Reed-Sternberg cells in Hodgkin’s lymphoma present features of cellular senescence

Abstract

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 p21Cip1 and p16INK4a and 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.

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

“…As per cell cycle inhibitors, senescent pEOCs displayed upregulated expression of p16, p21, and p53. These findings are consistent with the report on senescent Hodgkin's lymphoma-derived Reed-Sternberg cells [10] and epithelial cells overexpressing BRAF V600E [21], which exhibited increased levels of p16 and p21. High levels of p16 were also observed in the spontaneous senescence of pre-malignant lesions in the lungs from K-ras V12 mice [22].…”

“…In ovarian tumors, the senescent cells formed visible patches, while in breast tumors, only individual cells were identified as senescent [4]. Apart from breast cancer, the presence of spontaneously senescent cells in vivo has also been observed in mice with ductal hyperplasia and carcinoma in situ [9], as well as in Reed-Sternberg cells within Hodgkin's lymphoma specimens [10].…”

Curcumin formulated in solid lipid nanoparticles has enhanced efficacy in Hodgkin's lymphoma in mice

“…In L-540 cells, curcumin significantly reduced the expression of both of these cytokines in a concentration-dependent manner. Given that HL cells might support tumor survival and expansion by producing cytokines [25], our findings raise the possibility that curcumin could also be beneficial by reducing cytokine production. However, these results should be taken carefully since they were obtained in HL cells in culture and confirmation with HL patient's samples is warranted.…”

Mechanisms and significance of therapy-induced and spontaneous senescence of cancer cells

“…Analysis of frozen tumor sections from untreated mice showed detectable expression of SA-β-Gal, which was localized to limited tumor fragments and significantly lower compared with the enzyme staining in tumors from animals treated with 4-hydroxyphenyl retinamide [113]. An expression of SA-β-Gal combined with the presence of other markers of senescence, including p16 Ink4a and p21 Cip1 cell cycle inhibitors has also been observed in Reed-Sternberg cells within Hodgkin's lymphoma biopsies [150].…”