Depriving Amino Acids to Help Shrinking Tumors

Depriving Amino Acids to Help Shrinking Tumors ...

Physiologists at the Hopp Children''s Cancer Center Heidelberg (KiTZ), the German Cancer Research Center (DKFZ), the University of Heidelberg, and the HI-STEM* gGmbH have discovered the molecular implications behind this fact and how cancer cells might be turned off.

The Hopp Childrens Cancer Center Heidelberg (KiTZ) is a joint venture organization of the German Cancer Research Center (DKFZ), Heidelberg University Hospital (UKHD) and the University of Heidelberg (Uni HD).

Every year, one out of 100,000 children develops a new neuroblastoma, most often during their first year of existence. These cells form in immature nerve tissue during their initial development, especially in the adrenal gland, neck, chest, abdomen, and pelvis. Neuroblastomas are often difficult to treat and highly resistant to therapy. In some cases, the tumor progresses inexorably despite intense therapy.

MYCN, a cancer gene, is a major regulator that decides the direction in which the disease develops. Only recently it became known that this cancer gene sets the path for whether precursor cells develop into mature nerve cells or become malignant neuroblastoma cells. However, the high MYCN activity in turn switches on and off a large number of other genes. But what advantage does this give the cancer cell, and is it specific disrupted to actively fight the cancer cells?

A team of scientists led by Frank Westermann of the Hopp Children''s Cancer Center Heidelberg (KiTZ) and the German Cancer Research Center (DKFZ), Andreas Trumpp, DKFZ, and Thomas Hofer of DKFZ, discovered that neuroblastoma cells with high MYCN activity need one thing in particular: the amino acid cysteine. The fast-growing cancer cells need large amounts of these building blocks to produce new cells.

Cancer patients must obtain cysteine to protect themselves from harmful harmful peroxides that are produced conditionally by their highly active metabolism. Sina Kreth, another first author, believes that they use the import of the amino acid and build up an alternative synthetic chemical to obtain cysteine from the amino acid methionine.

To them, these adaptations make the neuroblastoma cells more sensitive. If the scientists removed cysteine, the MYCN-driven tumor cells could no longer inactivate toxic peroxides produced and died by ferroptosis, a special form of cell death. The researchers investigated whether this process might be a potential Achilles heel for a treatment against malignant neuroblastoma in mice.

The scientists said they removed the tap to tumors because they blocked cysteine uptake and cysteine synthesis, and they also switched off a key enzyme that normally prevents cancer cells from poisoning themselves with peroxides. Their own self-destruction began at the age of 30 through ferroptosis, and the tumors slowed.

"The death of Ferroptosis cell patients was discovered only a few years ago, and the results now show for the first time not only in cell cultures, but in cancer-bearing mice how this technique can be manipulated to kill highly aggressive human neuroblastoma cells," Hamed Alborzinia said.

According to Andres Florez, some neuroblastomas with moderate MYCN activity in infants and young children are relatively absent. Consequently, when they begin to divide uncontrollably, they soon run out of cysteine reserves and ferroptotic cell death is initiated. Eventually, some neuroblastomas without MYCN activity cannot escape this self-destruction and then died after a certain time when cysteine becomes scarce.

The first evidence suggests that cysteine uptake, production, and consumption should be disturbed in such a way that these cells can also initiate their self-destruction. Whether the newly discovered principle will also be effective in neuroblastoma patients, then it must be done in clinical trials.

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