors. If you are looking at photographs of cancer you can see that there is usually a line that is the basement membrane of the matrix right under the normal cells, but under the cancer cells the line disappears, as the protease opens up a hole and the cells just walk right through it. It removes the barrier.

At this point two steps have occurred: The cells have attached to the matrix, and they have cut holes. This means they are now ready to go to step three and move through the matrix. They do this through a very complex system. The outside matrix is connected to an inside matrix that allows the cells to move. It's kind of like ropes and pulleys that pull against each other and that allow them to move right through these areas. There are some wonderful pictures of tumor cells that are moving right underneath the skin of a mouse, and you can see the cell hanging onto things and pulling itself through. It's absolutely fascinating. And the cool thing is we're beginning to understand all those different steps, and the different molecules that are involved in making that happen.

The three steps of invasion are part of a bigger series of steps that result in metastasis. How do we put these steps together to create metastasis? It starts with the tumor cell growing. It becomes angiogenic. It then goes through the three steps of invasion, getting into the bloodstream. It circulates around. It goes through the heart and on to the lungs. It becomes stuck in a distant organ. Now, it has to do the invasion thing again to get into that distant organ. It is new to this organ and has to set up a home here. So, it starts calling in blood vessels and growing at that distant site. The interesting thing is that the tumor cell often goes many places, but there's a selectivity of where the tumor cell actually grows. Breast cancer cells will grow in the bone, lung and the brain. Colon cancer cells metastasize to the liver. Maybe that makes sense because they are so close together. But bladder cancer cells go to the brain. Why does that happen? There's a lot of very interesting biology going on trying to understand that. And again, the more we understand about it, the greater chance we have to stop it from occurring.

We can demonstrate the specificity of metastasis experimentally. For instance, if we take colon cancer cells and if we put them in the skin, they'll make a tumor, but they won't metastasize anyplace. If we put the same cells in the colon or near the colon, they'll go to the liver just like they do in humans. We use mice for these experiments so we can give them cancer, and study these specific processes. One hypothesis to explain why tumor cells metastasize to specific organs is that they get lodged in the smallest vessels in the bloodstream. The bloodstream gets smaller and smaller and then bigger and bigger as it goes back to the heart. So at the smallest point, some of these tumor cells just get stuck. In addition, there's a hypothesis that goes back to the late 1800s, which was developed by a very smart man, Sir Stephen Paget. He believed that there's a “seed and soil” effect, which means that specific tumor cells (the seed) need a certain soil to grow in. That helps explains why bladder cancer tends to metastasize to the brain or breast cancer will go to the bone when other cancers won't necessarily grow in these sites.

So, you can see how angiogenesis and tumor invasion and metastasis involve other parts of the body. But interestingly, even those basic things that are happening to the cancer cells themselves, such as the mutations that are occurring, are also being influenced by the tumor microenvironment, and I want to tell you a little bit more about some of those things.