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

Mol Oncol. 2019 Nov;13(11):2460-2475. doi: 10.1002/1878-0261.12577. Epub 2019 Oct 6.

Abstract

Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin (DOX)-pretreated or replicative senescent stromal cells (WI-38 and HUVEC) promote colorectal cancer (CRC) cell growth and invasion in vitro and in vivo. These pro-tumorigenic effects were attenuated by exogenous administration of Klotho, an anti-aging factor. We subsequently identified several senescence-associated secretory phenotype (SASP)-associated genes, including CCL2, which were significantly upregulated in both types of senescent stromal cells during replication and DNA damage-induced senescence. Importantly, we found that the secretion of CCL2 by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, CCL2 was found to accelerate CRC cell proliferation and invasion, while this effect could be blocked by administration of a specific CCR2 antagonist. We further show that Klotho can suppress NF-κB activation during DOX-induced senescence and thus block CCL2 transcription. Low expression of Klotho, or high expression of CCL2 in patient tumor tissues, correlated with poor overall survival of CRC patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of CRC. Klotho can suppress the senescent stromal cell-associated triggering of CRC progression by inhibiting the expression of SASP factors including CCL2. The identification of key SASP factors such as CCL2 may provide potential therapeutic targets for improving CRC therapy.

Keywords: CCL2; Klotho; colorectal cancer; senescence.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cellular Microenvironment* / drug effects
  • Cellular Senescence* / drug effects
  • Chemokine CCL2 / metabolism*
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology*
  • Disease Progression*
  • Down-Regulation / drug effects
  • Doxorubicin / pharmacology
  • Female
  • Glucuronidase / metabolism*
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Klotho Proteins
  • Male
  • Middle Aged
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Proportional Hazards Models
  • Signal Transduction / drug effects
  • Stromal Cells / drug effects
  • Stromal Cells / metabolism

Substances

  • Chemokine CCL2
  • NF-kappa B
  • Doxorubicin
  • Glucuronidase
  • Klotho Proteins