American Association for Cancer Research

The Tumor Microenvironment

Using Our Knowledge of the Microenvironment to Fight Cancer

So why do we care about this? We care about this because of its therapeutic potential. We think about a tumor cell progressing from benign to malignant, and when it does it can become a lethal tumor that keeps a person from living a normal lifespan. What we do with cytotoxic (cell killing) therapy is that we intervene and we try to kill all these cells. However, we know this doesn't always work. We can't always kill them all. Sometimes they come back faster than they would otherwise. Also, cytotoxic therapy causes a great deal of damage to normal tissues as well. So we now talk about cytostatic therapy. We talk about arresting the cancer, stopping it, making it static. This means that the cancer doesn't disappear but it doesn't grow anymore either, so it's static. Now, if that would work, we would be in great shape. What happens a lot of the time is that we end up being able to slow down how fast the cancer grows. We can't quite stop it, but we have learned that we're able to slow it down with cytostatic types of therapy.

Matrisian slide6Now, what you want to do when you really want to make an impact is to get to the cancer early. This is particularly true with cytostatic therapy—since you can only slow down and not stop the growth, you want to slow it down as early as possible so you can have the greatest chance of preventing patients from dying of cancer and letting them live a normal lifespan.

When you're talking about progression of the tumor, the tumor cells are marching along and they are accumulating mutations. But when they metastasize, they are in a new site, so the stroma in the new site has not been influenced yet by that cancer cell, and it is much earlier in terms of its progression. So when we hit the tumor with a therapy that targets the stroma, anti-stromal therapy, it's hitting earlier in the process and has a greater chance of influencing survival of the patient compared to a drug that targets the tumor cells themselves. This gives us some opportunities to intervene that I think are going to be very exciting and very important in the future.

Matrisian slide7The second reason to be excited about targeted cells in the tumor microenvironment is because of the lack of genetic instability in the stromal cells. There are all these mutations, all these genetic problems that are occurring within the cancer cell, that cause instability. This is one of the main reasons why we see drug resistance. These cells change when something happens to them. So say you give a drug to this purple cell. Well, you start giving it the drug and then that cell changes and it becomes this green cell. So the drug against the purple cell doesn't work anymore. That’s because the cells are very unstable. But when you hit the surrounding cells, the normal cells that are influenced by the tumor but are not themselves genetically unstable, you can talk them into influencing the tumor cells. It’s a way of getting a cell close to the cancer cells to talk to them and turn them into normal cells. That's why we're excited about this particular area. There are different research groups that are trying to fully understand all of the interactions taking place, and to then actually develop targeted therapies that are based on understanding the communication between these cells.
Matrisian slide8
So this is what we're trying to do: We’re trying to understand and target the microenvironment, the interface between the tumor cells and the normal stromal cells. The overall goal of all this research is to improve clinical practice. We do this with clinical research, by giving drugs to people and asking what works better. But in order to get to that point, we need this whole base of research underneath it. It’s like a pyramid.

I’ve been talking about the way that scientists try to understand the process of cancer, the way we try to get it down to individual molecules, the way we try to understand how they work and how we can interrupt them. By learning all of this we will be able to accelerate opportunities to take this information through the translational research process into clinical research and, in turn, eventually impact clinical practice.