Oncotarget

Research Papers: Gerotarget (Focus on Aging):

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

Umberto Galderisi _, Servet Özcan, Nicola Alessio, Mustafa Burak Acar, Guler Toprak, Zeynep Burcin Onal, Gianfranco Peluso

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Oncotarget. 2015; 6:39482-39492. https://doi.org/10.18632/oncotarget.5430

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Abstract

Servet Özcan1,5, Nicola Alessio2, Mustafa Burak Acar1,6, Güler Toprak1, Zeynep Burcin Gönen1, Gianfranco Peluso4, Umberto Galderisi1,2,3

1Genome and Stem Cell Center (GENKOK), Erciyes University, Kayseri, Turkey

2Department of Experimental Medicine, Biotechnology and Molecular Biology Section, Second University of Naples, Naples, Italy

3Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA

4Institute of Bioscience and Bioresources, CNR, Naples, Italy

5Department of Biology, Faculty of Sciences, Erciyes University, Kayseri, Turkey

6Graduate School of Natural and Applied Sciences, Erciyes University, Kayseri, Turkey

Correspondence to:

Umberto Galderisi, e-mail: tud23058@temple.edu

Keywords: Gerotarget, mesenchymal stem cells, senescence, secretome, apoptosis, cancer

Received: July 13, 2015     Accepted: October 05, 2015     Published: October 16, 2015

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.

Author Information

Umberto Galderisi
Primary Contact  _

Servet Özcan

Nicola Alessio

Mustafa Burak Acar

Guler Toprak

Zeynep Burcin Onal

Gianfranco Peluso


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