13 May 2022

The recidivist was tracked down

Scientists have identified the culprits of relapses in lung cancer patients

Phys Tech blog, Naked Science

The work was carried out with the support of the Russian Science Foundation, the results were published in the leading scientific journal International Journal of Molecular Sciences (Pustovalova et al., CD44+ and CD133+ Non-Small Cell Lung Cancer Cells Exhibit DNA Damage Response Pathways and Dormant Polyploid Giant Cancer Cell Enrichment Related to Their p53 Status). Non-small cell lung cancer accounts for almost 85 percent of all lung cancer cases, with a five-year survival rate of only about eight percent.

The standard method of treatment of inoperable patients with this disease is radiation therapy. However, despite the rather large doses of radiation and combination with other types of therapy, after a while patients may relapse. Researchers in many countries are searching for the reasons.

It is known that the tumor has heterogeneity, that is, it consists of different cells. Among them there are so-called cancer stem cells that have similar characteristics to normal stem cells. According to scientists, it is they who have increased resistance to radiation therapy and the ability to survive in the most adverse conditions. A scientific group led by Sergey Leonov, head of the MIPT laboratory, undertook to check whether these cells really have such properties.

Margarita Pustovalova, senior researcher at the Laboratory for the Development of Innovative Medicines and Agrobiotechnologies at MIPT, says: "It is known that there are populations of tumor stem cells inside the tumor that have abnormal resistance to radiotherapy and can subsequently metastasize and lead to relapses of cancer. It is also known that such cells carry certain markers on their surface. Using these markers, we isolated the stem cells we needed and exposed them to ionizing radiation."

Scientists have studied tumor stem cells. It was previously known that they have a high ability to repair DNA damage and avoid cell death. It turned out that these cells also have the ability to go into a special dormant state in a stressful situation for themselves — either at rest or a state called "premature aging".


Cancer stem cells (on the left) carry specific markers on their surface (for example, CD44+ and CD133+), which allow them to be isolated from the general population of cells. When stained with antibodies labeled with fluorochromes, these cells give a brighter glow compared to those cells that do not have such markers / © International Journal of Molecular Sciences

In it, they survive those doses of radiation that kill ordinary cells. And at the onset of a favorable period, they "wake up" and give a population of multinucleated cells, which then divide, giving new daughter cancer (including stem) cells and thus provoking a relapse of the disease. Similar populations of giant multinucleated tumor cells are found in almost all tumors.


Giant multicore cell / © Margarita Pustovalova

In addition, it was found that cancer stem cells behave differently in response to radiation. To survive after radiation, some plunge into rest, others prefer "premature aging". The researchers found that this is due to whether they have the p53 protein or not. Sergey Leonov, head of the Laboratory for the development of innovative medicines and agrobiotechnologies at MIPT, explains: "We compared two cell lines, which in particular differ in the status of the transcription factor, protein p53. This protein, often called the "guardian of the genome", is encoded in the cell by the oncosuppressor gene TR53, belonging to the family of anti-oncogenes.

Anti-oncogenes in the body control and prevent the accumulation of cells with abnormal genome changes that contribute to their malignant transformation. p53 triggers the transcription of a group of genes and is activated when DNA damage accumulates. When some mutations occur in the TR53 gene, or if there is no such gene in the cell at all, then the cell acquires malignant characteristics."

Biophysicists extracted cancer stem cells from the total mass of tumor cells and divided them according to the principle of the presence of the TR53 gene. It turned out that in the presence of such a gene, cells temporarily go into a "dormant" state, and in the absence of it, cells almost immediately begin to divide.

"Our study suggests the need for personalized therapy for patients with non-small cell lung cancer. It is necessary to check what is the status of TP53 in the cells of a particular patient. And in this regard, prescribe therapy. Because depending on the presence or absence of p53, the cell may include different survival mechanisms. It is necessary to take into account these mechanisms and influence them, preventing their development," Margarita Pustovalova added.

Scientists believe that cancer stem cells are the basis for possible relapses after radiation therapy, so treatment should be aimed not just at destroying the total mass of the tumor, but also be carried out taking into account the characteristics of its stem cells. In particular, it is necessary to detect the presence or absence of p53 in such cells. 

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