They proliferate without end – cancer cells can divide infinitely often and thus form the dreaded tumors. Researchers have now gained new insights into what makes this fatal immortality possible for cancer cells: They provide evidence of genetic mechanisms that prevent the degradation of the chromosome ends, which limits the division activity in healthy cells. The results could thus be used to develop therapies that address the immortality of cancer cells, the researchers say.
After about 50 cycles it is usually over: the cells of the human body have a limited ability to divide, which is determined by the length of the so-called telomeres. These end caps of the chromosomes, like the genes, consist of nucleotides, but do not contain building instructions for proteins. The DNA structures shorten with each cell division until a minimum length is finally reached – the telomer is then practically used up. It is an important molecular mechanism of cell aging.
Cancer cells get their telomeres young
It is already known that this system is switched off in cancer cells. Because they are dependent on intact telomeres for their rampant division activity. Their preservation is mediated by factors that have arisen from certain changes in the genetic makeup of the cancer cells. Earlier studies have shown that the increased activity of an enzyme is responsible for protecting the telomeres in around 85 percent of all tumors: the so-called telomerase ensures that the caps are preserved during the division. The remaining tumors, however, use other mechanisms of telomere lengthening that are so far unclear.
A team of researchers from the German Cancer Research Center in Heidelberg has now devoted a study to the further research into the basics of tumor cell immortality as part of the large-scale project “Pan-Cancer Analysis of Whole Genomes”. In the genome sequences of more than 2500 tumor samples, they looked for genetic peculiarities that could be linked to the ability of cancer cells to divide indefinitely.
As they report, only 13 percent of the samples encountered genetic changes in the DNA sequence that appear to be linked to the activation of telomerase. “In the majority of the 2500 cancer cases examined, we observed increased activity of the telomerase gene, but without recognizing changes in the genome that could explain this,” says lead author Lina Sieverling. “This could be due to epigenetic factors that leave no traces in the genome,” says the scientist.
Epigenetic factors and alternative mechanisms
The epigenetic factors are switch molecules that sit on certain sections of the DNA and affect their accessibility for reading. These attachment patterns can also be transferred to daughter cells during cell division. Many studies have already shown that this can strongly influence the characteristics of tissues. As can be seen from the current results, the system could also play a role in the immortality of some cancer cells.
The study has also provided new insights into the as yet unexplored alternative mechanisms of telomere extension, in which mutations in the genome do not affect the activity of telomerase. Of the 13 percent of those tumors whose genetic material showed evidence of the ability to extend telomeres, 64 cases affected these alternative mechanisms, the scientists report. The researchers discovered two peculiarities in these cancer cells: Telomeres are usually made up of hundreds of repetitions of the same sequence of six DNA building blocks. With the alternatively extended telomeres, however, a special process leads to unusual variants of these usual telomer sequences. In addition, short fragments of the telomeres are often incorporated into other parts of the genome in these cancer cells, genetic analyzes showed.
As the researchers emphasize, their work is basic research, but there is certainly medical potential in the results. “We have not yet been able to say whether and what significance the new findings have and whether they influence the course of cancer,” explains study leader Lars Feuerbach. “However, the active extension of the telomeres is an Achilles heel of all cancer cells and therefore an important starting point for the development of targeted therapies. Precise knowledge of all the underlying molecular processes is crucial for this, ”concludes the cancer researcher.
Source: German Cancer Research Center, technical article: Nature Communications, doi: 10.1038 / s41467-019-13824-9