Recent Study finds Cancer Cells are stronger in Groups

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?Even for cancer cells love to travel in groups. New research in mice suggests that cancer will never form metastatic tumors on their own, the cells travel in groups to increase their collective chances of survival, according to researchers at Johns Hopkins.


Even for cancer cells love to travel in groups. New research in mice suggests that cancer will never form metastatic tumors on their own, the cells travel in groups to increase their collective chances of survival, according to researchers at Johns Hopkins.


In a report on the study, published the week of Feb. 1 in the Proceedings of the National Academy of Sciences, the researchers found evidence that traveling cells differ from those multiplying within a primary tumor, this may make them naturally resistant to chemotherapy.


“The team found that cancer cells do two things to increase their chances of forming a new metastasis,” says Andrew Ewald, Ph.D., associate professor of cell biology at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center. “They turn on a molecular program that helps them travel through a diverse set of environments within the body, and they travel in groups.”


According to Ewald, cancer cells typically leave tumors one by one to colonize other areas of the body, but clinical and genetic evidence has mounted over the last 10 years to suggest they are beginning to travel in groups. The team, using mice with a form of mammary gland cancer, which consistently metastasizes to the lungs, began to figure out why this was happening.


In their first experiments, Ewald’s team removed tumors from mice whose cells were genetically engineered to glow either red or green under special lights. They then implanted those red and green tumors in the mammary glands of mice whose cells did not glow and looked for metastases in the lungs.


If single cells colonized new metastases, the cell clumps would only glow one color or the other. Instead, the researchers found many multicolored clumps. Using computer modeling of this pattern discovered that most of the single-colored clumps had also arisen from multiple cells and saw the glow was the same color. It was estimated that less than 3 percent of the metastases came from a single cell.


To see the cell clumps before they reached their destination in the lungs, the researchers looked at the tissue just outside the primary tumors, in the blood vessels surrounding the tumors and in circulating blood. Multicolored clusters of cells were observed.


To figure out if cell groups that traveled had an advantage, the team compared the ability of single cells and clusters to form colonies. They began with two test groups with equal numbers of cells in dishes filled with a gelatinlike commercial product that mimics the tissue surrounding mammary tumors. The clusters were more than 15 times better at forming colonies than single tumor cells. When the test was repeated in mice, the clusters were more than 100 times better at creating large metastases.


“Think of metastasis as The Amazing Race,” says Ewald. “The cells encounter many different challenges as they attempt to grow and spread, and some cells are better at different events than others, so traveling in a group makes sense.”


Ewald says the team also looked at whether traveling cells showed any particular molecular hallmarks that could be used to predict and ultimately prevent tumor spread. Previous work in the laboratory showed that cells are usually “led” out of tumors by cells decorated with the protein K14, so they started there.


The team found that K14 levels are quite low in primary tumors and large metastases but high in small, traveling clusters of cells. Experiments in petri dishes showed that the cells switched between two molecular programs — one for proliferation and one for metastasis — and that the level of K14 revealed which program was “on” in any given cell.


“Because most chemotherapeutic drugs target proliferating cells, metastasizing cells won’t be killed by them, leaving patients vulnerable to new tumors,” explains Ewald. “Our discoveries add to knowledge that could help overcome that vulnerability.” The team was able to use K14 to separate the two types of cells and compare their gene activity. “It was found that the activity of dozens of genes differs between proliferating and metastasizing cells,” says Ewald. “Since many of those genes encode cell surface proteins, these findings might eventually be used to develop new drugs that target metastasizing cells.”


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