Senescent peritoneal mesothelium creates a niche for ovarian cancer metastases

Cell Death Dis. 2016 Dec 29;7(12):e2565. doi: 10.1038/cddis.2016.417.

Abstract

Although both incidence and aggressiveness of ovarian malignancy rise with age, the exact reason for this tendency, in particular the contribution of senescent cells, remains elusive. In this project we found that the patient's age determines the frequency of intraperitoneal metastases of ovarian cancer. Moreover, we documented that senescent human peritoneal mesothelial cells (HPMCs) stimulate proliferation, migration and invasion of ovarian cancer cells in vitro, and that this effect is related to both the activity of soluble agents released to the environment by these cells and direct cell-cell contact. The panel of mediators of the pro-cancerous activity of senescent HPMCs appeared to be cancer cell line-specific. The growth of tumors in a mouse peritoneal cavity was intensified when the cancer cells were co-injected together with senescent HPMCs. This effect was reversible when the senescence of HPMCs was slowed down by the neutralization of p38 MAPK. The analysis of lesions excised from the peritoneum of patients with ovarian cancer showed the abundance of senescent HPMCs in close proximity to the cancerous tissue. Collectively, our findings indicate that senescent HPMCs which accumulate in the peritoneum in vivo may create a metastatic niche facilitating intraperitoneal expansion of ovarian malignancy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Aging / pathology*
  • Animals
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Cell Cycle / drug effects
  • Cell Cycle / genetics
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Cellular Senescence / drug effects
  • Culture Media, Conditioned / pharmacology
  • Disease Progression
  • Epithelium / drug effects
  • Epithelium / pathology*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mice, Inbred C57BL
  • Mice, SCID
  • Middle Aged
  • Neoplasm Metastasis
  • Ovarian Neoplasms / enzymology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • Peritoneum / pathology*
  • Phenotype
  • Solubility
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Culture Media, Conditioned
  • p38 Mitogen-Activated Protein Kinases