The Microenvironment and the Role that its Cells Play in Cancer
First, I’ll talk about the basement membrane. The
epithelial cell sits on the
basement membrane,
and that basement membrane tells that epithelial cell all sorts of
things, like whether it should grow or not grow. Let’s say, for
example, we have a breast epithelial cell. The cell knows whether it
should make milk or not make milk depending on what's in this basement
membrane, so there's information going back and forth between the
basement membrane and the cells.
Mina Bissell
has made an absolutely phenomenal observation. She can take normal
breast epithelial cells, put them in culture, in a petri dish, and they
will make little clusters of cells just like they would look in a
normal breast. But if you take breast cancer cells and put them in
there, they don't know which way is up. They're just going all over the
place. They don't know that they are supposed to make these nice,
little structures. But if she interrupts the interaction between the
cell and the surrounding matrix by interrupting the integrins—the
integrating connection between the cell and the matrix that I talked
about before—she can fool this cancer cell into thinking that it's
normal. It will ignore all those things that went wrong inside the
cancer cell—all the oncogenes that have been activated, the loss of the
tumor suppressor genes. Basically, you've overridden the signal by
disrupting the cell’s ability to interact with the
extracellular matrix.
And, as a result, the cell thinks that it's normal. Now, it isn't
normal. It's still genetically all messed up, but it's not behaving
like a cancer cell. It’s not invading and metastasizing. It's behaving
more like a normal cell. So you've overridden that by altering the
tumor microenvironment. And that's the type of message that a lot of us
are very excited about, because it means we can now use the power of
the microenvironment to influence that cancer cell. It’s a way of
talking to it through its surrounding cells and the surrounding
microenvironment.
Fibroblasts
are one of the cells that sit in the surrounding microenvironment
around the tumor cell, and that the fibroblast can tell the tumor cell
what to do. There is a really cool experiment that's been done with
human prostate cells and fibroblasts that show this. Gerald Cunha took
prostate cells that are slightly abnormal, but not yet cancer cells,
and fibroblasts and put them together under the kidney capsule of a
mouse. In this case the mouse is just an incubator to make cells grow.
When we do this we see that none of these cells by themselves make
cancer. But if you take a fibroblast that used to be next to a cancer
in a human and you put it with these slightly abnormal prostate cells
that wouldn’t grow before, now they will grow and kill the animal, even
though the cell itself has not gone through all the
mutations
necessary to become a cancer cell. What’s happened is that the
fibroblast told that cell to become cancer. So it's another example of
how, if we can understand this process, we can then figure out how to
stop the cycle of interaction between the tumor and the
microenvironment.
There are also infiltrating cells that come
from the blood stream that are part of the tumor microenvironment. So
what about these inflammatory cells? You've all heard of the immune
system and how the
immune system affects
cancer. Well, there's a good immune system. There's something called
immune surveillance: When you get a cancer, a little cancer, sometimes
your immune system will come in and kill it and protect you from that
cancer. There's literature on how people who are immunosuppressed have
more cancer because this good immune system is not working. This immune
system works through a variety of mechanisms. One of them is the
natural killer cell, a cell from the bloodstream that goes into tissues
and plays this role of getting rid of cancer cells.
Steve Rosenberg at the National Institutes of Health has been trying to take advantage of this mechanism. His lab is taking normal
lymphocytes and activating them with a chemokine or
cytokine,
which can turn them into natural killer cells, and trying to use this
as a mechanism of enhancing our normal immune system to kill our cancer.
However,
we also know the immune system produces inflammatory cells. When you
have a tumor, the immune system detects a chronic condition, so the
immune system is continually responding. As a result, there are many
inflammatory cells that are being put into the bloodstream. And these
inflammatory cells can get into the tumor, and when they do, they can
actually cause these tumors to grow more instead of fighting against
them. So here's another example of how if we can understand
inflammation—understand the molecules that are going back and forth in
the system—we can start to intervene so we can stop the inflammatory
cells from driving the tumor to grow more.
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