Reed-Sternberg cells in Hodgkin's lymphoma present features of cellular senescence.
Hodgkin's Lymphoma (HL) is one of the most prevailing malignancies in young adults. Reed-Sternberg (RS) cells in HL have distinctive large cell morphology, are characteristic of the disease and their presence is essential for diagnosis. Enlarged cells are one of the hallmarks of senescence, but whether RS cells are senescent has not been previously investigated. Here we show that RS cells have characteristics of senescent cells; RS cells in HL biopsies specifically express the senescence markers and cell cycle inhibitors p21Cip1and p16INK4aand are negative for the proliferation marker Ki-67, suggesting that these cells have ceased to proliferate. Moreover, the RS-like cells in HL lines, stained specifically for senescence-associated β-galactosidase (SA-β-gal). Oxidative stress promoted senescence in these cells as demonstrated by their staining for p21Cip1, p16INK4a, p53 and γH2AX. Senescent cells produce copious amounts of inflammatory cytokines termed 'senescence-associated secretory phenotype' (SASP), primarily regulated by Nuclear Factor κB (NF-κB). Indeed, we show that NF-κB activity and NF-κB-dependent cytokines production (e.g., IL-6, TNF-α, GM-CSF) were elevated in RS-like cells. Furthermore, NF-κB inhibitors, JSH-23 and curcumin reduced IL-6 secretion from RS-like cells. Thus, defining RS cells as senescent offers new insights on the origin of the proinflammatory microenvironment in HL.
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.|Department of Oncology, Soroka University Medical Center, Beer Sheva 84105, Israel.
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Gopas
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.
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Stern
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.
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Zurgil
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.
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Ozer
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.
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Ben-Ari
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.|Flow Cytometry Unit, Hematology Laboratory and Institute of Hematology, Beer Sheva 84105, Israel.
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Shubinsky
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.
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Braiman
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.
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Sinay
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.
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Ezratty
Department of Pathology, Soroka University Medical Center, Beer Sheva 84105, Israel.
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Dronov
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
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Balachandran
Department of Pathology, Soroka University Medical Center, Beer Sheva 84105, Israel.
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Benharroch
The Shraga Segal Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben Gurion University of The Negev, Beer Sheva 84105, Israel.
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Livneh
D014408:Biomarkers, Tumor / Q000378:metabolism; D001706:Biopsy; D045744:Cell Line, Tumor; D048429:Cell Size; D016922:Cellular Senescence; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress; D016539:Reed-Sternberg Cells / Q000378:metabolism / Q000473:pathology*; D001616:beta-Galactosidase / Q000378:metabolism
D014408:Biomarkers, Tumor; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D001616:beta-Galactosidase