Therapy-Induced Stromal Senescence Promoting Aggressiveness of Prostate and Ovarian Cancer

Cells. 2022 Dec 13;11(24):4026. doi: 10.3390/cells11244026.


Cancer progression is supported by the cross-talk between tumor cells and the surrounding stroma. In this context, senescent cells in the tumor microenvironment contribute to the development of a pro-inflammatory milieu and the acquisition of aggressive traits by cancer cells. Anticancer treatments induce cellular senescence (therapy-induced senescence, TIS) in both tumor and non-cancerous cells, contributing to many detrimental side effects of therapies. Thus, we focused on the effects of chemotherapy on the stromal compartment of prostate and ovarian cancer. We demonstrated that anticancer chemotherapeutics, regardless of their specific mechanism of action, promote a senescent phenotype in stromal fibroblasts, resulting in metabolic alterations and secretion of paracrine factors, sustaining the invasive and clonogenic potential of both prostate and ovarian cancer cells. The clearance of senescent stromal cells, through senolytic drug treatment, reverts the malignant phenotype of tumor cells. The clinical relevance of TIS was validated in ovarian and prostate cancer patients, highlighting increased accumulation of lipofuscin aggregates, a marker of the senescent phenotype, in the stromal compartment of tissues from chemotherapy-treated patients. These data provide new insights into the potential efficacy of combining traditional anticancer strategies with innovative senotherapy to potentiate anticancer treatments and overcome the adverse effects of chemotherapy.

Keywords: cisplatin; docetaxel; ovarian cancer; prostate cancer; therapy induced senescence; tumor microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Female
  • Humans
  • Male
  • Ovarian Neoplasms* / genetics
  • Phenotype
  • Prostate / pathology
  • Prostatic Neoplasms* / drug therapy
  • Tumor Microenvironment

Grants and funding

This research was supported by the University of Florence (Fondo ex-60%) and by the Associazione Italiana Ricerca sul Cancro (AIRC) (project code: 19515) for the project “Assaying tumor metabolic deregulation in live cells”. E. Pranzini is supported by an AIRC fellowship (project code: 24132). E. Pardella is supported by an AIRC fellowship for Italy (project code 26599).