During the processes of senescence and cancer, cytplasmic chromatin and DNA leads to inflammation

Senescence is “a state of a cell showing (usually) irreversible cell-cycle arrest.” Senescence is often considered to be a protective response to cellular insults –– such as high levels of DNA damage or stress associated with the expression of cancer-promoting genes. Senescent cells also exhibit a pro-inflammatory response known as the senescence-associated secretory phenotype (SASP). However, signals that trigger SASP have remained elusive. Some light is now shed on this mystery in recent papers, including the one attached, plus one in Nature Cell Biology [2o17; 19: 1061-1070] and one in Proc Natl Acad Sci USA [2o17; 114: 2612–2620].

Cell senescence occurs during normal embryonic development, as well as in several pathological contexts –– including cancer and some diseases associated with old age. During development, senescent cells can harness SASP to promote secretion of signaling molecules called cytokines. The cytokines recruit immune cells, which can remodel tissue through cell clearance. Senescence can also be beneficial, if cells express cancer-promoting genes or have high levels of DNA damage, because the combination of cell-cycle arrest and SASP-mediated inflammation, which can help to recruit tumor-targeting immune cells, provides a double-barrier against tumor formation.

However, senescence can also have harmful effects, for example, when SASP-associated factors promote the ability of cancer cells to invade other locations in the body.

Chromatin (DNA, sugars and proteins combined) is traditionally viewed as a nuclear entity that regulates gene expression and gene silencing. However, authors have recently discovered the presence of cytoplasmic chromatin fragments that pinch off from intact nuclei of primary cells during senescence. The functional significance of chromatin in the cytoplasm has been unclear. Authors [see attached] show that cytoplasmic chromatin activates the innate-immunity cytosolic DNA-sensing cGAS–STING (“cyclic GMP–AMP synthase-linked-to-stimulator-of-interferon genes”) pathway –– leading both to short-term inflammation –– to restrain activated oncogenes and to chronic inflammation that is associated with tissue destruction and cancer.

The cytoplasmic chromatin–cGAS–STING pathway promotes the SASP in primary human cells and in mice. Mice deficient in STING show impaired immuno-surveillance of the tumor-promoting RAS gene and decreased tissue inflammation following ionizing radiation. Furthermore, this pathway is activated in cancer cells, and correlates with pro-inflammatory gene expression in human cancers. Overall, these exciting data indicate that genomic DNA serves as a reservoir to initiate a pro-inflammatory pathway in cytoplasm during senescence and cancer. Targeting the cytoplasmic chromatin-mediated pathway may hold promise in treating inflammation-related disorders.

Nature 19 Oct 2o17; 550: 402–406 [full article] & pp 340–341 [editorial]

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