First step of metastasis halted in mice with breast cancer

December 12, 2013, Johns Hopkins University School of Medicine
A breast tumor (blue) uses leader cells (green) to invade muscle tissue (red) in a mouse. Credit: Kevin Cheung, Cell

Cell biologists at Johns Hopkins have identified a unique class of breast cancer cells that lead the process of invasion into surrounding tissues. Because invasion is the first step in the deadly process of cancer metastasis, the researchers say they may have found a weak link in cancer's armor and a possible new target for therapy. A summary of their results will be published online in the journal Cell on Dec. 12.

"Metastasis is what most threatens , and we have found a way to stop the first part of the process in mice," says Andrew Ewald, Ph.D., assistant professor of cell biology at the Johns Hopkins School of Medicine.

Before metastasis occurs, single cells on the edge of a tumor, termed leader cells, form protrusions into the surrounding tissue, like someone dipping a toe in to test the water before deciding to venture farther, Ewald says. If the conditions are right, the leader cells act as guides, with many tumor cells following behind, as they escape the confines of the tumor into the healthy tissue beyond. Full metastasis occurs when the cells succeed in migrating to a new location—the lungs, for example—and set up shop, creating a new tumor.

Beginning with the idea that some cells in the tumor might be more invasive than others, Ewald's team grew mouse tumors in the laboratory in special 3-D gels that mimic the environment that surrounds in human patients. Kevin Cheung, M.D., a medical oncology fellow in the Ewald lab, observed that the cancer cells infiltrated the gels in groups, with a few cells out in front and the rest following behind.

Looking for a molecular cause for the apparent "leadership" seen in the initiating cells, Cheung searched for proteins that were uniquely present in the leader cells. They identified one protein, cytokeratin 14, or K14, that was present in almost all leader cells but was very rare in the noninvasive parts of the tumor. When the team looked at tumors from mice that had other types of breast cancer—some more prone to invasion and others less prone—all had leader cells containing K14. The more invasive a tumor was, the more cells with K14 it had.

The team then grew breast tumors from 10 breast cancer patients in 3-D gels and found that the leader cells in these human tumors also contained K14. "Our research shows that the most invasive cells in breast tumors express K14 across all types of breast cancer," says Cheung. "Now we need to learn how to eliminate these leader cells from breast tumors in patients."

K14 is a protein that helps form the internal "skeleton" of many cell types, giving them structure and helping them to move. Although its presence in leader cells made its involvement in the invasion process seem likely, the investigators conducted further experiments to determine whether it was essential to the process or merely coincidental to it.

The researchers removed breast tumors from mice with breast cancer and divided them into an experimental group and a control group. Each group of tumors was exposed to viruses that had been reprogrammed to carry pieces of into the cells. The experimental group received genetic material designed to prevent the production of K14; the control group got genetic material that didn't affect the cells. The two groups of tumors were then transplanted into healthy mice, with experimental tumors on one side and control tumors on the other side of the same mouse.

After letting the tumors grow for some time, the team removed and examined them. As expected, in the , leader cells were present, contained K14 and were leading vigorous invasions into normal tissue. In the experimental tumors, whose cells had no K14, the tumor borders were smooth, with essentially no invasions occurring.

"We're still several years away from being able to use these insights to help patients with , but we now know which are the most dangerous, and we know some of the proteins they rely on to do their dirty work," says Ewald. "Just a few leader cells are sufficient to start the process of metastasis, and they require K14 to lead the invasion."

He also notes that K14 is present in cells within many other organs, so K14 may play a similar role in other types of cancer.

Explore further: Shape-shifting stops migrating cancer cells

More information: dx.doi.org/10.1016/j.cell.2013.11.029

Related Stories

Shape-shifting stops migrating cancer cells

December 4, 2013
Like a car with a front and back end, a steering mechanism and an engine to push it forward, cancer cells propel themselves through normal tissues and organs to spread cancer throughout the body. Researchers at Mayo Clinic ...

New study shows insight into breast cancer cell migration

October 29, 2013
(Medical Xpress)—A new study by University of Kentucky Markey Cancer Center researchers Min Chen and Kathleen O'Connor shows that a specific protein may assist breast cancer cells in metastasizing.

Breast cancer cells enticed to spread by 'tumorous environment' as well as genetic changes

October 22, 2012
(Medical Xpress)—A new study from Johns Hopkins researchers suggests that the lethal spread of breast cancer is as dependent on a tumor's protein-rich environment as on genetic changes inside tumor cells.

Study explains why drug may help more cancer patients

November 18, 2013
(Medical Xpress)—Recently some intriguing data has suggested that breast cancer patients whose tumors appear insensitive to a class of drugs known as anti-HER2 medications (the drug trastuzumab, marketed as Herceptin, is ...

One protein, two personalities: Study identifies new mechanism of cancer spread

December 11, 2013
Cancer involves a breakdown of normal cell behavior. Cell reproduction and movement go haywire, causing tumors to grow and spread through the body.

Researchers discover protein that may control the spread of cancer

February 26, 2013
Researchers at the University of Hawai'i Cancer Center have uncovered a novel mechanism that may lead to more selective ways to stop cancer cells from spreading. Associate Professor Joe W. Ramos PhD, a cancer biologist at ...

Recommended for you

How cancer metastasis happens: Researchers reveal a key mechanism

January 18, 2018
Cancer metastasis, the migration of cells from a primary tumor to form distant tumors in the body, can be triggered by a chronic leakage of DNA within tumor cells, according to a team led by Weill Cornell Medicine and Memorial ...

Modular gene enhancer promotes leukemia and regulates effectiveness of chemotherapy

January 18, 2018
Every day, billions of new blood cells are generated in the bone marrow. The gene Myc is known to play an important role in this process, and is also known to play a role in cancer. Scientists from the German Cancer Research ...

These foods may up your odds for colon cancer

January 18, 2018
(HealthDay)—Chowing down on red meat, white bread and sugar-laden drinks might increase your long-term risk of colon cancer, a new study suggests.

The pill lowers ovarian cancer risk, even for smokers

January 18, 2018
(HealthDay)—It's known that use of the birth control pill is tied to lower odds for ovarian cancer, but new research shows the benefit extends to smokers or women who are obese.

Researchers develop swallowable test to detect pre-cancerous Barrett's esophagus

January 17, 2018
Investigators at Case Western Reserve University School of Medicine and University Hospitals Cleveland Medical Center have developed a simple, swallowable test for early detection of Barrett's esophagus that offers promise ...

Scientists zoom in to watch DNA code being read

January 17, 2018
Scientists have unveiled incredible images of how the DNA code is read and interpreted—revealing new detail about one of the fundamental processes of life.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.