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Cancer gene MYC controls the development of embryonic stem cells
For a long time the actual function of the cancer gene MYC remained unclear. Now, scientists from the German Cancer Research Center (DKFZ) in Heidelberg have found out that MYC controls the development of stem cells in the early embryonic phase, but at the later stage may favor the formation of metastases via the same effect. The researchers published their results in the journal "Cell".
According to the DKFZ, many types of cancer can be considered: The more MYC they produce, the more aggressive the tumors grow. However, the scientists noticed that MYC is also active in embryonic stem cells. Now, the team led by Andreas Trumpp from the German Cancer Research Center proved that the gene controls the development of stem cells. In nature, the effect is observed, for example, in deer in the form of the so-called "dormancy" or "diapause".
In mouse blastocysts, the cancer gene MYC seems to control the biochemical switch state (diapause). (Picture credits: Andreas Trumpp, DKFZ / HI-STEM) Reproduction adapted to environmental conditions
"In order to give birth to their young at the best possible time, many animal species take a break in the development of their embryos," explains the DKFZ. Through this so-called diapause reproductive adapted to the environmental conditions. For example, fawns would be born "after a gestation period of about ten months in early summer - when it is warm and the food supply for the mother rich." Actually, according to the researchers for the development of the embryos six months would be sufficient, "but then come to the Mating in late summer fathered young animals already in the winter to the world. "By a hormone-controlled development break of the early embryos, the gestation period is therefore extended by nature.
Biochemical sleep state
The scientists of the DKZ and the stem cell institute HI-STEM could now prove that this process is controlled by the cancer gene MYC. When MYC is switched off, embryonic stem cells and early mouse embryos fall into a reversible biochemical sleep state, according to the DKFZ. Unaffected, however, remains the ability of the cells to develop into all the different cell types of the body. The sleeping cells remained alive and maintained their stem cell identity, the researchers emphasize. The cells would continue to have the important "stem cell factors" that allow them to differentiate into more than 200 different cell types of the body.
Function of MYC so far unclear
To decipher the function of the gene MYC, the researchers used embryonic stem cells from mice whose two MYC genes (c-MYC and N-MYC) could selectively switch them off, according to the DKFZ. According to the researchers, the "embryonic MYC-negative stem cells" greatly reduced the activity of those genes that are crucial for cell division, cell growth and metabolism. The cells were put into a kind of biochemical sleep state, "reminding us strongly of the process of diapause, which is so far completely misunderstood," says Roberta Scognamiglio, first author of the current study. In this case, "the early embryos, so-called blastocysts, are put into a sleep-like state without growth and with almost no metabolism" before implantation in the uterus.
MYC also responsible for the diapause?
To find out if the gene MYC is also responsible for the diapause, the researchers compared the activity of all genes in MYC-negative embryonic stem cells with those in pausing mouse blastocysts. In both cases, in addition to MYC, the same gene groups had been inactivated, according to the statement of the DKFZ. These were "mainly those genes that control protein synthesis and cell growth. By contrast, the stem cell factors were produced unchanged ", reports the German Cancer Research Center. When normal blastocysts in the culture dish were treated with the MYC inhibitor, they fell into a diapause-like state. Subsequent transmission of the sleeping embryos in surrogate mice, they grew according to the researchers to normal young animals.
Sleep state completely reversible
"In order to induce diapause or to put embryonic stem cells into a sleep state, it is sufficient to switch off the cancer gene MYC," explains Andreas Trumpp. The potential of the stem cells is not affected by this. "This is a very special property of stem cells, because all other cell types die after MYC blockade," said the expert. In addition, the condition is reversible. Immediately after discontinuation of the inhibitor, the cells would have resumed RNA, protein and DNA synthesis and proliferate indefinitely. "After reactivation of MYC, the sleeping embryos can develop into healthy animals," reports the DKFZ.
Growth of metastases influenced by MYC?
According to the scientists, MYC is likely to have a disastrous effect on cancer stem cells, especially on dormant metastatic stem cells. The latter could pass through the bloodstream in foreign organs during their migration and get under the influence of signal molecules, such as those arising in inflammation. Thus sleepers' MYC production can be re-stimulated, causing them to become metastases. "We are now trying to develop strategies to attack such dangerous sleeper cells with an MYC blockade," explains stem cell researcher Andreas Trumpp. (Fp)