Klotho‐mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments

摘要

Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin ( )‐pretreated or replicative senescent stromal cells ( ‐38 and ) promote colorectal cancer ( ) cell growth and invasion and . These pro‐tumorigenic effects were attenuated by exogenous administration of Klotho, an anti‐aging factor. We subsequently identified several senescence‐associated secretory phenotype ( )‐associated genes, including 2, which were significantly upregulated in both types of senescent stromal cells during replication and damage‐induced senescence. Importantly, we found that the secretion of 2 by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, 2 was found to accelerate cell proliferation and invasion, while this effect could be blocked by administration of a specific 2 antagonist. We further show that Klotho can suppress ‐κB activation during ‐induced senescence and thus block 2 transcription. Low expression of Klotho, or high expression of 2 in patient tumor tissues, correlated with poor overall survival of patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of . Klotho can suppress the senescent stromal cell‐associated triggering of progression by inhibiting the expression of factors including 2. The identification of key factors such as 2 may provide potential therapeutic targets for improving therapy.