The research group led by Dr. Eduardo Arzt published a paper in the journal Aging Cell in which they described a molecular mechanism that facilitates the persistence of tumor cells through a new pathway of cellular senescence, which could explain cellular resistance to cancer therapies.
Senescence is a natural mechanism that occurs in response to various cellular stressors that cause cells to stop dividing but remain alive and metabolically active. As a consequence of this process, the cells undergo a metamorphosis that allows them to continue to fulfil their functions, but without replicating. The “Neuro-endocrine tumors” group at the Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA, CONICET-Max Planck) has been studying this phenomenon for years, and in its latest paper, published in the journal Aging Cell, was able to elucidate a new mechanism involved in how cell senescence is maintained and how it impacts on tumors development.
“It is very important to study the phenomenon of senescence because it is involved in many pathologies associated with ageing, but it is not always the ‘bad guy’, and it is not clear that eliminating it will bring direct benefits”, says Florencia Herbstein, first author of the study. Senescence is a process that can be very beneficial when activated in tissue repair and regeneration, embryonic development, or to prevent the spread of damaged cells that could become cancerous, as happens in pituitary tumors. But its activation does not always have positive consequences. Like Dr. Jekyll and Mr. Hyde, senescence has two facets: it is also associated with the ageing process. Over time, the accumulation of senescent cells in tissues can contribute to a decline in organ function and the development of age-related diseases such as Alzheimer’s, Parkinson’s and cancer, among others.
As the cells enter senescence, they transform: known as ‘zombie cells’ because they would not let themselves die, senescent cells enlarge, “as if in a failed attempt to divide, and then the cell gets bigger. This enlargement is characteristic and can be seen under a microscope”, says Herbstein. Another characteristic is that they begin to secrete products, pro-inflammatory molecules, and export them out of the cell, one of which is the cytokine IL-6.
In the laboratory, they had already been studying this molecule in pituitary tumors. In previous work, they found that senescent cells in this gland produce IL-6 and transmit anti-division (i.e. in favor of senescence), but they also knew that this same molecule transmits a signal for cell proliferation. “For many years we have been trying to answer an intriguing question that we finally managed to answer with this paper: how the same molecule and the same receptor can trigger completely different signals in two neighboring cells: senescence or proliferation”, says team leader Eduardo Arzt.
“Understanding how IL-6 affects the tumor microenvironment is a relevant and poorly understood topic, especially in the context of senescent cells”, explains the recent PhD candidate, whose thesis elucidated the hypothesis that IL-6 has a dual role in the development of pathology. To corroborate this, they identified the molecular mechanisms involved in IL-6 senescent signaling in different models of tumor senescence: pituitary adenomas as a model of natural senescence and human lung carcinoma, melanoma and glioblastoma cell lines as models of therapy-induced senescence. In the research, they concluded that while one message is sent from the cell membrane, the opposite message is sent from inside the cell: IL-6 acts inwards into the cell, amplifying its senescent state; at the same time, it works ‘outwards’ by stimulating the proliferation of neighboring cells.
In this sense, this molecule plays a crucial role in controlling tumor growth. Through various experiments, the research team showed that when IL-6 is deactivated in senescent pituitary cells, these cells can become cancerous and form tumors, and that reactivating IL-6 restores the senescent cells’ ability to control tumor growth. This finding could explain tumor resistance to therapies, or the recurrence of cancer diseases, as two parallel signaling pathways -communication- may be activated simultaneously.
“In general, anti-cancer therapies are directed at the receptor in the membrane, as if they were trying to block the cell perimeter so that the message of division, of proliferation, does not get through”, explains Herbstein. “But if the communication pathway is intracellular, you will never get there with anti-tumor therapies that target receptors on the cell membrane”, adds the head of the Neuro-endocrine tumors lab. In summary, this discovery about intracellular IL-6 signaling in senescence opens up new possibilities for developing therapies based on these mechanisms, which could be especially useful for treating certain types of cancer and other ageing-related diseases.