Cell 'Suicide' Gene Linked To Metastasis


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REHOVOT, Israel - November 13, 1997 -A Weizmann Institute of Science study reported in the November 13 issue of Nature provides new evidence for an intriguing theory about the development of metastasis.

According to this theory, one of the factors contributing to metastasis - the spread of cancer from the site of the primary tumor to other body organs - is a loss of a mechanism by which cells "commit suicide."

In the new study, Weizmann researchers demonstrate that a cell-suicide gene called DAP-kinase can prevent metastasis. This finding suggests that a loss or malfunction of this gene allows metastasis to develop.
"In our experiment, we have shown that introducing a 'good' copy of DAP-kinase into metastatic cells restores the ability of these cells to follow the order to kill themselves," says research team leader Prof. Adi Kimchi of the Weizmann Institute's Molecular Genetics Department.

"It's important, however, to remember that this gene is only one of many factors involved in the development of metastasis, so that much research still needs to be conducted before we can find molecular ways to block this life-threatening process," she says.

Kimchi conducted the study with doctoral students Boaz Inbal and Ofer Cohen, as well as with Prof. Lea Eisenbach and Ezra Vadai of the Institute's Immunology Department, and Drs. Sylvie Polak-Charcon and Juri Kopolovic of the Sheba Medical Center in Tel Hashomer.

When cells 'refuse' to die

The DAP-kinase gene was discovered and isolated by Prof. Kimchi's team some two years ago. This gene was known to be involved in cell "suicide," also referred to as programmed cell death or apoptosis.
Cell death is essential for the proper renewal and turnover of tissues. But when cells "refuse" to die after they have finished performing their function - for example, because the DAP-kinase gene is lacking or doesn't function properly - the result can be unwanted cell proliferation and development of cancerous tumors.
Prof. Kimchi hypothesized that apart from contributing to the development of primary tumors, the lack or malfunctioning of DAP-kinase can also cause cancerous cells to break off from a tumor and set out to spawn metastases. Formation of metastases is the most dangerous stage in cancer.
Kimchi and colleagues found that in metastatic tumor lines DAP-kinase indeed is not functioning. To test their hypothesis further, they "engineered" DAP-kinase into cells removed from metastatic tumors in mice, and returned these cells into the laboratory animals. The result: the molecular activity that could lead to the formation of metastases ceased inside these cells.
This finding supported the notion that when the cells contain a normal, functioning copy of the DAP-kinase gene, they obey the signals that instruct them to die during the different stages of metastasis.
In contrast, when the gene is not doing its job the cell disobeys the "suicide" command, and this disobedience may result in metastasis.

Prof. Kimchi holds the Helena Rubinstein Chair of Cancer Research, and Prof. Eisenbach, the Georg F. Duckwitz Chair of Cancer Research.
This research was supported by QBI Ltd. and the Israel Ministry of Science.

The Weizmann Institute of Science is a major center of scientific research and graduate study located in Rehovot,   Israel.