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.
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.
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