Myeloma cells can corrupt senescent mesenchymal stromal cells and impair their anti-tumor activity.
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.
Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey.|Department of Biology, Faculty of Sciences, Erciyes University, Kayseri, Turkey.
Servet
S
Özcan
Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, Naples, Italy.
Nicola
N
Alessio
Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey.|Graduate School of Natural and Applied Sciences, Erciyes University, Kayseri, Turkey.
Mustafa Burak
MB
Acar
Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey.
Güler
G
Toprak
Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey.
Zeynep Burcin
ZB
Gönen
Institute of Bioscience and Bioresources, CNR, Naples, Italy.
Gianfranco
G
Peluso
Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey.|Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, Naples, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA.
Umberto
U
Galderisi
D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016922:Cellular Senescence; D002853:Chromatography, Liquid; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000378:metabolism* / Q000494:pharmacology; D004249:DNA Damage; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053719:Tandem Mass Spectrometry
D000970:Antineoplastic Agents; D017077:Culture Media, Conditioned
Gerotarget; apoptosis; cancer; mesenchymal stem cells; secretome; senescence