Senescent Stromal Cells Promote Cancer Resistance through SIRT1 Loss-Potentiated Overproduction of Small Extracellular Vesicles

Abstract

Improving the effectiveness of public health interventions relies as much on the attention paid to their design and feasibility as to their evaluation. Yet, compared to the vast literature on how to evaluate interventions, there is little to guide researchers or practitioners on how best to develop such interventions in practical, logical, evidence based ways to maximise likely effectiveness. Existing models for the development of public health interventions tend to have a strong social-psychological, individual behaviour change orientation and some take years to implement. This paper presents a pragmatic guide to six essential Steps for Quality Intervention Development (6SQuID). The focus is on public health interventions but the model should have wider applicability. Once a problem has been identified as needing intervention, the process of designing an intervention can be broken down into six crucial steps: (1) defining and understanding the problem and its causes; (2) identifying which causal or contextual factors are modifiable: which have the greatest scope for change and who would benefit most; (3) deciding on the mechanisms of change; (4) clarifying how these will be delivered; (5) testing and adapting the intervention; and (6) collecting sufficient evidence of effectiveness to proceed to a rigorous evaluation. If each of these steps is carefully addressed, better use will be made of scarce public resources by avoiding the costly evaluation, or implementation, of unpromising interventions.

miR155 Enhances Autophagy by Reducing MBD5 and METTL3 in Human Liver Cancer Stem Cells

“…Several studies suggest that senescent stromal cells promote cancer resistance dependent on SIRT1 loss (49). Inhibiting SIRT1 by SMURF2 suppresses CRC cell proliferation(50).Our results suggest that miR-155 enhances the occurrence of autophagy through Sirt1 in liver cancer stem cells.Autophagy proved bene cial in evading various foreign pathogens in the context of cancer (51).…”

The Regulatory Effect of SIRT1 on Extracellular Microenvironment Remodeling

“…In senescent stromal cells, SIRT1-loss also causes impairment of lysosomes acidification and protein degradation. That is why senescent cells presumably prefer to release small extracellular vesicles into the tumor microenvironment, which enhances the aggressiveness and drug resistance of recipient cancer cells mediated by ATP binding cassette subfamily B member 4 (ABCB4) 115 .…”

Procyanidin C1 is a natural agent with senolytic activity against aging and age-related diseases

“…Agents were delivered via i.p. once per biweekly starting from the beginning of the 3rd week, with totally three 2-week cycles throughout the whole regimen as reported formerly 16,17 .…”

“…We chose to employ a primary normal human prostate stromal cell line, namely PSC27, as a cell-based model for this purpose. Composed mainly of fibroblasts but with a minor percentage of non-fibroblast cell lineages including endothelial cells and smooth muscle cells, PSC27 is primary in nature and develops a typical SASP after exposure to stressors such as genotoxic chemotherapy or ionizing radiation [14][15][16][17] . We treated these cells with a pre-optimized sub-lethal dose of bleomycin (BLEO), and observed increased positivity for senescenceassociated β-galactosidase (SA-β-Gal) staining, decreased BrdU incorporation, and elevated DNA damage repair (DDR) foci several days afterwards (Supplementary Fig.…”