Rebels from apoptosis
Cancer cells build a line of defense
The concept of cancer stem cells has emerged relatively recently. But despite this, its rapid development has led to the fact that today cancer stem cells (RSCs) are considered as central participants in carcinogenesis and the main target in the development of new methods of cancer therapy.
The very formation of a malignant neoplasm begins with the initiating cancer stem cells. The increase in the degree of malignancy and the development of tumor resistance to various types of chemo- and radiotherapy is also determined by the RSC. It is the RSCs that are involved in the metastasis of the primary tumor, and it is they who are capable of transitioning to a dormant (from the English "dormancy" – resting state) state, for example, after treatment, from which they then "come out", giving rise to highly malignant, often fatal relapses.
In other words, all the key characteristics of malignant neoplasms that make them deadly diseases are determined by cancer stem cells. Accordingly, the RSCs themselves are the main obstacle to the complete cure of patients. And this is the main problem that does not allow achieving this goal in most cases. RSCs are extremely resistant to existing cancer treatment methods, and, even in cases of successful treatment, RSCs are the last to die among all tumor cells.
Recently, scientists at the University of Texas have discovered another amazing phenomenon associated with the resistance of cancer stem cells. The results of their study, published online on the website of the journal Nature Cell Death and Differentiation, showed that under certain experimental conditions, RSCs survive even after they enter apoptosis.
In short, apoptosis, or, as it is also called, programmed cell death, is a complexly organized process of activation of certain molecular cascades inside the cell, leading to its death. Accordingly, for normal cells, apoptosis is a terminal event of their fate. After this process enters a certain phase, cell death becomes inevitable. As it was shown earlier, cancer cells have many mechanisms that stop apoptosis before it enters an irreversible phase. However, the existence of mechanisms of cell survival at the terminal stages of apoptosis, when the dying cell breaks up into so-called apoptotic corpuscles, has not been assumed until now. It turned out that the RSC has such mechanisms.
In the experiments, the authors used the human bladder cancer cell line RT4P. It is known that during multiple repeated transplantations to mice, human cancer cells acquire the characteristics of RSC. Having performed this procedure with RT4P cells, the scientists were convinced of the development of the RSC phenotype in them by the expression of a number of cell surface markers characteristic of RSC. To trigger apoptosis, these cells were treated with the classic chemotherapeutic drug cisplatin, which is standard used for the treatment of bladder cancer and causes DNA damage in cells. Along with this, for greater persuasiveness, the suppression of two important protein regulators of glucose metabolism – GSK-3beta and p70S6K was used.
Cells that underwent a series of transplantations and acquired the phenotype of cancer stem cells through this, after such in vitro treatment, entered apoptosis, leading to the formation of apoptotic cells. However, in this case, the process did not end with their death. Instead, the apoptotic bodies of the RSC merged with each other, forming a shield-like structure surrounding the main apoptotic body containing DNA. The authors called such structures "vesicular shields" (blebbishields).
Further analysis showed that vesicular shields possess the main characteristics of stem cells and express Yamanaki transcription factors (factors characteristic of pluripotent stem cells). Moreover, like RSCs, vesicular shields have extreme survival.
Under conditions of high concentrations of cisplatin in vitro, these structures formed spheroidal cell formations characteristic of cultured cancer stem cells.
Illustrations for the article by Jinesh et al. Blebbishields, the emergency program for cancer stem cells: sphere formation and tumorigenesis after apoptosis
C – formation of vesicular shields. Real-time recording. The arrows indicate apoptotic corpuscles initiating the formation of a vesicular shield;
D – scanning (left) and transmission (right) electron microscopy of vesicular shields at the early (top) and late (bottom) stages of formation. The formation of a full-fledged active cell with decondensed active chromatin is visible.
N – nucleus, C – cytoplasm, aNu – active nucleolus, cNu – cytoplasmic nucleolus, NM – nuclear membrane, Blebs – apoptotic corpuscles.
In addition, the cell colonies formed by vesicular shields, as well as the population of RSCs of the most malignant tumors, are characterized by high heterogeneity, which is determined by the expression of a set of transcription factors and signaling proteins.
Finally, vesicular shields are also capable of triggering tumor formation during transplantation to mice.
At the same time, tumors formed by vesicular shields grow significantly faster than tumors initiated by cells that have not undergone apoptosis.
Thus, cancer stem cells under certain conditions are able to survive even after the start of the terminal phases of apoptosis, and after survival, such cells acquire greater malignancy and aggressiveness.
The results of this work, which demonstrated the existence of previously unknown mechanisms of truly extreme survival of cancer stem cells, should certainly lead to a revision of the criteria for the effectiveness of the developed methods of treating malignant neoplasms, and the search for new ways to destroy RSCs.
Portal "Eternal youth" http://vechnayamolodost.ru04.12.2012