The first step in the deadly process of breast cancer metastasis, where tumor cells migrate to other parts of the body, appears to be led by a special class of cells - leader cells - that require the presence of a particular protein to act.Now, a new study in mice shows knocking out this protein may render leader cells incapable of carrying out the first crucial step in metastasis and offers a new target for therapy.
Cell biologists at Johns Hopkins University in Baltimore, MD, summarize their findings about leader cells in breast cancer and the protein cytokeratin 14, or K14, in a recent online issue of Cell.
Senior author Andrew Ewald, assistant professor of cell biology at the Johns Hopkins School of Medicine, says:
"Metastasis is what most threatens breast cancer patients, and we have found a way to stop the first part of the process in mice."
The researchers also suggest their discovery may apply to other types of cancer, since K14 is not confined to breast cancer cells.
Leader cells take first steps in the process of metastasis
Prof. Ewald says leader cells are cells on the edge of a tumor that form protrusions into surrounding healthy tissue, as if to "test the water" before venturing into it.
If the conditions are right, the leader cells venture first into the surrounding tissue and beyond, acting as guides to other following tumor cells.
If the cells succeed in migrating to a new site, such as in the lungs, they start a new tumor. This completes the process of metastasis.
Before they discovered leader cells, the team had a hunch some tumor cells were more invasive than others, and they set out to investigate using mouse tumors grown in 3D gels that mimicked the environment of human breast tumors.
As they observed the tumors, they saw that gradually, groups of cells began to invade the surrounding gel, with a few cells in each group out in front, and the rest following behind.
Search for unique protein led to K14
In the next part of the study, the team looked for a molecular cause of the leader cell behavior by searching for proteins that might be unique to leader cells.
They found K14 was present in nearly all leader cells but quite rare in cells in the noninvasive parts of the tumors.
K14 is known to be important for giving cells a physical structure and helping them to move.
They then looked at tumors in mice with other types of breast cancer, some more invasive than others, and found they too had leader cells containing K14. Moreover, the more invasive a tumor, the more cells with K14 it had.
The team then took tumor tissue from 10 breast cancer patients and grew them in 3D gel in the lab. They found the tumors contained leader cells, and these contained K14.
Is K14 key to first stage of metastasis?
Up until this stage, all the team had proven was that leader cells exist, they seem to lead the process of metastasis and they all have K14, which is largely absent in the follower cells.
But this does not prove K14 is actively involved in helping leader cells take those first steps in metastasis.
In the final stage of the study, the researchers took tumors from mice with breast cancer and treated half with viruses genetically programmed to enter the cancer cells and prevent production of K14, and the other half with viruses carrying genetic material that had no effect on the cells (the controls).
Both groups of tumors were then transplanted into healthy mice: in each mouse, the experimental tumor on one side and the control on the other.
After a while, the researchers removed and examined the tumors and found, as expected, that the control tumors had leader cells containing K14 and were vigorously leading invasions into healthy tissue.
The experimental tumors, however, where cells contained no K14, had smooth borders (without the telltale protrusions that leader cells create into neighboring tissue) and essentially no invasion occurring into healthy tissue.
Still years away from using discovery to help patients
Prof. Ewald says they are still some years away from being able to use the discovery to help patients with breast cancer. However, he adds:
"We now know which tumor cells are the most dangerous, and we know some of the proteins they rely on to do their dirty work. 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 since we know cells in many other organs contain K14, then perhaps their findings may also apply to other types of cancer.
Grants from the National Cancer Institute, the National Institute of Environmental Health Sciences, the Department of Defense CDMRP Breast Cancer Program, the American Cancer Society, the Mary Kay Foundation, the Safeway Foundation, the Avon Foundation, and the Cindy Rosencrans Fund for Triple Negative Breast Cancer Research helped finance the study.
Earlier this year, another team of US scientists - writing in an April 2013 online issue of Nature Communications - describe how they decoded the "molecular chatter" that makes cancer cells more aggressive and more likely to metastasize.