Expression of CCR5 receptors on Reed–Sternberg cells and Hodgkin lymphoma cell lines: Involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions

Aldinucci, Donatella; Lorenzon, Debora; Cattaruzza, Lara; Pinto, Antonio; Gloghini, Annunziata; Carbone, Antonino; Colombatti, Alfonso

doi:10.1002/ijc.23119

Cited by 140 publications

(134 citation statements)

References 42 publications

(77 reference statements)

Supporting

Mentioning

123

Contrasting

Unclassified

Order By: Relevance

“…As we confirm here, RS cell proliferation alone is insufficient for expansion or maintenance of the HRS cell clone. However, considering the longevity of RS cells, as shown here, as well as the important role of the microenvironment in HL (16,37,38), one may speculate that RS cells support tumor clone survival and expansion by producing cytokines and chemokines and promoting cellular interactions with other immune cells (39)(40)(41)(42), shaping the HL microenvironment in a way that supports the proliferating Hodgkin cells (43)(44)(45)(46). Based on this idea, understanding the mechanisms involved in fusion-based RS cell formation might lead to new therapeutic interventions making use of this process.…”

Section: Discussionmentioning

confidence: 92%

Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed–Sternberg cells

Rengstl

Newrzela

Heinrich

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Multinucleated Reed-Sternberg (RS) cells are pathognomonic for classical Hodgkin lymphoma (HL), and their presence is essential for diagnosis. How these giant tumor cells develop is controversial, however. It has been postulated that RS cells arise from mononucleated Hodgkin cells via endomitosis. Conversely, continuous single-cell tracking of HL cell lines by long-term time-lapse microscopy has identified cell fusion as the main route of RS cell formation. In contrast to growth-induced formation of giant Hodgkin cells, fusion of small mononuclear cells followed by a size increase gives rise to giant RS cells. Of note, fusion of cells originating from the same ancestor, termed re-fusion, is seen nearly exclusively. In the majority of cases, re-fusion of daughter cells is preceded by incomplete cytokinesis, as demonstrated by microtubule bonds among the cells. We confirm at the level of individual tracked cells that giant Hodgkin and RS cells have little proliferative capacity, further supporting small mononuclear Hodgkin cells as the proliferative compartment of the HL tumor clone. In addition, sister cells show a shared propensity for re-fusion, providing evidence of early RS cell fate commitment. Thus, RS cell generation is related neither to cell fusion of unrelated Hodgkin cells nor to endomitosis, but rather is mediated by re-fusion of daughter cells that underwent mitosis. This surprising finding supports the existence of a unique mechanism for the generation of multinuclear RS cells that may have implications beyond HL, given that RS-like cells are frequently observed in several other lymphoproliferative diseases as well.

show abstract

Section: Discussionmentioning

confidence: 92%

Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed–Sternberg cells

Rengstl

Newrzela

Heinrich

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…HRS cells express the chemokine receptor CCR5 and abundantly secrete its cognate ligand CLL5. 25 In addition, signaling through the CCR5/CCL5 system regulates HRS cell growth. 25 Furthermore, interleukin 13 (IL-13) and its receptor have been shown to be frequently expressed in cultured and primary HRS cells.…”

Section: Discussionmentioning

confidence: 99%

“…25 In addition, signaling through the CCR5/CCL5 system regulates HRS cell growth. 25 Furthermore, interleukin 13 (IL-13) and its receptor have been shown to be frequently expressed in cultured and primary HRS cells. 27 Treatment of cultured HRS cells with IL-13-neutralizing antibodies resulted in a dosedependent proliferation arrest, indicating IL-13 involvement in HRS cell growth.…”

Section: Discussionmentioning

confidence: 99%

“…It is known that HRS cells abundantly secrete soluble factors, such as cytokines and chemokines, and that they are involved in forming the particular microenvironment in cHL, and trigger HRS cell proliferation and survival. 14,[25][26][27] We incubated HRS cells with fresh or conditioned medium of untreated L540cy, L1236, KM-H2 and L428 cells, and simultaneously added GSI XII for 24 h. NF-kB p52 levels, which are indicative for alternative NF-kB signaling, remained stable in L540cy cells upon stimulation of cells with conditioned medium (Figure 5a, upper panel). Accordingly, conditioned medium efficiently reversed the loss of cell viability of GSI-treated HRS cells (Figure 5a, lower panel and Supplementary Figures S2A and B).…”

Section: Stimulation Of Alternative Nf-kb Signaling Rescues Hrs Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

2011

View full text Add to dashboard Cite

A major pathogenetic mechanism in classical Hodgkin lymphoma (cHL) is constitutive activation of canonical nuclear factor-jB (NF-jB) p50/p65 signaling, controlling lymphoma cell proliferation and survival. Recently, we demonstrated that aberrant Notch1 activity is a negative regulator of the B cell program in B cell-derived Hodgkin and Reed-Sternberg (HRS) cells. Despite abundant evidence for a complex contextdependent cross talk between Notch and NF-jB signaling in hematopoietic cells, it is unknown whether these pathways interact in HRS cells. Here, we show that Notch-signaling inhibition in HRS cells by the c-secretase inhibitor (GSI) XII results in decreased alternative p52/RelB NF-jB signaling, interfering with processing of the NF-jB2 gene product p100 into its active form p52. As a result, expression of Notch and NF-jB target genes is reduced, and survival of HRS cells is impaired. Stimulation of alternative NF-jB signaling in the Hodgkin cell line L540cy by activation of the CD30 receptor rescued GSI-mediated loss of cell viability and apoptosis induction. Our data reveal that Notch is an essential upstream regulator of alternative NF-jB signaling and indicate cross talk between both the pathways in HRS cells. Therefore, we suggest that targeting the Notch pathway is a promising therapeutic option in cHL.

show abstract

“…Buri et al found that CCL5 was only expressed in the infiltrated non-neoplastic leukocytes of CHL but not in HRS cells (6). However, subsequent studies demonstrated the expression of CCL5 in HRS cells and its potential role in the recruitment of inflammatory cells into lymphoma tissue (7,8). Emmerich et al found that NF-кB transcription factor iкBα is overexpressed in RS cells (9).…”

Section: Introductionmentioning

confidence: 99%

Analysis of CCL5 expression in classical Hodgkin's lymphoma L428 cell line

Liu

Zhang

et al. 2011

Mol Med Report

View full text Add to dashboard Cite

Abstract. CCL5 is one of the chemoattractant cytokines involved in inflammatory observed in both diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin's lymphoma (CHL). However, the pathological effects of CCL5 remain unclear. To gain a better understanding of the role of CCL5 in CHL and DLBCL, we examined the expression of CCL5 in the CHL cell line L428 and the DLBCL cell lines Ly1 and Ly8, as well as its chemotactic effect on CD4 + T cells. CCL5 mRNA expression was detected by real-time quantitative RT-PCR. Intracellular CCL5 protein expression was analyzed using confocal microscopy, and CCL5 protein secretion was detected by ELISA. The chemotactic function of CCL5 was assessed using a Transwell coculture system, and the number of migrated CD4 + T cells was counted. Moreover, the p-iкBα and p65 levels of NF-кB signaling molecules in these lymphoma cell lines were detected by Western blotting. The results showed that CCL5 mRNA and protein expression in the L428 cells was significantly higher than in Ly1 and Ly8 cells (p<0.05). L428 cells secreted more CCL5 than the Ly1 or Ly8 cells, and the secreted CCL5 was capable of inducing CD4 + T cell migration. The expression levels of the NF-кB transcription factors p65 and p-iкBα were examined in these lymphoma cells. L428, Ly1 and Ly8 cells expressed similar levels of p65, while p-iкBα expression was higher in the L428 cells than in the Ly1 or Ly8 cells, indicating that a high CCL5 expression may be related to the increased activity of the NF-кB signaling pathway in L428 cells.

show abstract

Expression of CCR5 receptors on Reed–Sternberg cells and Hodgkin lymphoma cell lines: Involvement of CCL5/Rantes in tumor cell growth and microenvironmental interactions

Cited by 140 publications

References 42 publications

Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed–Sternberg cells

Incomplete cytokinesis and re-fusion of small mononucleated Hodgkin cells lead to giant multinucleated Reed–Sternberg cells

Notch is an essential upstream regulator of NF-κB and is relevant for survival of Hodgkin and Reed–Sternberg cells

Analysis of CCL5 expression in classical Hodgkin's lymphoma L428 cell line

Contact Info

Product

Resources

About