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

Abstract

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.

Cellular senescence: A potential mode of circular RNAs regulating prostate cancer

“…Another research confirmed that senescent cancer cells induced by ADT escaped growth inhibition and regained malignant capabilities whereby promote the development of CRPC 40 . Furthermore, a recent study showed that anticancer chemotherapy promoted the senescent phenotype of stromal fibroblasts, leading to metabolic changes and secretion of paracrine factors, thereby facilitated the invasion and proliferation of PCa cells 77 …”

A senescence-specific lncRNA controls metabolic rewiring of senescent cells

“…Platinum-based therapies, currently used as the first line of treatment for patients with ovarian cancer, are known to induce senescence in cancer cells 67 . Although therapy-induced senescence (TIS) has been considered a desirable outcome of cancer therapy, the activation of the senescence program has been shown to induce the rewiring of cellular metabolism promoting the pro-tumorigenic and pro-metatastic potential of ovarian cancer cells 68 . Here, we show that sin-lncRNA is specifically induced in ovarian cancer cells that undergo senescence and contributes to sustain the metabolic demands to maintain senescence in cancer cells upon drug treatment.…”

Senescent Stromal Cells in the Tumor Microenvironment: Victims or Accomplices?

“…Decades ago, Krtolica et al demonstrated the capacity of senescent fibroblasts to promote tumorigenesis, indicating cellular senescence as a case of evolutionary antagonistic pleiotropy that, despite restraining tumor growth in the early stages, may nevertheless exhibit pro-tumorigenic effects when senescence occurs in benign stromal cells [ 26 ]. Emerging evidence supports the role of senescent stromal cells as an accomplice in the growth of a variety of epithelial-derived solid tumors [ 52 , 99 , 100 ]. Similarly, recent studies have shown that senescent mesenchymal stromal cells contribute to the development of myeloid tumors [ 101 , 102 , 103 , 104 ].…”