Healthy cells can only divide a limited number of times during the life of the organism. On the other hand, tumor cells are immortal: they proliferate indefinitely and uncontrollably, and this is the characteristic that defines cancer.
Researchers from the Telomeres and Telomerase Group of the CNIO (National Cancer Research Center), led by Maria Blasco, have studied for the first time the possibility of treating lung cancer by directing the treatment to the telomeres, the structures that protect the ends of the chromosomes and whose state determines the cell’s ability to divide indefinitely.
The results, as explained by the researchers in the journal Cell Death & Differentiation, show that, indeed, targeting treatment at telomeres “may be an effective therapeutic strategy” against non-small cell lung cancer, responsible for much of the mortality in patients with lung cancer.
The work has Sergio Pineiro as first author, beneficiary of a postdoctoral contract from the Spanish Association Against Cancer (AECC).
“Removing the immortality of tumor cells is a therapeutic strategy that has not yet been exploited in the fight against cancer,” he says. Maria Blasco.
Focus on the tumor microenvironment
Lung cancer is one of the leading causes of cancer death. The long-term ineffectiveness of current therapies, and late diagnosis, mean that only one in five patients survives more than five years. Specifically, non-small cell lung cancer is responsible for 85% of lung cancer-associated deaths.
The work now published focused on the so-called tumor microenvironment, which is a set of cells and factors that surround the tumor and that play a crucial role in the development of cancer and in its response to therapies. the researchers studied the effect on the cellular microenvironment of non-small cell lung tumors of telomerase deficiency, which is the enzyme that repairs telomeres. They also looked at the impact of dysfunctional telomeres.
Telomeres are protein structures located at the ends of chromosomes. With each cell division, telomeres shorten. until, after a certain number of divisions, the shortening becomes excessive and the cell stops dividing. This happens in healthy cells, but not in most tumor cells.
In 90% of human tumors the expression of telomerase is reactivated, that fulfills the function of repairing telomeres. Thanks to telomerase, the telomeres of tumor cells maintain a minimum functional length, and this allows them to divide indefinitely.
In the work now published, the researchers studied what happened when causing a telomerase deficiency in the lung tumor microenvironment. Also deliberately damaged their telomeres, by the compound 6-thio-dG.
“It was the first time that the involvement of telomerase and dysfunctional telomeres in the lung tumor microenvironment has been investigated,” explains Sergio Piñeiro, currently at the Higher Council for Scientific Research (CSIC) in La Rioja.
Damaged telomeres slow down lung cancer
Telomerase deficiency and dysfunctional telomeres slowed tumor progression. The researchers observed reduced implantation and vascularity of the tumors in the lung, along with an increased vulnerability of the tumors to DNA damage and cell death. It also decreased the proliferation of tumor cells and inflammation, and the antitumor response of the immune system was strengthened.
As the authors write in Cell Death & Differentiation“Our results show that telomere-targeted therapy could be an effective therapeutic strategy for the treatment of non-small cell lung cancer.”
Reference article: Piñeiro-Hermida, S., Bosso, G., Sánchez-Vázquez, R. et al. Telomerase deficiency and dysfunctional telomeres in the lung tumor microenvironment impair tumor progression in NSCLC mouse models and patient-derived xenografts. Cell Death Differ (2023).