Can breast cancer cells tell each other to metastasize?

Extracellular vesicles exosomes microRNA breast cancer metastasis
Breast cancer cells might be able to give each other the ability to metastasize using microRNAs packaged into extracellular vesicles similar to these exosomes. (Photo: Kourembanas Laboratory, Boston Children's Hospital)

Not all cancer cells are created equal. In fact, to call a cancer a cancer, in the singular, is something of a misnomer. Really, a patient could be said to have cancers, as every tumor is actually a mixture of cells with different mutations and capabilities.

One of those capabilities is the ability to escape the main tumor and spread, or metastasize, to other sites in the body. Not every cancer cell has this ability. But just like bacteria can share the ability to resist antibiotics, at least some cancer cells may be able to share the ability to spread.

According to a study by Judy Lieberman, MD, PhD, of Boston Children’s Hospital’s Program in Cellular and Molecular Medicine, breast cancer cells that can metastasize can tell those that can’t to turn that ability on. That conversation takes place via small pieces of RNA called microRNAs, delivered in microscopic packages called extracellular vesicles.

According to Lieberman, not only do her team’s data give insight into the metastatic process, they might also reveal the first example of cancer cells teaching each other.

Malignant conversations

Scientists have known for some time that cancer cells can communicate with their surrounding environment. Molecular crosstalk between a tumor and its milieu is the basis of angiogenesis (attracting blood vessels), and is a strong factor in immune evasion and metastasis too.

According to Lieberman and her team, that communication extends to crosstalk between different kinds of malignant cells within a tumor. “The idea that these mixtures can talk within themselves and to each other in a way that affects something important like metastasis is really new,” she says.

Her lab’s efforts point to microRNAs as being one vehicle for that communication.

MicroRNAs regulate gene activity much like the volume knob on a stereo, changing how “loudly” particular genes are expressed. In the 16 years since they were first noticed in worms, thousands of microRNAs have been identified in species up and down the evolutionary tree. They’ve also been shown to have a profound effect on many diseases.

“Ever since microRNAs were found in the circulation, researchers have been interested in finding out whether they could be diagnostic or prognostic of disease,” says Lieberman. “But whether they had a function in communication has been unclear.”

Metastatic cells microRNAs breast cancer
Non-metastatic breast cancer cells (green) take up miR-200 (red dots) from metastatic cells (blue outlines). (Photos: Minh Le, Lieberman laboratory)

Tumor cells often release microscopic packages called extracellular vesicles that are full of microRNAs. Several of those tumor microRNAs act on healthy cells to fuel angiogenesis or inflammation. And one microRNA in particular, called miR-200, is known to have some kind of relationship with breast cancer metastasis.

In a recent paper in the Journal of Clinical Investigation (JCI), Lieberman and Minh Le, PhD, a postdoctoral fellow in her lab, tried to dissect the nature of that relationship. Using breast cancer cell lines—some capable of metastasis, others not—and animal models of breast cancer, they showed that miR-200-carrying vesicles released by metastatic cells give non-metastatic cells the ability to establish new tumors in the lungs.

What’s more, non-metastatic cells picked up the ability to metastasize even if miR-200-producing cells were on the other side of the body.

How does miR-200 confer metastatic powers? Lieberman explains that when non-metastatic cells take up miR-200, their gene expression pattern changes in a way that helps them overcome one of the rate-limiting requirements of metastasis: the ability to thrive in a non-tumor environment. “miR-200 might give tumor cells a little push, enough to allow them to colonize a foreign site, grow and take it over,” she says.

Scrambling transmission

In some ways, the results raise more questions than they answer. What triggers metastatic cells to start releasing miR-200? Do cancer cells make more microRNAs than other cells? Or are they better than healthy cells at picking up microRNAs?

And might it be possible to cut off communications between metastatic and non-metastatic cells by blocking miR-200 or other microRNAs?

Lieberman isn’t sure. Part of the issue is microRNAs’ functional complexity. “There are tumors where miR-200 might have the opposite effect,” she notes. “This is a long way from therapy.”

But speaking broadly, microRNA-focused therapies may be possible. “There are tumor suppressor microRNAs as well as oncogenic ones,” Lieberman says, “and some clinical trials are already trying to deliver tumor-suppressing ones to cancers.”

Lieberman and Le’s paper is available from JCI.