Myeloma cells can corrupt senescent mesenchymal stromal cells and impair their anti-tumor activity

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.

Identification of senescent cells in multipotent mesenchymal stromal cell cultures: Current methods and future directions

“…The SASP secretome consist of growth factors and cytokines including interleukin-1 (IL-1), IL-3, IL-4, IL-6, IL-8, epidermal growth factor), hepatocyte growth factor, insulin growth factor, platelet derived growth factor, TGF-and vascular endothelial growth factor (VEGF) [46] that amongst their other roles, regulate MSCs proliferation in culture and are crucial to MSC senescence as well [2]. Senescent MSC secretome can induce senescence and apoptosis in other cells [47], as well an inflammatory responses in neighbouring cells [16,27]. Critically, transplantation of even small numbers of senescent cells can cause age-related disease phenotypes, such as osteoarthritis, as shown recently by Xu et al [48].…”

“…Senescent cell accumulation is likely to be responsible for a decrease in the overall multipotent differentiation ability of long term expanded MSCs [26,49]. Finally, senescent cells SASP can accelerate ageing [48] or induce apoptosis [47] in the neighbouring cells. Thus, having a direct method for identification, quantification and ultimately, removal of senescent cells in MSC cultures would have a significant value for ensuring the quality of MSCs intended for clinical applications.…”

Filamin B and CD13 are components of senescent secretomes that may be involved in primary (stress induced) and paracrine senescence of mesenchymal stromal cells

“…Although many studies highlighted the importance of the SASP in regulating cellular response to senescence signaling, the identification of secreted factors is still a challenging issue, since the typology of secreted proteins strictly depends on genotoxic stress and cell type (2)(3)(4). To date, a comprehensive analysis of the secretome profile of senescent MSCs is still lacking.…”

“…Cellular senescence is the permanent cell cycle arrest evoked in response to a variety of stressors (1). This physiological response to stress has a pleiotropic effect: i) beneficial, since senescence can counteract tumor growth by blocking the proliferation of transformed cells, ii) detrimental by contributing to organismal aging (2)(3)(4). Recently, it has been demonstrated that senescence may also contribute to organism development and tissue repair processes (5).…”

Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging

“…These different results could be due to the effect of cancer cells on MSCs. Actually, the SASP of naïve senescent cells (not primed by cancer cells) may block the proliferation and induce senescence of an immortalized lymphoblastoid cell line, whereas primed senescent MSCs show an impaired anti-proliferative and pro-senescence activity due to a significant modification of the SASP composition induced by priming with cancer cells [179]. Moreover, treatment of immortalized prostate and metastatic prostatic cancer cell lines with the SASP from naïve acute senescent MSCs induced senescence of immortalized cells but not of cancer cells [180].…”