Two-Step Senescence-Focused Cancer Therapies

doi:10.1016/j.tcb.2018.04.006

Trends in Cell Biology

Volume 28, Issue 9, September 2018, Pages 723-737

https://doi.org/10.1016/j.tcb.2018.04.006 Get rights and content

Highlights

Senescent cells are a cell cycle-arrested but highly bioactive cell type. Although the proportion of senescent cells in tissues is relatively low, these cells are causally implicated in aging and in an ever-expanding list of diseases including cancer.

Cancer-associated senescent cells can modulate all stages of tumor development, with their contributions being either detrimental or beneficial towards tumor initiation, growth, metastasis, or cancer relapse.

Although highly context-dependent, the senescence-associated secretory phenotype (SASP) serves many functions in the tumor microenvironment, including mitogenic induction, immune surveillance, or immune deterrence.

A two-step anticancer therapeutic concept, senescence-inducing chemotherapy followed by senotherapy, may represent a viable option to maximize therapeutic efficiency and patient outcome.

Damaged cells at risk of neoplastic transformation can be neutralized by apoptosis or engagement of the senescence program, which induces permanent cell-cycle arrest and a bioactive secretome that is implicated in tumor immunosurveillance. While from an evolutionary perspective senescence is beneficial in that it protects against malignancies, the accumulation of senescent cells in tissues and organs with aging and at sites of various pathologies is largely detrimental. Because induction of senescence in cancer cells is emerging as a therapeutic concept, it will be important to consider these detrimental effects, including tumor-promoting properties that may drive the formation of secondary tumors or cancer relapse. In this review we discuss the complex relationship between senescence and cancer, and highlight important considerations for therapeutics.

Section snippets

Senescent Cells: Modulators of Aging and Cancer

Advanced age is the leading risk factor for numerous chronic diseases including various types of cancer [1]. Although the causes and mechanisms of aging remain poorly understood, senescent cells have emerged as a central contributor to premature and natural aging [2] and to age-related diseases 3, 4, 5. Various studies in mice demonstrate that senescent cells represent a druggable target to extend healthy lifespan and ameliorate various chronic diseases 2, 3, 4, 6. These findings have prompted

Senescent Neoplastic Cells

Historically, cellular senescence has been described as a tumor-protective mechanism that inhibits the uncontrolled proliferation of cancer-prone cells. Activation of particular oncogenes or the loss of particular tumor-suppressor genes induces the senescence program to establish a durable cell-cycle arrest [8] (Figure 1A, Key Figure). This mechanism is described in a plethora of cellular systems with multiple oncogenes in vitro, as well as in murine tissues, including but not limited to liver (

Cancer and the Aging Immune System

Both the adaptive and innate immune systems are capable of infiltrating and clearing tumor cells. While T cells (CD4⁺ helper and CD8⁺ cytotoxic), tumor-associated macrophages, and natural killer (NK) cells prevent tumor growth by targeting antigenic tumor cells, regulatory T cells that secrete immunosuppressive cytokines as well as myeloid and stromal cells suppress T cell responses in lesions that have lost immunogenicity 9, 78, 79. Interestingly, these same immune cell types are effective in

The SASP and Cancer

Senescent cells restrict and contribute to cancer via both cell-autonomous (restriction of cell proliferation or transformation) and cell non-autonomous mechanisms (SASP) that can result in extracellular matrix remodeling, growth stimulation, or suppression of adjacent cells and signaling to the immune system. Senescence-associated paracrine signaling seems to be context-dependent, with the type of senescence stimulus and cell type having dramatic consequences on the SASP profile 47, 94.

The

Senotherapy as an Anticancer Strategy

Although the central objective of chemo- and radiation therapies is to prevent the proliferation of cancer cells through the induction of cellular senescence or cell death [116], the persistence of therapy-induced senescent cells after treatment is detrimental. The use of senotherapy in combination with currently used cancer therapies should be taken into consideration to control this problem [43]. Several cancer types are discussed here which represent suitable candidates for consideration of

Concluding Remarks and Future Directions

Cellular senescence is a feature of cancer that can be induced by multiple mechanisms in and around tumors, and can have both beneficial and detrimental effects on tumor initiation, growth, therapeutic efficacy, and tumor recurrence. However, the features of these different senescent cell types, as well as the mechanisms for their phenotypic impact on neoplastic cells, remain incompletely understood, and in-depth in vivo analysis is currently lacking (see Outstanding Questions). Although these

Acknowledgments

The authors would like to acknowledge the following funding and support sources: NIH (R01CA166347 and R01CA96985), the Glenn Foundation for Medical Research, Mayo Clinic Center for Biomedical Discovery, and the Mayo Clinic Graduate School of Biomedical Sciences.

Glossary

Acute senescent cells: senescent cells that are generated quickly after an environmental insult or stress (for example during wound healing) or during programmed senescence in embryogenesis. These cells are typically eliminated by the immune system in a fast and efficient manner. Because these cells are only temporarily present and are associated with physiological processes, acute senescent cells are hypothesized to be beneficial for the organism.
CDKN2A: the gene encoding the tumor suppressors p16

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Cited by (143)

Therapy-induced senescent tumor cells in cancer relapse
2023, Journal of the National Cancer Center
Cellular senescence is characterized by a generally irreversible cell cycle arrest and the secretion of bioactive factors known as the senescence-associated secretory phenotype (SASP). In an oncogenic context, senescence is considered a tumor suppressive mechanism as it prevents cell proliferation and inhibits the progression from pre-malignant to malignant disease. However, recent studies have demonstrated that senescent tumor cells, which could spontaneously exist within cancer tissues or arise in response to various cancer interventions (the so-called therapy-induced senescence, TIS), can acquire pro-tumorigenic properties and are capable of driving local and metastatic relapse. This highlights the complex and multifaceted nature of cellular senescence in cancer biology. Here, we summarize the current knowledge of the pathological function of therapy-induced senescent tumor cells and discuss possible mechanisms by which tumor cell senescence contributes to cancer relapse. We also discuss implications for future studies toward targeting these less appreciated cells.
Aurora A Kinase Plays a Key Role in Mitosis Skip during Senescence Induced by Ionizing Radiation
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To investigate the fate and underlying mechanisms of G2 phase arrest in cancer cells elicited by ionizing radiation (IR).
Human melanoma A375 and 92-1 cells were treated with X-rays radiation or Aurora A inhibitor MLN8237 (MLN) and/or p21 depletion by small interfering RNA (siRNA). Cell cycle distribution was determined using flow cytometry and a fluorescent ubiquitin-based cell cycle indicator (FUCCI) system combined with histone H3 phosphorylation at Ser10 (pS10 H3) detection. Senescence was assessed using senescence-associated-β-galactosidase (SA-β-Gal), Ki67, and γH2AX staining. Protein expression levels were determined using western blotting.
Tumor cells suffered severe DNA damage and underwent G2 arrest after IR treatment. The damaged cells did not successfully enter M phase nor were they stably blocked at G2 phase but underwent mitotic skipping and entered G1 phase as tetraploid cells, ultimately leading to senescence in G1. During this process, the p53/p21 pathway is hyperactivated. Accompanying p21 accumulation, Aurora A kinase levels declined sharply. MLN treatment confirmed that Aurora A kinase activity is essential for mitosis skipping and senescence induction.
Persistent p21 activation during IR-induced G2 phase blockade drives Aurora A kinase degradation, leading to senescence via mitotic skipping.
Senescence in cancer: Advances in detection and treatment modalities
2023, Biochemical Pharmacology
Senescence is a form of irreversible cell cycle arrest. Senescence plays a dual role in cancer, as both a tumor suppressor by preventing the growth of damaged cells and a cancer promoter by creating an inflammatory milieu. Stress-induced premature senescence (SIPS) and replicative senescence are the two major sub-types of senescence. Senescence plays a dual role in cancer, depending on the context and kind of senescence involved. SIPS can cause cancer by nurturing an inflammatory environment, whereas replicative senescence may prevent cancer. Major pathways that are involved in senescence are the p53-p21, p16^INK4A-Rb pathway along with mTOR, MAPK, and PI3K pathways. The lack of universal senescence markers makes it difficult to identify senescent cells in vivo. A combination of reliable detection methods of senescent cells in vivo is of utmost importance and will help in early detection and open new avenues for future treatment. New strategies that are being developed in order to tackle these shortcomings are in the field of fluorescent probes, nanoparticles, positron emission tomography probes, biosensors, and the detection of cell-free DNA from liquid biopsies. Along with detection, eradication of these senescent cells is also important to prevent cancer reoccurrence. Recently, the field of nano-senolytic and immunotherapy has also been emerging. This review provides up-to-date information on the various types of advancements made in the field of detection and treatment modalities for senescent cells that hold promise for the future treatment and prognosis of cancer, as well as their limitations and potential solutions.
Senescent alveolar macrophages promote early-stage lung tumorigenesis
2023, Cancer Cell
Senescent cells play relevant but context-dependent roles during tumorigenesis. Here, in an oncogenic Kras-driven lung cancer mouse model, we found that senescent cells, specifically alveolar macrophages, accumulate early in neoplasia. These macrophages have upregulated expression of p16^INK4a and Cxcr1, are distinct from previously defined subsets and are sensitive to senolytic interventions, and suppress cytotoxic T cell responses. Their removal attenuates adenoma development and progression in mice, indicating their tumorigenesis-promoting role. Importantly, we found that alveolar macrophages with these properties increase with normal aging in mouse lung and in human lung adenocarcinoma in situ. Collectively, our study indicates that a subset of tissue-resident macrophages can support neoplastic transformation through altering their local microenvironment, suggesting that therapeutic interventions targeting senescent macrophages may attenuate lung cancer progression during early stages of disease.
Mechanisms of carboplatin- and paclitaxel-dependent induction of premature senescence and pro-cancerogenic conversion of normal peritoneal mesothelium and fibroblasts
2024, Journal of Pathology
Cellular senescence and nanoparticle-based therapies: Current developments and perspectives
2024, Nanotechnology Reviews

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Trends in Cell Biology

ReviewTwo-Step Senescence-Focused Cancer Therapies

Highlights

Section snippets

Senescent Cells: Modulators of Aging and Cancer

Senescent Neoplastic Cells

Cancer and the Aging Immune System

The SASP and Cancer

Senotherapy as an Anticancer Strategy

Concluding Remarks and Future Directions

Acknowledgments

Glossary

Cell

Cell

Cell

Cancer Cell

Cancer Cell

Radiother. Oncol.

Clin. Lung Cancer

Cell Rep.

Cancer Cell

Cancer Cell

J. Biol. Chem.

Hum. Pathol.

Cell

Cell

Am. J. Pathol.

Cell Rep.

Int. J. Biochem. Cell Biol.

Mech. Ageing Dev.

Cell

Osteoarthr. Cartil.

Gynecol. Oncol.

Hematol. Oncol. Clin. North Am.

Cell

Trends Immunol.

Exp. Gerontol.

Cell

Exp. Gerontol.

Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan

Nature

Senescent intimal foam cells are deleterious at all stages of atherosclerosis

Science

Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment

Nat. Med.

Cellular senescence in renal ageing and disease

Nat. Rev. Nephrol.

Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice

Nat. Med.

Senescent cells: an emerging target for diseases of ageing

Nat. Rev. Drug Discov.

Senescence surveillance of pre-malignant hepatocytes limits liver cancer development

Nature

Senescent tumor cells lead the collective invasion in thyroid cancer

Nat. Commun.

Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis

Nat. Commun.

Oncogene-induced senescence as an initial barrier in lymphoma development

Nature

Oncogenic RAS-induced senescence in human primary thyrocytes: molecular effectors and inflammatory secretome involved

Oncotarget

Dose-dependent oncogene-induced senescence in vivo and its evasion during mammary tumorigenesis

Nat. Cell Biol.

Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

Nature

Skp2 targeting suppresses tumorigenesis by Arf–p53-independent cellular senescence

Nature

CKIalpha ablation highlights a critical role for p53 in invasiveness control

Nature

Senescence mediates pituitary hypoplasia and restrains pituitary tumor growth

Cancer Res.

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Nat. Genet.

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Oncogene

Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas

Clin. Cancer Res.

The differential impact of p16(INK4a) or p19(ARF) deficiency on cell growth and tumorigenesis

Oncogene

Recurrent hemizygous deletions in cancers may optimize proliferative potential

Review
Two-Step Senescence-Focused Cancer Therapies