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.NEXT→