American Association for Cancer Research

The Tumor Microenvironment

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.
Matrisian slide2
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.