Cell immortalization is a necessary step for cancer development. Scientists believe that the main reason is to turn on an enzyme-telomerase-to extend chromosomal telomeres and prevent normal cell death. A new study shows that turning on telomerase is not a one-step process. In melanoma and possibly other cancers, mutations increase telomerase slightly, allowing cells to survive long enough to make other changes that upregulate telomerase.
The key to immortality is an enzyme called telomerase, which keeps the chromosomes in cells that divide frequently. The enzyme lengthens the caps or telomeres at the ends of chromosomes, which are worn away during each cell division. When the telomeres are too short, the ends stick to each other, causing severe damage during cell division and in most cases killing the cell.
Since telomeres become shorter as cells age, scientists believe that cancer cells that never age will be immortalized by turning on the production of telomerase in cells that do not normally produce telomerase, thereby making these cells indefinitely To maintain its long telomeres. It is estimated that 90% of all malignant tumors use telomerase to achieve immortality, and various cancer treatments proposed are aimed at reducing the production of telomerase in tumors. A new research studied the immortalization process of using genome-engineered cells in culture and followed the development of skin cells from moles to malignant melanomas. The results showed that the role of telomerase in cancer is more complicated.
Immortalization is a two-step process, initially driven by mutations that turn on telomerase, but at a very low level. The mutation occurs in the promoter, a region upstream of the telomerase gene (called TERT). Studies have shown that about 70% of malignant melanomas have the same mutation in the TERT promoter. Mutations in the TERT promoter will not produce enough telomerase to immortalize precancerous cells, but will delay normal cell senescence, thereby allowing more time to initiate other changes in telomerase. Scientists suspect that telomerase levels are sufficient to extend the shortest telomeres, but not to make them healthy in the long term.
If cells cannot activate telomerase, they cannot live forever and eventually die of short telomeres because the chromosomes stick together and then break when the cell divides. Cells with mutations in the TERT promoter are more likely to up-regulate telomerase, although telomeres are very short, which allows them to continue to grow. However, it is not clear what causes the upregulation of telomerase, which ultimately immortalizes cells. This is unlikely to be another mutation, but an epigenetic change that affects the expression of the telomerase gene, or a change in the expression of a transcription factor or other regulatory protein that binds to the upstream promoter of the telomerase gene.
Although most cancers seem to require telomerase to live forever, only about 10% to 20% of cancers have a single nucleotide change in the promoter upstream of the telomerase gene. However, these account for approximately 70% of all melanomas, and 50% of all liver and bladder cancers. The evidence supporting the theory that TERT promoter mutations up-regulate telomerase has been conflicting: cancer cells tend to have chromosomes with short telomeres, but higher telomerase levels should produce longer telomeres.
If a mutation in the TERT promoter occurs, pushing precancerous lesions (mold or mole) to melanoma, people with short telomeres have a greater chance of dying before upregulating the cells. Telomerase makes cells immortal. This research also involves engineering TERT promoter mutations in cells different from human pluripotent stem cells and tracking their development towards cell immortality.