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

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.

Automated summary

Cancer progression is supported by the interaction between tumor cells and the surrounding stroma. Chemotherapy-induced senescence in both tumor and non-cancerous cells contributes to the adverse effects of therapies. It has been found that chemotherapy drugs promote senescence in stromal fibroblasts, leading to metabolic alterations and secretion of paracrine factors, thereby enhancing the invasive and clonogenic potential of prostate and ovarian cancer cells. Clearance of senescent stromal cells can reverse the malignant phenotype of tumor cells. This has important implications for combining traditional anticancer strategies with innovative senotherapy to enhance anticancer treatments and overcome the adverse effects of chemotherapy.