The Tumor and its Microenvironment: How they communicate, and why it’s important
For
years researchers have focused on the cancer cell itself; more recently
we’ve begun to think more molecularly about how the rest of our body
influences the cancer cell. We call this the study of the
microenvironment: the normal cells and molecules that surround a tumor
cell.
When a normal cell transforms into a benign tumor, it
loses some of its growth regulation. But as a benign tumor, it's not
able to invade and metastasize. For that to occur, it has to accumulate
more
mutations.
This gives the cells the ability to move through the bloodstream and
end up at distant sites. When we think about cancer, it’s those cells
that we are worried about.
But there are other components of a
tumor. The word tumor just means a growth, and a tumor can be a benign
growth or it can be a malignant growth. In either case, the growth, or
tumor, is made up not only of tumor cells, but of other cells that are
there to support it.
For example, on the outside of your skin are
epithelial cells.
Underneath the epithelial cells there is supporting tissue, called
connective tissue, which is there to support the epithelial cells. So
what happens when you get skin cancer? Well, these epithelial cells go
crazy: They grow, start to accumulate mutations and develop their own
growth signals. As they do this they take along the supporting
structure, called
stroma.
As a result, a tumor contains both stroma and the malignant tumor cells
themselves. Within the stroma there are things like blood vessels,
which bring the nutrients that the tumor cell needs to grow, and immune
or inflammatory cells that come from the bloodstream and get into the
tumor. So a tumor is really an organ—not just a single cell type—as it
contains multiple cell types and multiple different components. This
increases a tumor’s complexity. But it also gives us some opportunities
that I'm hoping we can take advantage of.
So what is in the tumor and microenvironment? There are normal epithelial cells—those that are not cancer yet. There are
fibroblasts
and the cells that make up the blood vessels. There are the
infiltrating immune cells that come from the bloodstream. There are the
structural components comprised of proteins—little strands of fibers
that hold our cells together—which we call the
extracellular matrix
because it's outside of the cell. Then there are lots of molecules.
Some of the molecules are special kinds of growth factors called
chemokines and
cytokines, which are
chemical activators and cellular activators. There are also chemicals,
like oxygen, and chemicals that can change the acidity or the
alkalinity of the tissue. All of these different things make up the
tumor microenvironment.
The
communication between the tumor cells and the surrounding cells—the
microenvironment—helps drive the process of tumor progression. So going
from normal to benign, benign to malignant, malignant to metastatic is
driven not just by what's happening inside the tumor cell itself but by
what's happening around it.
Two of the key hallmarks of cancer are dependent on the surrounding microenvironment. One of these is
angiogenesis and the other is invasion and
metastasis.
Angiogenesis creates the blood vessels that give the tumor its oxygen
supply. Invasion and metastasis give the tumor the ability to invade
into other areas and to travel to different parts of the body. If a
cancer cell didn’t have these special characteristics, it would not be
able to continue to grow.
We’ve learned that we can make drugs that disrupt angiogenesis. One way we do this is by targeting the molecule
vascular endothelial growth factor,
VEGF, which is made by tumor cells. This is possible because the
scientific community has been able to find out exactly what the VEGF
molecule looks like and then make an inhibitor, like the drug Avastin,
which can interrupt the pathway between VEGF and the tumor.
VEGF
interacts with its receptor, producing all these signals, which allows
the blood vessels to grow. By making an inhibitor that blocks this
interaction, you go from a tumor that's calling in blood vessels to a
tumor in which the blood vessels have disappeared because they aren't
getting the signal to make them. And this has therapeutic
opportunities. For instance, the drug Avastin has been approved for
treatment of colon cancer and it's looking very positive in a number of
other tumor types as well. So this is an example of how we can use
information about the interactions that take place between the tumor
cell and the surrounding cells to make drugs that inhibit that activity.
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