A Tiny Piece of Genetic Material Makes a Big Splash in Cancer Research

Cancer and metastasis

by Ruth Tennen, Stanford University

Cancers like this breast cancer
are most dangerous when
they spread.

Each day, more than 1500 people die of cancer in the United States. In almost all these cases, patients die when the tumor spreads, or metastasizes.

Thanks to research published in the journal Nature last week, scientists may be one step closer to figuring out how cancer cells travel from an initial tumor to other parts of the body.

Cancer is a disease in which our cells grow and divide too quickly. Unlike normal cells that know when to stop growing, cancer cells grow even when they shouldn't. These cancer cells can grow into solid tumors like those seen in breast and colon cancer.

What makes cancer cells so dangerous? First, they grow and divide too fast. This can cause big problems in places like the brain, where there isn't a whole lot of room.

But for the most part, cancer cells are content to stay where they are. This allows doctors to remove them with surgery or to kill them with localized radiation. And this is why most people don't die from a primary (initial) tumor.

But sooner or later, some of these cancer cells get restless, and they decide to explore the rest of the body. This is what happens in metastasis.

In order for a cancer cell to become metastatic, it needs to be able to do many things. First, it needs to release itself from the tumor, just like an explorer sailing off from the coastline. Most cells like to stick together, so this is harder than you might think.

Second, the cancer cell needs to get into the bloodstream so it can travel to a new place. It does this by squeezing through the wall of the nearest blood vessel. This is called intravasation.

Next, the cell needs to find an exit off of the bloodstream highway. So it squeezes through the wall of the blood vessel, this time in the opposite direction. This process is called extravasation. And once it arrives at its destination, the cell has to start growing and dividing to form a new tumor.

We know that metastasis plays a critical role in cancer. But scientists still don't know much about the process. One of the most important questions is, what turns a regular ‘sedentary' cancer cell into a metastatic cancer cell?

Recently, scientists at MIT have found that a tiny snippet of genetic information—called a microRNA—is expressed at very high levels in patients with metastatic breast cancer. And this may be big news for the field of cancer metastasis.

microRNA 10-b makes breast cancer cells metastatic

Mice like this can help scientists
figure out how cancer spreads.

Cancer is caused by mutations, or changes in our DNA. These mutations cause cells to grow and divide too quickly. (Click here to learn about how mutations are made.)

Different cancers have different mutations. Some cancer cells have mutations that make them grow even when they should stop growing. Others have DNA mistakes that prevent them from dying when they're supposed to die. (Click here to learn more.)

One thing that all cancer cells have in common is that they use their DNA in different ways. They turn on genes that are normally turned off, or they silence genes that should be turned on.

In order to figure out which DNA changes help cancer cells become metastatic, scientists at MIT focused on breast cancer. They looked at ‘sedentary' cancer cells—cells that stay in one place—and metastatic cancer cells, and they searched for genes that were turned on extra high in the metastatic cells.

These scientists, led by a researcher named Li Ma, found that a special gene—called microRNA10-b (or miR10-b for short)—was turned on at very high levels in metastatic breast cancer cells. They then set out to prove that miR10-b could cause breast cancer cells to become metastatic.

They did this in a couple of ways. First, they looked at the cells by themselves in a Petri dish. They took away miR10-b from metastatic breast cancer cells and found that these cells could no longer invade a gel-like material in the Petri dish. (This experiment is the Petri-dish version of a metastatic cancer cell invading into nearby tissues.) And when the researchers forced non-metastatic breast cancer cells to express miR10-b by giving them extra copies of the miR10-b gene, these cells became better at invading.

To get a little closer to real breast cancer, the scientists moved from Petri dishes to mice, which are often used as models for human cancer. They took non-metastatic breast cancer cells and forced them to make more miR10-b. As a control, they used non-metastatic breast cancer cells that did not have extra miR10-b. Then they put both sets of cells into the mammary fat pads of mice to see if the cells would form breast cancers.

What they saw was striking. Both sets of cells were able to form breast cancers in the mice. But only the cells with the extra miR10-b—and not the control cells—were able to invade the muscle and blood vessels surrounding the tumor. Even more amazing, these cells metastasized all the way from the breast to the lungs.

So Ma and her colleagues knew that miR10-b could make breast cancer cells more migratory and invasive. But how is miR10-b doing this?

More Information

Breast cancer facts and figures (from ACS)

miR10-b turns on a gene that helps cells move

Macrophages attack a spreading
cancer cell.

To figure this out, the scientists thought about what microRNAs do. Most genes in our DNA code for messenger RNA (mRNA) that is made into proteins. These proteins then go on to do all the work in our cells.

But microRNA genes code for tiny pieces of RNA, only about 21 letters (or nucleotides) long. These snippets of RNA act like brake pedals for proteins. They bind to the mRNA of normal genes, and they prevent the mRNA from being made into protein.

If scientists can figure out which proteins miR10-b shuts off, then maybe they can discover how the microRNA is causing breast cancer cells to start traveling. Luckily, scientists know how microRNAs choose which proteins to shut off.

RNA is made up of four different letters, called nucleotides. And each RNA is unique because the nucleotides are arranged in a certain order.

Just like in DNA, certain nucleotides in RNA like to pair up. G always pairs with C, and A always pairs with U.

MicroRNAs do their job by binding to a ‘buddy' sequence in an mRNA. Imagine that an mRNA has AUCG. A microRNA could bind to this sequence if it was UAGC. Once the microRNA binds to the mRNA, the mRNA can no longer be read and made into protein. (Click here to learn more about microRNAs.)

So the MIT scientists used the miR10-b sequence to figure out which mRNAs it might bind to. One of these mRNAs was coded for by the HoxD10 gene.

HoxD10 is a gene that's important in development; it helps pattern our bodies before we're born. The HoxD10 protein is a transcription factor, which means that it helps control which genes are on in a cell. One job of the HoxD10 protein is to make sure that a gene called RHOC is turned off. And it turns out that RHOC is known to be important in metastasis.

So here's what the scientists think might be going on. Something happens that causes a cancer cell to start cranking out extra miR10-b. This microRNA then binds to the HoxD10 mRNA and prevents it from being made into HoxD10 protein. Without enough HoxD10 protein around, the RHOC gene gets turned on and makes the cells metastatic.

To test this hypothesis, the scientists again took their non-metastatic breast cancer cells and put in extra copies of miR10-b. But this time, they also got rid of RHOC. And guess what? These cells were not metastatic. In other words, extra miR10-b only matters if RHOC is around.

Clues to a cancer treatment?

This is the first time scientists have found that turning on a single microRNA can contribute to cancer metastasis. But changes in the levels of microRNAs—either too little or too much—have been found in certain primary cancers.

For example, the miR15 and miR16 genes are often missing in a type of cancer called chronic lymphocytic leukemia. High levels of miR155 are sometimes seen in a cancer called Burkitt lymphoma. And people with colon cancer often have too little miR143 and miR145.

Can we use this new information about miR10-b to help treat breast cancer patients? Maybe. If we can figure out a way to block miR10-b—or RHOC—, we might be able to keep cancers in check and prevent them from invading the muscle and metastasizing to other parts of the body. Then surgery and localized radiation might be able to remove or kill all the cancer cells at the primary site.

It looks like big things can come in small packages.

Ruth Tennen

More Information

Content provided by the Department of Genetics, Stanford University.