Senescence-associated secretory phenotype (SASP)
The senescence-associated secretory phenotype (SASP) is the collection of proteins that senescent cells release into the tissue around them. The set includes inflammatory cytokines, chemokines, growth factors, and proteinases, and it develops over several days after a cell settles into the arrested senescent state. The secretions act on neighboring cells and can reinforce the arrest, recruit immune cells, and damage the surrounding tissue.12
Composition
Coppé and colleagues profiled the proteins that senescent cells release with antibody arrays and found a broad group of factors tied to inflammation and malignancy. The inflammatory cytokines interleukin-6 (IL-6) and CXCL8) carry much of the paracrine activity in their assays. The profile is large and mixed: inflammatory mediators, chemokines that recruit immune cells, growth factors, and proteinases that remodel the extracellular matrix appear together.12
Development
The program develops slowly. In culture it emerged over several days and followed DNA damage of a magnitude sufficient to induce senescence, which separates it from an immediate stress response. Fibroblasts, normal epithelial cells, and epithelial tumor cells produced similar profiles after genotoxic stress, and tumor cells sampled from prostate cancer patients treated with DNA-damaging chemotherapy showed the same pattern in vivo. The consistency across cell types placed the SASP inside the core senescence program.1
Regulation
Two cancer-relevant inputs changed the strength of the response. Oncogenic RAS expression and functional loss of p53 each amplified and accelerated the SASP, and both exacerbated its pro-malignant paracrine effects. The link to p53 gave the secretory program a direct connection to p53, the tumor suppressor that also enforces the division arrest. The authors proposed that p53 restrains, and oncogenic RAS promotes, age-related cancer through effects on the tissue microenvironment.1
Function
The SASP carries the senescence program beyond the cell that stops dividing. In premalignant epithelial cells the secretions induced an epithelial-to-mesenchymal transition and invasive behavior through a paracrine mechanism that depended largely on IL-6 and IL-8. That result made the secretory program a way for a senescent cell to alter its neighbors while its own proliferation stays blocked. The 2010 review described this as the “dark side of tumor suppression”: the arrest suppresses the individual cell’s cancer risk while the secretions can promote progression in the tissue.2
In aging
When senescent cells accumulate in a tissue, their secretions supply a persistent inflammatory signal. This links cellular senescence to tissue dysfunction in aging, and it makes the senescent cell burden a therapeutic target as well as a marker. The INK-ATTAC experiments removed p16-positive cells and improved organ function, and senolytics pursue the same goal with drugs. The distinction between the arrest and its secretions matters for therapy, because different senescent and quiescent states carry different secretory profiles.
Limits
The SASP varies with cell type, the stimulus that produced the senescence, and the time since the arrest, so a single set of markers captures part of a moving program. The strongest mechanistic evidence comes from cultured cells and a defined group of factors, and the contribution of individual factors to tissue aging in a living animal remains an active area of study.2
See also
References
Footnotes
- Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology. 2008;6(12):2853–2868. doi:10.1371/journal.pbio.0060301. ↩↩2↩3↩4
- Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual Review of Pathology. 2010;5:99–118. doi:10.1146/annurev-pathol-121808-102144. ↩↩2↩3↩4