Manuel Collado Rodríguez
50 years ago, US President Richard Nixon declared the "war on cancer" . Thus, it followed in the wake of other successful programs that concentrated efforts to achieve a goal that would put the country at the forefront of world progress. Years before, the resources had been put to develop the atomic bomb and reach the Moon. In the case of cancer, the initiative aimed to promote research centers that bring together the best researchers to find treatments against a disease that posed an increasing threat to society.
Many successes and failures later, we are now witnessing a new effort to advance biomedical research against cancer. This is the basis of the initiative Great Cancer Challenges which started in 2015. Its objective is to improve our capacity to prevent, detect and treat the disease. To do this, it seeks to identify the key questions pending to be resolved.
A committee of wise men asks what are those big questions that need to be answered before moving forward. One of these great challenges is to understand and exploit in our favor cell senescence .
What is cell senescence?
Cell division is the process that makes one cell gives rise to two identical daughters. This is the basis of cell proliferation. senescence consists of the inability to carry out this cycle.
During senescence, cells undergo changes in their morphology and gene expression pattern, and show extracellular secretions (which we call SASP). This state is reached in response to damage to the integrity of the cell. Various cellular aggressions set this process in motion.
Apoptosis (the process of cellular suicide) and cellular senescence are the two essential defense programs of the organism against irreparable damage that endanger the entire transmission of genetic information and correct activity of cells. If these mechanisms fail and we allow the damaged cells to continue to proliferate, the aberrant cells will grow disorderly to form a tumor.
Therefore, both are essential antitumor defense mechanisms. There we have a first compelling reason to consider that research in cell senescence is key to understanding cancer.
Throughout life, all kinds of attacks on cells occur and, on many occasions, this results in induction of senescence. This contrasts with the fact that cancer is fundamentally a disease of aging, much more frequent in adults and whose incidence clearly increases with age.
If an aging organism accumulates cells that have activated a protective response against cancer with Success, how is it that cancer occurs more in elderly people whose organs and tissues are already defending themselves? One possibility is that the accumulation of damage with age ends with disabling the protective response of senescence. Another, disturbing, is that senescent cells that cannot divide alter the rest until they become tumorous.
Thus, what initially protects us could turn against us and facilitate the disease.
The damaged cells that trigger the senescence put on the brake to prevent their uncontrolled proliferation. Also, they secrete the SASP to send complex signals to their environment. We believe that they may be destined to promote the repair and regeneration of damaged tissue.
Thus, a cellular attack is responded to by stopping the proliferation of the cell –now damaged– to prevent it from dividing into a group of cells. aberrant cells. In addition to stopping proliferating, these cells secrete molecular messages to the outside that, on the one hand, warn their environment, on the other they call for repair and finally stimulate their own elimination.
This would be the system when it works perfectly.  Too many insults or an ineffective system of eliminating damaged cells can lead to constant and damaging repair signaling that causes disease. This is the case of pathologies associated with aging such as osteoarthritis, pulmonary and renal fibrosis, Alzheimer's and cancer. We know aspects of this complex response and we have indications of the association between the accumulation of senescent cells and the development of disease, but we need to further specify how the process develops in order to better understand it and be able to manipulate it to our benefit.
In science, what not seen does not exist. Or, at least, it is assigned less importance than it may have. In the case of cellular senescence, and after decades of study, we lack specific "markers" of the process, biomolecules whose appearance is associated with the appearance of senescence and its evolution. This makes laboratory work difficult and its application to human disease. We must advance in this regard. For this, we need to use all the resources that various disciplines can offer and that, with novel approaches, allow the development of new tools.
How kill senescent cells
In recent years we have learned that it is possible to kill senescent cells. This does not seem to harm the body and has shown, so far in animals, an amazing ability to improve diseases associated with aging. All of them are based on the accumulation of senescent cells that alter the tissues in which they reside and have accumulated.
One of the most advanced therapeutic approaches, in clinical experimentation in humans to know their therapeutic potential, are compounds senolytics . This is the generic name for compounds capable of inducing the specific death of senescent cells, leaving normal cells intact. But it may be unrealistic to consider a cancer therapy through the administration of senolytics in a preventive way to eliminate these damaged cells, as they arise, to avoid their accumulation. A great deal of knowledge will be required to ensure that such a strategy is safe and can be used without fear of causing greater harm than is intended to be avoided.
A more direct line of research to exploit our knowledge of cellular senescence in cancer therapy consists of trying to control tumor growth. How? Reactivating this protective response of the body in tumor cells that proliferate uncontrollably. Finding drugs that induce this state of proliferative disability can prevent the progression of tumors. In fact, re-evaluating some of the antitumor drugs currently used in chemotherapy, developed with the aim of inducing the death of tumor cells, we find that on many occasions they induce senescence in tumor cells.
To what extent senescence is our ally against cancer is something that at the moment we do not know. One possibility that we address is that the induction of senescence during antitumor treatment may limit the efficacy of the therapy. The only good tumor cell is the dead tumor cell, and leaving tumor cells zombies in the body can be beneficial in the short term, but can lead to harmful after-effects. For many, the senescent tumor cells produced by chemotherapy are the basis for the frequent relapses in patients after therapy. On many occasions, these relapses are caused by tumors that show even more aggressive characteristics than the original ones.
The “one-two” strategy
In this context the “one-two” strategy arises. This aims to stop: first, tumor growth by inducing cellular senescence of the tumor cell. Second, to selectively induce their death by applying a senolytic. This strategy has already begun to be tested in animal models of cancer and what we have observed is that the effect of the combination of senescence-inducing chemotherapy together with senolytic is more effective than chemotherapy alone.
There is an extra positive aspect that is not negligible in this strategy. The aggressive treatments cause unpleasant side effects in patients undergoing chemotherapy. Apparently, in many cases these side effects derive from the induction of senescence in non-tumor cells that are damaged. These can be effectively eliminated by senolytic agents at the same time as senescent tumors generated by chemotherapy, which could provide a beneficial therapeutic effect with minimal side effects.
All these aspects mentioned in the article are the objective of a multitude of research groups in the world. Defining the priority objectives of this research, proposing new initiatives to resolve doubts and developing new and more effective therapeutic interventions based on the use of cellular senescence constitute the effort in which many groups have embarked. They try to join forces in multidisciplinary international consortia to seek financial support from the Great Cancer Challenges initiative, which will allow us to take a great leap forward in our knowledge and management of cancer.
About the author: Manuel Collado Rodríguez Researcher, director of the research laboratory on Stem Cells in Cancer and Aging, SERGAS Servizo Galego de Saúde
The article Cellular senescence: the great challenge to understand and treat cancer has been written in Cuaderno de Cultura Científica .