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

Sapega,Olena; Mikyšková,Romana; Bieblová,Jana; Mrázková,Blanka; Hodný,Zdeněk; Reiniš,Milan

doi:10.3892/ijo.2018.4553

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

Authors:
- Olena Sapega
- Romana Mikyšková
- Jana Bieblová
- Blanka Mrázková
- Zdeněk Hodný
- Milan Reiniš
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Affiliations: Laboratory of Immunological and Tumour Models, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Prague 4 142 20, Czech Republic, Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Prague 4 142 20, Czech Republic, Laboratory of Genome Integrity, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., Prague 4 142 20, Czech Republic
Published online on: September 5, 2018 https://doi.org/10.3892/ijo.2018.4553
Pages: 1997-2009
Copyright: © Sapega et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 4.0].

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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.

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