Stem tags: laser taught to "hit" the most tenacious tumor cells
Russian scientists have tested a technology that can destroy not only tumor structures, but also the main "culprits" of relapses, metastases and tumor resistance to treatment — cancer stem cells. In the experiment, photodynamic therapy with a new photosensitizer reduced their number by an average of 30-40%. However, the method has a number of limitations, experts told Izvestia. The next stage of preclinical and clinical studies should include not only an assessment of tumor volume reduction, but also evidence of the technology's effect on long-term metastases and survival, the experts noted.
The source of tumor spread in stem cells
Scientists from Sechenov University, together with colleagues from the A.M. Prokhorov Institute of General Physics of the Russian Academy of Sciences, MISIS University, the Institute of Biotechnology of the Russian Academy of Sciences and Fudan University (China), for the first time studied cancer stem cells (RSC) in lung adenocarcinoma, cervical cancer, glioblastoma and other tumors in detail. As the scientists explained, such structures are considered one of the sources of relapses and resistance to therapy. Due to genetic breakdowns and exposure to carcinogens, they are reborn from normal, "useful" stem cells and begin to "work" on the tumor.
The researchers tested photodynamic therapy against cell cultures "rich" in CSC, and developed a unique photosensitizer for this, a compound that enhances the effect of a laser.
— In tumors, cancer stem cells can remain dormant for a long time, that is, dormant, and drugs simply do not penetrate them. In addition, their unique molecular composition becomes an additional protection for them. Therefore, the existing methods of antitumor therapy have practically no effect on them," said Professor Evgenia Kogan, director of the Reference Center for Pathological Anatomy at Sechenov University.
According to her, it has now been confirmed that there may be not one, but several types of heterogeneous, that is, heterogeneous cancer stem cells in a tumor. When they "wake up" under the influence of certain factors, they begin to divide and give rise to CSCs and a clone of ordinary cancer non—stem cells - this causes tumor growth, the professor explained. In addition, like any stem cells, their pathogenic "sisters" can "travel" through the body and generate new tumor foci, which leads to the appearance of metastases.
"If we learn how to recognize and, most importantly, kill all types of cancer stem cells, we will solve the issue of cancer treatment," said Evgenia Kogan.
The study showed that in each tumor there is a whole hierarchy of such cells, and each type has its own, and each CSC plays its own role.
— There are certain markers on the surface of all cells of our body — specific molecules that can be used to recognize a particular cell by immunohistochemical and molecular methods. They are also found for cancer stem cells, and each has its own role. A high level of the ALDH1 marker indicates resistance to antitumor therapy, the CD34 marker indicates the ability to form new vessels to nourish tumors, and the CD133 marker indicates the risk of tumor progression and metastasis," said Anna Romanovskaya, Deputy Director for Scientific Work at the Institute of Clinical Morphology and Digital Pathology at Sechenov University.
Personalized Laser Cancer Treatment
Accurate knowledge of the cellular composition of the tumor will allow us to select personalized treatment for each patient. A promising approach that Russian scientists have explored is photodynamic therapy (PDT). A team of biochemists, physicists, pathologists and clinicians from Sechenov University and other scientific centers conducted an experiment by using special drugs and a laser on lung cancer cells.
The first stage of the research was the development of a photosensitizer, a substance used to treat biological tissues in order to increase their sensitivity to light.
— Polycationic phthalocyanines, special substances containing metals with a positive charge, turned out to be the most effective for our task. Since the cell membranes of cancer cells have a negative charge, such positively charged molecules bind firmly to cells and enhance light absorption, eventually leading to the destruction of all tumor cells, including cancer stem cells," Igor Reshetov, director of the Levshin Institute of Cluster Oncology, explained to Izvestia.
Photodynamic therapy has affected the entire hierarchy of cancer structures. The density of all tumor cells decreased by 2-3 times, and the number of cancer stem cells, which determine the resistance and aggressiveness of the tumor, decreased by an average of 30-40%. Cell activity and their ability to divide have also decreased. And the level of apoptosis, that is, the intracellular program that leads to cell death, on the contrary, has increased.
The term "sensitization" itself means an increase in the sensitivity of tumor cells to external influences, explained Nikolai Sergeev, professor of the Department of Radiology at the University of Pirogov. The prefix "photo" means light, that is, increased sensitivity to light radiation. The patient is injected with a photosensitizer, which accumulates in the neoplasm for several hours. Then, without affecting healthy tissues, this tumor site is exposed to radiation of a certain wavelength, including a laser.
— The method has proven itself well in the treatment of tumors of the skin, oral mucosa, small formations of the bladder and some others. In this case, the research is aimed at improving the technique of photodynamic therapy, which involves a selective effect on cancer stem cells. This will lead to a more radical destruction of the tumor and a significant reduction in the likelihood of recurrence," he said.
However, there are a number of limitations. The main problem is the selectivity of this method, Maxim Kotov, an oncologist and surgeon at the N.N. Petrov National Research Medical Center of Oncology and a participant in the NTI Helsnet market, told Izvestia.
— For a real effect on cancer stem cells, it is necessary to ensure the predominant accumulation of photosensitizer in this population or to deliver it using targeted carriers that recognize tumor markers. The second limitation may be hypoxia: classical PDT depends on oxygen, and it is the hypoxic zones that often serve as a niche for the most resistant tumor cells," the specialist said.
The next stage of preclinical and clinical studies should include not only an assessment of tumor volume reduction, but also evidence of an effect on the frequency of local recurrence, distant metastases and survival, Maxim Kotov emphasized.
The study was supported by a grant from the Russian Science Foundation as part of a joint Russian-Chinese project aimed at developing polycationic photosensitizers for the treatment of cancer.
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