Scientists discover way to block spread of breast cancer
Scientists have found a way to thwart the spread of breast cancer in mice by blocking a protein involved in the deadly process of metastasis, which is the migration of tumor cells to other parts of the body.
In a new study published in the journal Cell, cell biologists at Johns Hopkins University say that the first step in breast cancer metastasis is apparently controlled by so-called “leader cells”, which require the presence of the protein cytokeratin 14, or K14, for cancer to spread.
Senior study author, Andrew Ewald, assistant professor of cell biology at the Johns Hopkins School of Medicine, says he and his colleagues have found a way to halt this first step in the deadly process of metastasis, which he says is what “most threatens breast cancer patients.”
Their discovery may also work at stopping metastasis in other types of cancer as well, as the protein K14 is not limited only to breast cancer cells.
According to Ewald, the “leader cells” that initiate the process of metastasis are located on the edge of a cancerous tumor where protruding extensions develop around healthy tissue, just waiting for the opportunity to reach out and spread to the surrounding tissue.
In this regard, the leaders cells serve as guides, directing other tumor cells to follow. If successful in migrating to another part of the body, such as the lungs, then a new tumor is started; thus, completing the process of metastasis.
Prior to discovering how these leader cells act in the process of metastasis, the researchers already suspected that some tumor cells were more invasive than other tumor cells, so they launched their study by using mice with tumors grown in 3D gel that were similar to human breast tumors.
While examining these mouse tumors, the research team noticed that clusters of cells started invading the surrounding gel, with some of the cells protruding as they led the rest of the cells to follow.
Next, the researchers attempted to find a molecular reason for the leader cell behavior by looking for proteins that appeared distinctive to leader cells, which is when they discovered that the K14 protein was present in almost all of the leader cells.
However, they found that the K14 protein, which is required for the formation of the cell’s physical structure and helping them migrate, was rarely present in cells located in the noninvasive portions of the tumor cells.
The research team also examined tumors in mice with other breast cancer types, some of which were more invasive than others, and they discovered that these other types also had leader cells with the K14 protein present. Indeed, the tumors that were more invasive had the most K14 present.
The researchers then took tumor tissue from 10 breast cancer patients and grew them in 3D gel in the lab. As a result, leader cells were found in the tumors, which also had the K14 protein present.
At this point, the team had successfully demonstrated that leader cells exist with the presence of the protein K14 in all of them, and that such cells apparently initiate the process of metastasis. Despite these findings, however, what had not yet been proven was whether or not K14 was actively involved in stimulating leader cells to take the initial steps toward starting metastasis.
Accordingly, the researchers then took tumors from mice with breast cancer and injected half of them with viruses that had been genetically designed to go into cancer cells to prevent the production of K14, while the other half were treated with a control virus containing genetic material that did not have any effect on the cells.
Next, the two groups of tumors were transplanted in healthy mice, with each of the mice receiving the K14 blocking virus on one side and the control virus on the other.
After some time, the team removed the tumors. As they had predicted, the researchers found leader cells with the K14 protein present that were in the control tumors, which were aggressively leading invasions into the surrounding healthy tissue.
On the other hand, the experimental tumors without the K14 protein had smooth edges; thus, there were none of the protrusions from leader cells directing the spread of cancer into surrounding tissue.
Although it may be a few years before the research team’s discovery is used to help breast cancer patients, the study’s lead author says that they “now know which tumor cells are the most dangerous” and that they depend on proteins like K14, which is required in order to activate the start of the metastasis process.
SOURCE: Collective Invasion in Breast Cancer Requires a Conserved Basal Epithelial Program; Kevin J. Cheung, Edward Gabrielson, Zena Werb, Andrew J. Ewald; Cell, 12 December 2013; DOI: 10.1016/j.cell.2013.11.029