Cellular senescence: A link between cancer and age-related degenerative disease? (original) (raw)
Related papers
2016
Cellular senescence is defined as the physiological program of terminal growth arrest; in mammals it is an important tumor-suppressor mechanism since it stops premalignant cell proliferation. However, senescence also contributes to the decline associated to aging and the development of several diseases. This is explained by the fact that senescent cells secrete diverse molecules, which compromise the cellular microenvironment, and altogether are referred as senescent-associated secretory phenotype (SASP). The SASP is composed by cytokines, chemokines, growth factors, proteases, etc., whose function is to maintain the antiproliferative state and promote senescent cell clearance by the immune system. Nevertheless, over time, and particularly during old age, SASP might stimulate proliferation and premalignant cell transformation. The multifunctional roles of SASP would depend on the cell type and their physiological nature. Therefore, relying on the biological context, SASP could be be...
Cellular senescence in aging and age-related disease: from mechanisms to therapy
Nature Medicine, 2015
Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy. Aging is the progressive loss of tissue and organ function over time 1. The antagonistic pleiotropy theory of aging proposes that organismal fitness declines, at least in part, because natural selection favors genetic programs that have beneficial effects on reproductive fitness early in life without regard for negative impacts on health at later, post-reproductive ages 2. One set of genes that is likely to qualify as antagonistically pleiotropic is the regulators of cellular senescence 3 , a potent anticancer mechanism that prevents malignancies by permanently withdrawing (pre-) neoplastic cells from the cell cycle 4,5 but also has been implicated as a driver of aging and age-related disease 6-8. The emerging evidence suggests that the drawbacks of senescence are twofold. First, as one might expect, senescence causes a loss of tissue-repair capacity because of cell cycle arrest in progenitor cells. Second, senescent cells produce proinflammatory and matrix-degrading molecules in what is known as the senescence-associated secretory phenotype (SASP).
Cancer Response to Therapy-Induced Senescence: A Matter of Dose and Timing
Cancers, 2021
Cellular senescence participates to fundamental processes like tissue remodeling in embryo development, wound healing and inhibition of preneoplastic cell growth. Most senescent cells display common hallmarks, among which the most characteristic is a permanent (or long lasting) arrest of cell division. However, upon senescence, different cell types acquire distinct phenotypes, which also depend on the specific inducing stimuli. Senescent cells are metabolically active and secrete a collection of growth factors, cytokines, proteases, and matrix-remodeling proteins collectively defined as senescence-associated secretory phenotype, SASP. Through SASP, senescent cells modify their microenvironment and engage in a dynamic dialog with neighbor cells. Senescence of neoplastic cells, at least temporarily, reduces tumor expansion, but SASP of senescent cancer cells as well as SASP of senescent stromal cells in the tumor microenvironment may promote the growth of more aggressive cancer subclo...
Cellular Senescence as a Therapeutic Target for Age-Related Diseases: A Review
Advances in Therapy
Life expectancy has increased substantially over the last few decades, leading to a worldwide increase in the prevalence and burden of aging-associated diseases. Recent evidence has proven that cellular senescence contributes substantially to the development of these disorders. Cellular senescence is a state of cell cycle arrest with suppressed apoptosis and concomitant secretion of multiple bioactive factors (the senescence-associated secretory phenotype—SASP) that plays a physiological role in embryonic development and healing processes. However, DNA damage and oxidative stress that occur during aging cause the accumulation of senescent cells, which through their SASP bring about deleterious effects on multiple organ and systemic functions. Ablation of senescent cells through genetic or pharmacological means leads to improved life span and health span in animal models, and preliminary evidence suggests it may also have a positive impact on human health. Thus, strategies to reduce ...
Impact of Cellular Senescence in Aging and Cancer
Current Pharmaceutical Design, 2013
Cellular senescence is a response to nonlethal intrinsic or extrinsic stress that results in persistent growth arrest with a distinct morphological and biochemical phenotype. The engagement of senescence may represent a key component for therapeutic intervention in the eradication of cancer. Nevertheless, for many years, the role of senescence in opposing tumour growth in vivo had previously been underestimated. The potential role of cellular senescence in anti-cancer therapy may be particularly attractive in advanced age, because of the age-related changes occurring at the level of both tumor suppressor genes and immune functions. This review, which is focused on the impact of cellular senescence in aging and cancer, summarises the intrinsic pathways and the molecular and epigenetic changes involved in the induction of cellular senescence, and analyzes the changes occurring at the level of these pathways during aging and cancer.
Context-dependent effects of cellular senescence in cancer development
British Journal of Cancer, 2016
Cellular senescence is an established tumour-suppressive mechanism that prevents the proliferation of premalignant cells. However, several lines of evidence show that senescent cells, which often persist in vivo, can also promote tumour progression in addition to other age-related pathologies via the senescence-associated secretory phenotype (SASP). Moreover, new insights suggest the SASP can facilitate tissue repair. Here, we review the beneficial and detrimental roles of senescent cells, highlighting conditions under which the senescence response does and does not promote pathology, particularly cancer. By better understanding the context-dependent effects of cellular senescence, it may be feasible to limit its detrimental properties while preserving its beneficial effects, and develop novel therapeutic strategies to prevent or treat cancer and possibly other ageassociated diseases.
The role of senescence in cancer development
Seminars in Cancer Biology, 2019
While research on cancer development is traditionally focusing mainly on the neoplastic cell per se, nowadays the role of tumor stroma in this process is indisputable. The stroma-mainly composed of extracellular matrix (ECM)-is a source of mediators and signals originating from heterotypic cell-cell and cell-matrix interactions that steer the progression of the disease in a context-and a cancer type-dependent manner. With advancing age the stroma exhibits alterations, important being the accumulation of senescent cells. Senescence is often triggered by exogenous stresses, including genotoxic anticancer treatment modalities (such as chemotherapy or radiotherapy) and is manifested as an inhibition of cell proliferation, ascribing to cellular senescence the role of a potent antitumor barrier. On the other hand, senescent cells, through their specific senescence-associated secretory phenotype (SASP)comprising cytokines, growth factors, ECM components and ECM-degrading enzymes-can establish an immunosuppressive, inflammatory and catabolic microenvironment that may
Cellular Plasticity: A Route to Senescence Exit and Tumorigenesis
Cancers
Senescence is a dynamic, multistep program that results in permanent cell cycle arrest and is triggered by developmental or environmental, oncogenic or therapy-induced stress signals. Senescence is considered as a tumor suppressor mechanism that prevents the risk of neoplastic transformation by restricting the proliferation of damaged cells. Cells undergoing senescence sustain important morphological changes, chromatin remodeling and metabolic reprogramming, and secrete pro-inflammatory factors termed senescence-associated secretory phenotype (SASP). SASP activation is required for the clearance of senescent cells by innate immunity. Therefore, escape from senescence and the associated immune editing would be a prerequisite for tumor initiation and progression as well as therapeutic resistance. One of the possible mechanisms for overcoming senescence could be the acquisition of cellular plasticity resulting from the accumulation of genomic alterations and genetic and epigenetic repr...
Four faces of cellular senescence
The Journal of Cell Biology, 2011
Cellular senescence is an important mechanism for preventing the proliferation of potential cancer cells. Recently, however, it has become apparent that this process entails more than a simple cessation of cell growth. In addition to suppressing tumorigenesis, cellular senescence might also promote tissue repair and fuel inflammation associated with aging and cancer progression. Thus, cellular senescence might participate in four complex biological processes (tumor suppression, tumor promotion, aging, and tissue repair), some of which have apparently opposing effects. The challenge now is to understand the senescence response well enough to harness its benefits while suppressing its drawbacks.