Distinct phenotypes and ‘bystander’ effects of senescent tumour cells induced by docetaxel or immunomodulatory cytokines

Abstract

Cellular senescence is the process of the permanent proliferative arrest of cells in response to various inducers. It is accompanied by typical morphological changes, in addition to the secretion of bioactive molecules, including proinflammatory cytokines and chemokines [known as the senescence-associated secretory phenotype (SASP)]. Thus, senescent cells may affect their local environment and induce a so-called ‘bystander’ senescence through the state of SASP. The phenotypes of senescent cells are determined by the type of agent inducing cellular stress and the cell lineages. To characterise the phenotypes of senescent cancer cells, two murine cell lines were employed in the present study: TC-1 and B16F10 (B16) cells. Two distinct senescence inductors were used: Chemotherapeutic agent docetaxel (DTX) and a combination of immunomodulatory cytokines, including interferon γ (IFNγ) and tumour necrosis factor α (TNFα). It was demonstrated that DTX induced senescence in TC-1 and B16 tumour cell lines, which was demonstrated by growth arrest, positive β-galactosidase staining, increased p21Waf1 (p21) expression and the typical SASP capable of inducing a ‘bystander’ senescence. By contrast, treatment with a combination of T helper cell 1 cytokines, IFNγ and TNFα, induced proliferation arrest only in B16 cells. Despite the presence of certain characteristic features resembling senescent cells (proliferation arrest, morphological changes and increased p21 expression), these cells were able to form tumours in vivo and started to proliferate upon cytokine withdrawal. In addition, B16 cells were not able to induce a ‘bystander’ senescence. In summary, the present study described cell line- and treatment- associated differences in the phenotypes of senescent cells that may be relevant in optimization of cancer chemo- and immunotherapy.

Downregulation of the inflammatory network in senescent fibroblasts and aging tissues of the long‐lived and cancer‐resistant subterranean wild rodent, Spalax

“…Accumulating data suggest that SASP or inflammatory cytokines may trigger DDR and inflammatory signaling in the surrounding microenvironment, an effect known as “bystander” senescence (Hubackova, Krejcikova, Bartek, & Hodny, ; Sapega et al, ). Multiple inflammatory factors secreted by aggressive metastatic MDA‐MB‐231 breast cancer cells, including extremely high concentrations of IL1β, were able to induce NF‐κB signaling and secretion of inflammatory cytokines and chemokines in bystander cells (Escobar et al, ).…”

Senescent Tumor Cells in the Peritoneal Carcinomatosis Drive Immunosenescence in the Tumor Microenvironment

“…One hallmark of senescence, independent of the inducer of senescence, is that senescent cells secrete multiple factors including pro-inflammatory cytokines, chemokines, growth factors and proteases ( 55 ). Some of these factors are known to induce “bystander” senescence in neighboring cells ( 56 ). In mouse PC samples, we found the same upregulation of senescence-associated markers accompanied by downregulation of proliferation as in human samples.…”

Enhanced target-specific delivery of docetaxel-loaded nanoparticles using engineered T cell receptors

“… 41 We suspect that this may prove to be the case for TCR-NPs in the setting that different populations of cancer cells within the tumour express varying levels of HLA. Similarly, docetaxel-induced cell death has been shown to induce bystander effects in tumours 42 further mitigating against the issue of tumour cell heterogeneity.…”