Senescence: tumor cells in hibernation

5. January 2012

Cells that threaten to degenerate often go into a sort of "hibernation". This so-called senescence program provides the immune system with the ability to detect and eliminate these cells selectively.  As such, this prevents the formation of tumors.

It could be all so simple: the immune system recognises all cancerous cells and removes them. There would no longer be malignant tumors; doctors, nurses and researchers would have more leisure time. Unfortunately, the body’s own defence against tumors is not so good that this wish could be realised. However scientists at the Helmholtz Centre for Infection Research (HZI) in Braunschweig are on the track of a mechanism which shows how the immune system defends itself in advance against degenerated cells or cells at risk of degeneration. That the immune system can recognise tumor cells and, to a certain extent, make them harmless, was already known. The matter which has been discussed controversially until now, however, is whether the immune system can also detect precursor cells, which are only prone to degenerating, and what its corresponding role could be.

The malignant transformation can be interpreted as being a showdown between the oncogenic impetus and the cellular drive to push back. If a tumor has formed, then the tumor suppressor mechanisms of the cell have been defeated. Degenerate cells, whose cell cycles end up being out of control, are often driven by an intracellular cascade or by an extracellular-induced reaction into programmed cell death, or apoptosis. Scientists led by Professor Lars Zender from the HZI have now discovered another mechanism. Cells that are particularly vulnerable to becoming tumor cells frequently leave their normal cell cycle and go into a dormant state which is labelled senescence. Senescent cells are in a sort of “hibernation”: they do not divide and therefore cannot replicate uncontrollably. At the same time, they differ in morphology and in various biochemical and physiological parameters from replicating cells. Of greater significance is that they are still metabolically active. Senescent cells communicate with their environment by secreting a cocktail of hundreds of messengers – for example, cytokines and growth factors. Only then they are visible to the immune system and henceforth subject to intensive control. “In this way the body prevents the cells from changing further and even growing into a cancer,” says Lars Zender.

Senescent cells are ticking time bombs

In mice with an immune deficiency, whereby no T-helper cells were available for immune defence, the researchers observed that senescent liver cells developed into a liver cell carcinoma. In contrast, it was able to be observed in laboratory mice, in which the senescence program was triggered artificially, that the immune system reacted strongly to the altered cells: after a few weeks, the senescent cells were removed from the body. The experiments also show that it is appropriate for the immune system to remove the senescent cells quickly. If this does not happen, the cells could, firstly, re-emerge from their “winter sleep” and go into an uncontrolled growth cycle. Secondly, the cocktail of messenger agents secreted can promote two different reactions: in the previously described case the immune system is activated, in the other case adjacent cells are stimulated to also leave their normal cell cycle, as Prof. Zender explains.

But if cells sitting in a senescent state are a ticking time bomb, why are they not sent immediately into apoptosis? This is one of the key questions on which the scientists are still working. They already know, however, that the decision – apoptosis or senescence – depends on cell type and on different types of stimuli. In haematopoietic cells, for example lymphocytes, damage to the cell through an oncogene leads mostly to apoptosis. In epithelial cells, in which the same oncogene is expressed, the cells more frequently shift into senescence.

Shortening of telomeres leads to senescence

Why it is the case at all that both mechanisms exist side by side may be explained as follows: The term “replicative senescence” was coined in 1961 by Leonard Hayflick. He established by his in-vitro experiments that human diploid fibroblasts, after an average of 50 divisions, irrevocably cease doing so and enter into senescence. The cause of this event was found in the telomere, the non-coding DNA-protein complexes at the end of chromosomes. The direction the DNA polymerase takes during replication of the genetic material in the course of cell divisions allows continuous replication for only one DNA strand. The other strand is replicated in a discontinuous mode, by means of so-called Okazaki fragments. On this strand there remains at each division one overhang section which is not used for copying. This leads to a loss of up to 200 base pairs per cell division. If the telomere length is reduced to that less than the essential length needed for DNA replication, a cell ceases its dividing process and becomes senescent.
Consequently, the phenomenon of senescence is typical of ageing cells. In fact, one finds in older people, with markedly shortened telomeres, more senescent cells than in young people. If cells reaching the point of division incapacity were to go into apoptosis rather than senescence, those cells would be missing in the organs. So, with the help of senescence, the organ function can be maintained even when cells no longer divide. These “age-senescent” cells are also not eliminated by the immune system, even though it would be beneficial for the welfare of the surrounding cells, as a publication in Nature recently showed. One of the next logical steps to take according to Professor Zender is an analysis of the messenger cocktails. How does the composition in “ageing” senescent cells differ from that in “oncogenic” senescent cells?

A universal principle?

The findings on senescence and its influence on the immune system were obtained from potential cancer precursor cells in the liver. They demonstrate for the first time that the immune system plays an important role in preventing tumors. This was especially evident when persons with Hepatitis C infection who were positive for HIV were examined. They have a heightened risk of developing hepatocellular carcinomas. The number of senescent cells in the liver was significantly higher than numbers found in a control group of hepatitis C patients without HIV infection. “In HIV patients, the immune system defence given by T-helper cells is impaired, so that in livers of HIV patients senescent liver cells probably cannot be removed effectively,” says Zender.

Automatically the question is raised, as to whether the discovered mechanism is specific to the liver, or whether it is in fact a universal one. According to recent studies, it seems that a similar mechanism exists in the pancreas and in the lungs. In contrast, senescent cells in nevi, where they occur in large numbers, are apparently tolerated by the immune system. Since nevi are benign, a purge of the senescent cells there by the immune system at that point may not be necessary.

Great potential for prevention and therapy

Professor Zender is convinced that beyond this discovery there is huge potential for the treatment and prevention of cancer. When the exact composition of the cocktail which the senescent cells secrete is known, substances could be inhibited specifically in order to intervene in the process. Selective triggering of the senescence program in tumor cells and simultaneously stimulating the immune system is yet another idea. From chemotherapy it is known that many chemotherapeutic agents induce senescence, particularly in low-dose chemotherapy. In high doses, increased apoptosis is observed. If a balance could be found between senescence-induction in tumors and a potent immune system, the body’s defence mechanism could be better used. Even though various approaches are possible in selectively employing the mechanism of senescence in therapy, reaching the point of clinical application will still take several years. Until then, all that probably remains for every healthy person is to just keep the immune system fit enough, via sport and healthy diet, so that it recognises the one or the other senescent cell and disposes of it in due time.

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So impressive findings!

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