There Goes the Neighborhood
Q&A with scientist Zena Werb on cancer, immunity and the microenvironment.
By Chris Palmer
A tumor is often thought of as a uniform lump of misbehaving cells. In reality, it is a neighborhood or “microenvironment” made up of different cell types, including immune cells, blood vessels, connective tissue and, of course, cancer cells. For more than two decades, Zena Werb’s lab at the University of California, San Francisco (UCSF) has studied how the microenvironment influences cancer initiation, progression and metastasis, and how, in turn, cancer cells modify their surroundings.
Werb, co-leader of the UCSF Cancer, Immunity and Microenvironment Program, began her scientific career with an interest in how the body develops. She started studying the mammary gland because it is the only organ that develops after birth. She expanded her focus to cancer when she became curious about what causes normal development to go awry. This research overlapped with her longstanding interest in the extracellular matrix, a network of large molecules within the microenvironment. Scientists had long viewed the extracellular matrix primarily as a support structure for maintaining tissue shape. Werb’s lab discovered that the matrix does much more: It plays an important role in tissue development, and when its molecular composition is significantly altered, diseases such as cancer can occur.
recently spoke with Werb about the microenvironment’s role in cancer and how a healthy immune system can fend off cancer by keeping the neighborhood healthy and inhospitable to cells that start to act abnormally.
Q: What is the relationship between cancer cells and the neighborhood in which they live?
A: More than 125 years ago, the British surgeon Stephen Paget said that what’s important for cancer is not only the seed—the cancer cell—but also the soil in which it is planted. Not only do you need the mutations in the tumor cells, but you have to put those cells in the proper neighborhood for them to flourish as a tumor.
Q: How do neighborhoods turn bad?
A: Mutations naturally occur when cells reproduce. By the time you’re an adult, you have many, many cells with mutations in your body. Most of those you will live your life with and nothing will happen. However, if those mutated cells happen to find themselves in a place where the neighborhood, or microenvironment, has changed—as the result of inflammation or a weakened immune system, for example—you can get cancer.
In the case of cancer of the stomach, for example, you have a bacterium (Helicobacter pylori) that causes inflammation, creating a suitable environment for a cancer cell to grow. Another example is inflammation of the gastrointestinal tract, such as in Crohn’s disease. People with this disease have a much higher risk of colon cancer.
Q: How does the microenvironment influence whether tumor cells will spread to other parts of the body?
A: It’s clear that certain microenvironments—especially those that, like
the breast, contain a lot of threadlike
connective tissue called collagen
fiber—are pro-metastasis. People thought the fibers would be a barrier, like they were going to wall off the tumor. That can happen, but collagen fibers also work like tracks to build a superhighway along which cells can move quite quickly into the bloodstream.
Q: Once tumor cells metastasize, how do they acclimate to their new neighborhoods?
A: Cancer is not a local disease, even if it hasn’t metastasized. Tumor cells make all sorts of molecules that can change the whole body. Even though you have cancer in your breast, your lung may have changed too. It is believed, and there’s some evidence to back it up, that some of these factors can change the environment to make it more amenable to metastasis.
Q: What can people do to improve their microenvironments?
A: Boosting your immune system through diet and exercise may be very helpful. Also, baby aspirin, which people take to decrease heart problems, improves immune system function. And a reasonable amount of vitamin C may make the extracellular matrix a lot more stable. However, these only help a little. The most important thing is to have an overall healthy diet.
Q: Will we one day have drugs that could “treat” the microenvironment?
A: When you have a tumor cell, it has mutations in it. Then when you treat it with a drug, some of the cells that survive have made new mutations, which make the cells resistant to the drug. The cells that make up the neighborhood do not mutate and will not develop resistance to drugs, but they can regulate the susceptibility of tumor cells to drugs. So the idea of being able to target the microenvironment with drugs is of interest. But will it tip the balance enough to stop cancer or slow it down? That’s probably going to depend on the cancer.