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Team Discovers How "Sleeping Cells" Are Triggered To Form Fatal Metastases

Team Discovers How "Sleeping Cells" Are Triggered To Form Fatal Metastases

Team Discovers How "Sleeping Cells" Are Triggered To Form Fatal Metastases

Team Discovers How "Sleeping Cells" Are Triggered To Form Fatal Metastases

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Subsidiary ulcers can develop in the body even years after an apparently successful cancer treatment. These metastases come from cancer cells that migrated from the original tumor to other organs and remained inactive there for a long time. Researchers have now discovered how these “sleeping cells” are kept at rest and how they wake up and form metastases. They report on this in the journal “Nature”.

It is an ominous seed that a tumor can leave behind in the body: Individual cancer cells migrate from the tumor to other tissues in the body and survive chemotherapy there in a kind of hibernation. Cancer medicine is currently focusing on observing those affected after the disease in order to determine whether these cells have awakened and metastases develop. One of the biggest questions in cancer research is what exactly triggers this "waking up".

"This state of rest is an important time window for new therapeutic approaches when the number of cancer cells and their heterogeneity can still be managed," explains Prof. Dr. Mohamed Bentires-Alj, research group leader at the Department of Biomedicine at the University of Basel and the University Hospital Basel. Understanding the mechanisms behind the dormant state of these cancer cells is therefore important in order to prevent cancer from recurring. His team has now taken an important step in this direction.

His colleague Dr. Ana Correia and colleagues used experiments with mice and human tissue samples to decipher the transition from “hibernation” to “waking” in cancer cells that had migrated to the liver from a breast tumor.

Guardian of the sleeping cancer cells

Two cell types play a key role in this transition: on the one hand, so-called natural killer cells, i.e. immune cells that kill degenerate or infected cells, but can also slow down their reproduction. This is exactly what they seem to do with the sleeping cancer cells, as the researchers found. The natural killer cells release a messenger substance called interferon-gamma, which keeps the cancer cells in hibernation.

The other cell type, the so-called hepatic stellate cells, influence the natural killer cells. If these liver stellate cells are activated, they inhibit the immune cells, which in turn enables the cancer cells to wake up from hibernation. "There can be various reasons why the hepatic stellate cells are activated, for example chronic inflammation in the body or persistent infection," explains Correia. The researchers want to clarify the exact causes in further studies.

The now published results show several possible points of attack to prevent metastasis formation: an immunotherapy based on interleukin-15, which increases the number of natural killer cells in tissue, an interferon-gamma therapy, which keeps the cancer cells in a sleeping state, as well Inhibitors against the mechanism by which the hepatic stellate cells paralyze the natural killer cells. Corresponding therapies already exist. However, they must first be clinically tested.

Natural barrier against metastases

"Our results raise the hope that immunotherapies with a focus on natural killer cells are well suited as a preventive strategy to prevent dormant cancer cells from developing into metastases," says Bentires-Alj. “The next step on the long way to therapy will be to show that stimulation of the natural killer cells also prevents metastasis in humans. A project for which we are currently looking for funding and which we are discussing with our collaboration partners at the university hospital. "

"These cells represent a natural barrier in the body against the formation of metastases in the liver," explains Correia. If they could be used to prevent the development of daughter ulcers in other organs, a new cancer could possibly be prevented permanently. “My team is already investigating such mechanisms in other tissues, where metastases can typically form, and the results are promising,” adds Bentires-Alj.

Reference: Correia AL, Guimaraes JC, Auf der Maur P, et al. Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy. Nature. 2021:1-6. doi: 10.1038/s41586-021-03614-z

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