A mutation that helps make cells immortal is critical to the development of a tumor, but new research suggests that becoming immortal is a more complicated process than originally thought.
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.
Because telomeres get shorter as cells age, scientists theorized that cancer cells - which never age - become immortalized by turning on production of telomerase in cells that normally don't produce it, allowing these cells to keep their long telomeres indefinitely. An estimated 90 percent of all malignant tumors use telomerase to achieve immortality, and various proposed cancer therapies focus on turning down the production of telomerase in tumors.
The new research, which studied the immortalization process using genome-engineered cells in culture and also tracked skin cells as they progressed from a mole into a malignant melanoma, suggests that telomerase plays a more complex role in cancer.
"Our findings have implications for how to think about the earliest processes that drive cancer and telomerase as a therapeutic target. It also means that the role of telomere biology at a very early step of cancer development is vastly underappreciated," said senior author. "It is very likely that what we find in melanoma is true for other cancer types as well, which would warrant that people look more carefully at the role of early telomere shortening as a tumor suppressing mechanism for cancer."
The research is reported in the journal Science.
Researchers found that immortalization is a two-step process, 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 - that regulates how much telomerase is produced. Four years ago, researchers reported that some 70 percent of malignant melanomas have this identical mutation in the TERT promoter.
The TERT promoter mutation does not generate enough telomerase to immortalize the pre-cancerous cells, but does delay normal cellular aging, senior author said, allowing more time for additional changes that turns telomerase up.
If cells fail to turn up telomerase, they also fail to immortalize, and eventually die from short telomeres because chromosomes stick together and then shatter when the cell divides. Cells with the TERT promoter mutation are more likely to up-regulate telomerase, which allows them to continue to grow despite very short telomeres.
Yet, the author says, telomerase levels are marginal, resulting is some unprotected chromosome ends in the surviving mutant cells, which could cause mutations and further fuel tumor formation.
"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," senior authorr said. "We are showing that the TERT promoter mutation is not immediately sufficient to stop telomeres from shortening."
It is still unclear, however, what causes the eventual up-regulation of telomerase that immortalizes the cell. Senior author says that it's unlikely to be another mutation, 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 binds to the promoter upstream of the telomerase gene.
"Nevertheless, we have evidence that the second step has to happen, and that the second step is initiated by or is occurring at a time where telomeres are critically short and when telomeres can be dysfunctional and drive genomic instability," he said.
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. However, these include about 70 percent of all melanomas and 50 percent of all liver and bladder cancers.
Senior author said that the evidence supporting the theory that the TERT promoter mutation up-regulated telomerase has always been conflicting: cancer cells tend to have chromosomes with short telomeres, yet have higher levels of telomerase, which should produce longer telomeres.
According to the new theory, the telomeres are short in precancerous cells because telomerase is turned on just enough to maintain but not lengthen the telomeres.
"Our paper reconciles contradictory information about the cancers that carry these mutations," senior author said.
The finding also resolves another recent counterintuitive finding: that people with shorter telomeres are more resistant to melanoma. The reason is that if a TERT promoter mutation arises to push a precancerous lesion - the mole or nevus - toward a melanoma, the chances are greater in someone with short telomeres that the cell will die before it up-regulates telomerase and immortalizes the cells.
The study also involved engineering TERT promoter mutations in cells differentiated from human pluripotent stem cells and following their progression toward cellular immortality.
http://news.berkeley.edu/2017/08/17/two-step-process-leads-to-cell-immortalization-and-cancer/
http://science.sciencemag.org/content/early/2017/08/16/science.aao0535?rss=1
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