Cells can become senescent in reaction to a variety of environmental stresses or forms of damage, activating a program that halts cellular replication and triggers the generation of a mix of potent signals that can influence surrounding cells and tissue structure, a state known as the senescence-associated secretory phenotype (SASP). Senescent cells have a role in embryonic development, controlling the shaping of tissues at the extremities, such as the growth of fingers. Their existence in adults is perhaps because the same mechanism, particularly the arrested growth aspect of it, serves to suppress cancer risk - or at least it does so initially and while senescent cells are present in only modest numbers. Evolution tends to lead to complex systems in which every component part is reused in many ways.
Among the signals making up SASP there are those that encourage the immune system to destroy senescent cells, should those cells fail to trigger their own programmed cell death processes. The immune system has its own issues that manifest during the aging process, however, and it becomes ever less effective at all of its tasks, whether that is protecting the body from invading pathogens or destroying unwanted and potentially dangerous native cells. Over a lifetime ever more of the cells in our tissues become senescent and linger rather than being cleared out. Their collective SASP grows in influence, degrading tissue function and contributing greatly to age-related frailty and disease. With enough senescent cells present the original outcome of cancer suppression is swept away and the toxic environment begins to encourage cancer formation.
There is a great deal yet to learn about the nature of the senescent state, exactly why senescent cells accumulate, and how their presence contributes to specific manifestations of age-related disease. There is enough detail yet to be mapped to keep a much larger research community than presently exists occupied for decades. Fortunately all of that can be skipped over if a good way of clearing senescent cells can be developed: periodically remove these cells and you remove the problem. That is a much less complex proposition than reaching a full understanding of senescence, and builds on research already well advanced in other parts of the medical research establishment: how to identify types of cell reliably from their distinctive chemistry, and how to selectively destroy them without harming their neighbors. Cancer researchers are making good progress towards achieving those goals for the types of cell they are interested in, and many of the technologies will be adaptable to senescent cells.
Back to the learning, however. Do we accumulate senescent cells because the immune system falls down on its job? Or it is a matter of there being numerous subtly different types of senescent state, some of which only come into play in a meaningful way in later life? Or perhaps the nature of SASP changes with age for other reasons, such as a reaction to other forms of cellular and tissue damage. At this point any of that might be plausible - and while all interesting, it can all be bypassed by the senescent cell clearance short cut to removing that contribution to degeneration aging. While parts of the aging research community are interesting in removing senescent cells, parts of the cancer research community are interesting in the possibility of creating more of them as a cancer therapy, however. That requires learning enough about senescence to be able to tread the fine line between suppressing and encouraging cancer, and it is not simply a matter of the number of senescent cells present. One thing that is emerging from the intersection of cancer research and senescent cell research is that there is a lot of room to tinker with the mechanisms involved:
Cellular senescence is a stable form of cell cycle arrest that limits the propagation of damaged cells and can be triggered in response to diverse forms of cellular stress. This anti-proliferative program was initially considered a cell-autonomous mechanism that promotes tumor suppression and tissue homeostasis. However, several groundbreaking studies performed in the last decade have established that senescent cells can impact their environment through the secretion of growth factors, cytokines, chemokines, immune modulators and extracellular matrix-degrading enzymes. This process, collectively known as the senescence-associated secretory phenotype (SASP), enables the non-cell-autonomous activities of senescent cells. The functions exerted by the SASP are diverse and include the autocrine reinforcement of cell cycle arrest as well as the paracrine transmission of the senescent phenotype to neighboring cells, thereby maintaining and propagating tumor suppression. Moreover, SASP can directly modulate the tissue microenvironment, elicit immune surveillance of senescent cells, and paradoxically, promote tumorigenesis by supporting the proliferation of surrounding malignant or pre-malignant cells.
Many of the findings that illustrate the impact of SASP on the microenvironment stem from in vivo studies in the liver. Upon liver injury, hepatic stellate cells (HSCs) activate, proliferate, and develop a profibrotic secretome. Activated HSCs eventually undergo cellular senescence and produce a SASP enriched in fibrolytic molecules, contributing to fibrosis resolution. Moreover, senescent HSCs also secrete pro-inflammatory cytokines that direct the immune surveillance of senescent HSCs, further limiting liver fibrosis. The production of a proper SASP and subsequent immune-mediated clearance of senescent cells appear to be critical for the beneficial effects of cellular senescence on liver homeostasis and tumor suppression. Accordingly, genetic or chemical abrogation of the immune system leads to increased liver fibrosis, liver cancer, and delayed tumor regression after p53 reactivation in liver cancer cells. Intriguingly, in a murine model of HCC driven by a chemical carcinogen and obesity, senescence of HSCs and the corresponding SASP were associated with hepatocarcinogenesis. These contradictory findings could potentially be explained by differences in the senescence trigger, in the composition of the SASP, or by defective senescence surveillance. In fact, the clearance of senescent HSCs was not observed in the latter study, further emphasizing the importance of efficiently eliminating senescent cells.
Pro-senescence therapy has recently emerged as a novel therapeutic approach for treating cancer and could be applied to liver cancer, a disease that lacks effective treatment. However, if senescent tumor cells are not properly eliminated by the immune system, the SASP can promote the growth of non-senescent adjacent tumor cells. One solution could be to manipulate SASP to restrict its protumorigenic properties and/or enhance its ability to engage the immune system. An elegant work clearly showed how Pten-loss-induced senescence creates an immunosuppressive and protumorigenic microenvironment in prostatic intraepithelial neoplasias. However, pharmacological inhibition of the Jak2/Stat3 pathway reprogrammed SASP, restoring immune surveillance and the anti-tumor effects. Another appealing option is to boost the immune system to improve the surveillance of senescent tumor cells. Treatment with the anti-programmed cell death protein 1 (PD1) immune checkpoint antibodies or ipilimumab, an antibody that enhances the activation of cytotoxic T cells by blockade of the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) receptor, could improve the anti-tumor potential of pro-senescence therapies. Understanding and manipulating the signaling pathways that control SASP as well as identifying the key mediators of SASP will be essential to unleash the full potential of the senescence program.