Study identifies two-step process leading to cell immortalization, cancer

Updated 2017-08-19 10:01:40 Xinhua

A group of university researchers in the San Francisco Bay Area has identified a two-step process that leads to cell immortalization as well as cancer.

The key to immortalization is an enzyme called telomerase, which keeps chromosomes healthy in cells that divide frequently. The enzyme lengthens the caps, or telomeres, on the ends of chromosomes, which wear off during each cell division.

While the telomeres get shorter as cells age, and ultimately too short, the ends stick to one another, wreaking havoc when the cell divides and in most cases killing the cell. Because cancer cells never age, scientists theorized that they become immortalized by turning on production of telomerase in cells that normally don't produce it.

Reported online this week as a "first release" publication from the journal Science, the new research studied the immortalization process using genome-engineered cells in culture, and tracked skin cells as they progressed from a mole into a malignant melanoma, with results suggesting that telomerase play a more complex role in cancer.

Senior author Dirk Hockemeyer, a University of California, Berkeley, assistant professor of molecular and cell biology, and his colleagues, in collaboration with dermatopathologist Boris Bastian and his colleagues at the University of California, San Francisco, found that the immortalization process, in its first step, is driven initially by a mutation that turns telomerase on, but at a very low level. That mutation is in a promoter, a region upstream of the telomerase gene - referred to as TERT, short for telomerase reverse transcriptase - that regulates how much telomerase is produced.

The TERT promoter mutation does not generate enough telomerase to immortalize the pre-cancerous cells, but does delay normal cellular aging, allowing more time for additional changes that turn telomerase up.

Hockemeyer suspects that the telomerase levels are sufficient to lengthen the shortest telomeres, but not to keep them all long and healthy. If cells fail to turn up telomerase, they fail to immortalize, and eventually die from short telomeres. Cells with the TERT promoter mutation are more likely to up-regulate telomerase, as the second step, which allows them to continue to grow despite very short telomeres. The marginal levels of telomerase in the cell result in some unprotected chromosome ends in the surviving mutant cells, which could cause mutations and further fuel tumor formation.

It is unclear, however, what causes the eventual up-regulation of telomerase that immortalizes the cell.

"Before our paper, people could have assumed that the acquisition of just this one mutation in the TERT promoter was sufficient to immortalize a cell; that any time when that happens, the telomere shortening is taken out of the equation," Hockemeyer was quoted as saying in a news release. "We are showing that the TERT promoter mutation is not immediately sufficient to stop telomeres from shortening."

It's unlikely to be another mutation, according to Hockemeyer, but rather an epigenetic change that affects expression of the telomerase gene, or a change in the expression of a transcription factor or other regulatory proteins that bind to the promoter upstream of the telomerase gene.

Though most cancers seem to require telomerase to become immortal, only some 10 to 20 percent of cancers are known to have a single-nucleotide change in the promoter upstream of the telomerase gene. But these include about 70 percent of all melanomas and 50 percent of all liver and bladder cancers.

The new evidence supports the assumption that cancer cells tend to have chromosomes with short telomeres, yet have higher levels of telomerase, which should produce longer telomeres.

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