Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
Level 5 - mechanism / opinion, no new human data
Bench and in vitro mechanistic cell culture study with correlative patient tissue analysis.
PubMed 19053174 · doi:10.1371/journal.pbio.0060301
What was done
Authors used modified quantitative antibody arrays to profile factors secreted by human cells induced to senesce by genotoxic stress. Secretion profiles were evaluated in cultured normal fibroblasts, normal epithelial cells, and epithelial tumor cells, as well as in epithelial tumor cells in vivo from prostate cancer patients treated with DNA-damaging chemotherapy. They also assessed the paracrine effects of the senescence-associated secretory phenotype (SASP) on cultured premalignant epithelial cells with and without oncogenic RAS expression or p53 tumor suppressor inactivation.
What was found
The abstract reports no numerical values. Senescent cells secreted inflammatory and malignancy-associated factors, developing slowly over several days after severe DNA damage. SASPs induced epithelial-mesenchyme transition and invasiveness in premalignant epithelial cells via paracrine signaling largely dependent on IL-6 and IL-8. Oncogenic RAS expression and functional loss of p53 markedly amplified and accelerated SASP development and exacerbated its pro-malignant paracrine activity.
Why it matters
This study defines the senescence-associated secretory phenotype (SASP) and demonstrates a cell-nonautonomous mechanism whereby senescent cells can stimulate tumor progression in adjacent premalignant cells. It illustrates how p53 loss and oncogenic RAS alter the tissue microenvironment to promote age-related cancer.
Limits
The abstract provides no sample sizes (n is not reported for patient samples or cell experiments), effect sizes, or quantitative statistical values. Most findings rely on in vitro cell culture models rather than clinical outcomes.
Cited by
- supports Senescent cells secrete signaling molecules and factors that cause damage to neighboring cells.