Abstract
Senescent cells secrete several molecules that help to prevent the progression of cancer. However, cancer cells can also misuse these secreted elements to survive and grow. Since the molecular and functional bases of these different elements remain poorly understood, we analyzed the effect of senescent mesenchymal stromal cell (MSC) secretome on the biology of ARH-77 myeloma cells. In addition to differentiating in mesodermal derivatives, MSCs have sustained interest among researchers by supporting hematopoiesis, contributing to tissue homeostasis, and modulating inflammatory response, all activities accomplished primarily by the secretion of cytokines and growth factors. Moreover, senescence profoundly affects the composition of MSC secretome. In this study, we induced MSC senescence by oxidative stress, DNA damage, and replicative exhaustion. While the first two are considered to induce acute senescence, extensive proliferation triggers replicative (i.e., chronic) senescence. We cultivated cancer cells in the presence of acute and chronic senescent MSC-conditioned media and evaluated their proliferation, DNA damage, apoptosis, and senescence. Our findings revealed that senescent secretomes induced apoptosis or senescence, if not both, to different extents. This anti-tumor activity became heavily impaired when secretomes were collected from senescent cells previously in contact (i.e., primed) with cancer cells. Our analysis of senescent MSC secretomes with LC-MS/MS followed by Gene Ontology classification further indicated that priming with cancer profoundly affected secretome composition by abrogating the production of pro-senescent and apoptotic factors. We thus showed for the first time that compared with cancer-primed MSCs, naïve senescent MSCs can exert different effects on tumor progression.
Highlights
Confronted with endogenous and exogenous stresses, cells may respond by becoming senescent
mesenchymal stromal cell (MSC) secretome can contribute to tumor growth in several ways: by promoting angiogenesis, creating a niche to support cancer stem cells survival, modulating the organism’s immune response against cancer cells, and by promoting the formation of metastasis [14]. To contribute to these findings, we investigated the effects of senescent MSC secretome upon the in vitro behavior of ARH-77 cells, which constitute a useful model of myeloma
Annexin V assay showed that unlike all other conditioned media (CM), only Naïve-D induced a significant increase in the percentage of apoptosis in ARH-77 cultures (Figure 1C)
Summary
Confronted with endogenous and exogenous stresses, cells may respond by becoming senescent. Genomic stressors such as the shortening of chromosome telomeres, non-telomeric DNA damage, excessive mitogenic signals, and non-genotoxic stress such as perturbations to chromatin organization are all considered to be damaging events. It may contribute to other biological processes such as development, tissue repair, and aging [1, 2]. Though cellular senescence has been deemed a unique intracellular event triggered by the activation of cytoplasmic signaling circuitry, it is evident that senescent cells secrete dozens of molecules, for which the term senescence-associated secretory phenotype (SASP) has been proposed. The secreted factors contribute to www.impactjournals.com/oncotarget cellular proliferative arrest through autocrine/paracrine pathways [3,4,5]
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