Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2020 Feb;111(2):304-311.
doi: 10.1111/cas.14266. Epub 2019 Dec 27.

Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer

Tze Mun Loo  1 , Kenichi Miyata  1 , Yoko Tanaka  1 , Akiko Takahashi  1   2   3
Affiliations
Review

Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer

Tze Mun Loo et al. Cancer Sci. 2020 Feb.

Abstract

Cellular senescence is historically regarded as a tumor suppression mechanism to prevent damaged cells from aberrant proliferation in benign and premalignant tumors. However, recent findings have suggested that senescent cells contribute to tumorigenesis and age-associated pathologies through the senescence-associated secretory phenotype (SASP). Therefore, to control age-associated cancer, it is important to understand the molecular mechanisms of the SASP in the cancer microenvironment. New findings have suggested that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway, a critical indicator of innate immune response, triggers the SASP in response to accumulation of cytoplasmic DNA (cytoplasmic chromatin fragments, mtDNA and cDNA) in senescent cells. Notably, the cGAS-STING signaling pathway promotes or inhibits tumorigenesis depending on the biological context in vivo, indicating that it may be a potential therapeutic target for cancer. Herein, we review the regulatory machinery and biological function of the SASP via the cGAS-STING signaling pathway in cancer.

Keywords: DNA damage; SASP; cGAS-STING; cellular senescence; tumorigenesis.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflict of interest.

Figures

Figure 1
Figure 1
The characteristics of cellular senescence. Cellular senescence is triggered by various stressors, such as irradiation, reactive oxygen species (ROS), oncogene activation and telomere shortening. The senescent cells show increased expression of p16INK4a and/or p21WAF1/CIP1, senescence‐associated secretory phenotype (SASP) factors, DNA damage foci and senescence‐associated heterochromatin foci (SAHF) formation. In addition, cell proliferation is inhibited and Lamin B1 expression is decreased. Senescent cell cycle arrest is induced by p16INK4a and/or by p21WAF1/CIP1
Figure 2
Figure 2
The biological function of senescence‐associated secretory phenotype (SASP) factors in physiological and pathological conditions. SASP factors play important roles in common physiological conditions, as shown by the red arrows, such as wound healing (PDGF‐AA, platelet‐derived growth factor‐AA), embryonic development (TGF‐β, transforming growth factor‐β; Wnt) and immune recruitment (CXCL1, CCL2 and CCL5). However, SASP factors also induce tumor progression and migration (MMP; IL‐1β, interleukin‐1β; VEGF, vascular endothelial growth factor) and suppression of anti–tumor immunity (PGE2, prostaglandin E2) under pathological conditions, as shown by the blue arrows. Moreover, SASP factors induce and maintain senescence cell cycle arrest through paracrine and autocrine factors
Figure 3
Figure 3
The cGAS‐STING pathway in senescence‐associated secretory phenotype (SASP) regulation. Various stressors such as reactive oxygen species (ROS) or UV irradiation cause accumulation of DNA fragments from nucleic double‐strand breaks (DSB), termed cytoplasmic chromatin fragments (CCF), in senescent cells. Damaged mitochondria release mtDNA into the cytoplasm. Long‐interspersed element‐1 (LINE‐1) transcription is upregulated, thereby promoting cDNA production in senescent cells. These DNA fragments are recognized by cGAS to generate 2′3′‐cyclic GMP‐AMP (2′3′‐cGAMP). 2′3′‐cGAMP activates both STING and TANK‐binding kinase 1 (TBK1), resulting in phosphorylation of IRF3. 2′3′‐cGAMP also activates IκBa. These transcription factors enter the nucleus and induce expression of type‐I interferon (IFN) and inflammatory cytokines. Both IRF3 and NF‐κB induce senescence‐associated secretory phenotype (SASP) factors such as IFN‐β, IL‐6 and IL‐8, which are known to induce ROS and maintain cellular senescence
Figure 4
Figure 4
The cGAS‐STING pathway plays two different roles in liver tumorigenesis. DNA damage induces cellular senescence in hepatic stellate cells (HSC) and hepatocytes in the liver. Accumulation of cytosolic DNA leads to activation of the cGAS‐STING pathway, resulting in production of senescence‐associated secretory phenotype (SASP) factors. Short‐term exposure to SASP factors drives recruitment of immune cells to clear pre–malignant cells and senescent cells, thereby preventing tumorigenesis. However, long‐term exposure to SASP factors generates chronic inflammation and promotes tumorigenesis in obese mice
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685‐705. - PMC - PubMed
    1. Munoz‐Espin D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15:482‐496. - PubMed
    1. Hayflick L, Moorhead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585‐621. - PubMed
    1. Serrano M, Lee H, Chin L, Cordon‐Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996;85:27‐37. - PubMed
    1. McHugh D, Gil J. Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol. 2018;217:65‐77. - PMC - PubMed