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Annals of Clinical & Laboratory Science 32:339-351 (2002)
© 2002 Association of Clinical Scientists

The Reed-Sternberg Cell: Molecular Characterization by Proteomic Analysis with Therapeutic Implications

Robert E. Brown and Nazmi R. Kamal
Division of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania

Address correspondence to Robert E. Brown, M.D., Division of Laboratory Medicine, Geisinger Medical Center, Danville, PA 17822-0131, USA; tel 570 271 6332; fax 570 271 6105; e-mail rebrown{at}geisinger.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective: To characterize Reed-Sternberg (R-S) cells by proteomic analysis in order to gain insight into the molecular pathways that control their growth and thereby to discern potential molecular interventions in Hodgkin’s disease. Methods: Ten cases of the nodular sclerosing (NS) subtype and 4 cases of the lymphocyte-predominant (LP) subtype were studied. Immunohistochemical procedures were performed to detect the following antigens: CD20, CD30, c-kit, platelet-derived growth factor receptor (PDGFR)-{alpha}, cathepsin D, angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor, phosphorylated c-Jun N-terminal kinase (p-JNK), c-Jun, Ki-67, the latency-associated peptide (LAP) of transforming growth factor-beta 1 (TGF-ß1), and the TGF-ß receptor (TGF-ßRII). Immunoreactivities were scored from 0 to 3+ positivity using bright-field microscopy. Results: The tyrosine kinase signal transducer, PDGFR-{alpha}, the AT1 receptor transactivator, the p-JNK downstream effector, Ki-67, and proapoptotic TGF-ß1 (LAP) were detected in R-S cells of the NS and LP subtypes; companion dendritic cells expressed cathepsin D and ACE. Intranuclear c-Jun was present in the NS subtype and stronger immunoreactivity for TGF-ßRII was evident in the LP subtype. Conclusion: These data corroborate observations in the literature, characterizing R-S cells as possessing molecular pathways that incorporate PDGFR-{alpha} signaling and angiotensin transactivation with a potential for growth inhibition through activation of TGF-ß1 and upregulation of its receptor. Specific therapies to target R-S cells in Hodgkin’s disease might include STI571, an AT1 receptor inhibitor, and retinoids.

(received 9 April 2002; accepted 24 June 2002)

Keywords: Reed-Sternberg cell, proteomics, immunohistochemistry, Hodgkin’s disease, molecular signaling pathways


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The Reed-Sternberg (R-S) cell, as the putative malignant cell, is the principal therapeutic target in Hodgkin’s disease. In this regard, many workers have attempted to define the lineage of the R-S cell and its mononuclear variants (Hodgkin’s cells) in order to select appropriate therapies. Such efforts began in 1902 with Dorothy Reed’s description of them by brightfield microscopy as "endothelial" and epithelioid, suggesting a histiocytic lineage [1]; the efforts have continued by use of histochemical and immunohistochemical phenotyping techniques. The latter have variably suggested T-lymphocytic, dendritic, B-lymphocytic, and natural killer cell lineages for the classic R-S cell and B-cell lineage for the L & H variant in lymphocyte-predominant Hodgkin’s disease [2–4]. Recent applications of microdissection techniques and molecular analysis have shown that most R-S cells exhibit an immunoglobulin gene rearrangement consistent with B-cell lineage [4,5]. However, occasional isolated classic R-S cells exhibit T-cell gene rearrangement [4,6]. Uncertainty regarding a definitive single cell lineage has been fueled by genomic analysis that revealed under- and over-representation of genes in classic R-S cells vis-á-vis germinal center B-cells [5].

This report delineates an alternative approach to the molecular characterization of R-S cells, including both classic and L & H variants. Proteomic analysis, defined in this study as the immunohistochemical detection, visual quantification, cellular compartmentalization, and functional grouping of proteins, was applied to R-S cells in nodular sclerosing and lymphocyte-predominant subtypes of Hodgkin’s disease in order to delineate a molecular profile of each subtype. The selection of specific proteins for this study was based in part on a report by Pinto et al [7] regarding the expression of c-kit (CD117) antigen (a member of the platelet-derived growth factor receptor family) in R-S cells and their mononuclear variants and in part on our discovery of PDGFR-{alpha} antigen in R-S cells on the control slide generally used for detection of CD30 antigen.

The selected proteins included tyrosine kinase-mediated signal transducers, as well as transactivators, downstream effector molecules, and indicators of the genomic impact of molecular signaling, or, obversely, potential downstream molecular inhibitors of the PDGFR-{alpha} signal transduction pathway. The authors postulated that such profiles might provide insights into the molecular pathways that control the growth of R-S cells and suggest possibilities for therapeutic intervention.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study population.  With the approval of our institutional review board (IRB), 10 patients with the nodular sclerosing (NS) subtype and 4 patients with the lymphocyte-predominant (LP) subtype of Hodgkin’s disease were included in this study. Confirmation of the initial diagnosis in each case was carried out by the authors utilizing hematoxylineosin (H&E) stained slides and appropriate immunoreactivities for CD15 and/or CD30 in the NS subtype and for CD20 in the LP subtype. Patients with the NS subtype included 4 men and 6 women (age 14–87 yr, mean 39 yr). Patients with the LP subtype included 4 men (age 9–58 yr, mean 26 yr).

Immunohistochemistry.  A panel of antibodies was assembled to detect the following antigens in the lesional tissues: c-kit (CD117), platelet-derived growth factor receptor-alpha (PDGFR-{alpha}), cathepsin D, angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor, phosphorylated c-Jun N-terminal kinase (p-JNK), c-Jun, Ki-67, the latency-associated peptide (LAP) of transforming growth factor-beta-1 (TGF-ß1), and TGF-ß receptor II (TGF-ßRII).

Rabbit polyclonal anti-human c-kit (CD117) antibody (code #A4502; DAKO Corp., Carpinteria, CA) was used to detect the corresponding antigen, a protein that functions as a transmembrane tyrosine kinase receptor.

Mouse monoclonal anti-human PDGFR-{alpha}(clone 35264.111, IgG1k; R&D Systems, Inc., Minneapolis, MN) was used to detect the corresponding antigen, a protein that functions as a tyrosine kinase receptor [8] and, when activated, as a signal transducer.

Rabbit polyclonal anti-human cathepsin D (code #A0561; DAKO) was used to detect the corresponding antigen, a lysosomal enzyme involved in intracellular protein turnover.

Mouse monoclonal anti-human ACE (clone CG2–1193–36–18; Accurate Chemical & Scientific Corp., Westbury, NY) was used to detect the corresponding antigen, an endopeptidase that generates angiotensin II from angiotensin I.

Rabbit polyclonal anti-human AT1 receptor (catalog #sc-579; Santa Cruz Biotechnology, Inc., Santa Cruz, CA) was used to detect the corresponding antigen, the protein receptor that mediates effects of angiotensin II, which include the activation of several signal transduction pathways.

Mouse monoclonal anti-human p-JNK antibody (clone G7; catalog #sc-6254, Santa Cruz Biotechnology) was used to assess the nuclear expression of the corresponding antigen, which mediates the phosphorylation of c-Jun and stimulates its transactivating function.

Mouse monoclonal anti-c-Jun antibody with human immunoreactivity (clone 3; BD Transduction Laboratories, Becton, Dickinson and Co., East Rutherford, NJ) was used to assess the nuclear expression of the corresponding antigen, a protein product of the corresponding proliferation-associated, immediate-early gene and a component of the activator protein (AP-1) transcription factor.

Mouse monoclonal anti-human Ki-67 antibody (clone MIB-1; DAKO) was used to detect the corresponding antigen, a non-histone nuclear protein associated with all active phases of the cell cycle (G1, S, G2, and M).

Goat polyclonal antibody to LAP of human TGF-ß1 (catalog #AB-246-NA; R&D Systems) was used in this study. This antibody reacts with latent TGF-ß1 in immunohistochemical applications.

Rabbit polyclonal anti-human TGF-ß RII antibody (catalog #sc-220; Santa Cruz Biotechnology) was used to assess expression of the corresponding antigen, a glycoprotein that mediates a signal from active TGF-ß.

Immunohistochemical staining was performed as previously described [2], including positive controls using immunoreactive tissues and a negative control utilizing each of the study cases.

Scoring of immunoreactivity.  Immunoreactivities of all of the cases were scored from 0 (negative) to 3+ positivity using bright-field microscopy. Instances in which the chromogenic signal was faint (between negative and 1+) were assigned a ± status and a numerical score of 0.5. The final score in each individual case for each of the protein analytes incorporated the range of signals and the relative percentages of positive R-S and Hodgkin’s cells or companion cells. Each slide was evaluated by both authors and the scores represent a consensus.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In addition to the characteristic features of the NS subtype on routine H&E staining, the R-S cells (Fig. 1Go, panel A) in all 10 cases of this subtype displayed immunoreactivity for CD30 antigen (Fig. 3Go, panel A); 9 cases also showed CD15 antigen expression (focal in 5). Similarly, CD20 immunopositivity was detected on R-S cells of all 4 cases of the LP subtype (weak expression of CD30 antigen in 1 case); all 4 cases lacked detectable CD15 antigen).



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  		Fig. 1. Reed-Sternberg (R-S) cells and their variants in nodular sclerosing Hodgkin’s disease (H&E, panel A; diaminobenzidine chromogen, panels B,C,D; all original magnifications x788). Panel A: binucleate and poly-lobated nuclei (arrows R-S) and a mummified (apoptotic) form (double arrows). The latter is contiguous with a lacunar cell (H&E). Panel B: strong (3+) cytoplasmic immunoreactivity for PDGFR-{alpha} protein (arrows). Panel C: mild (1+) intranuclear immunoreactivity for phosphorylated c-Jun-N-terminal kinase (p-JNK) protein (arrowheads). Panel D: strong (3+) cytoplasmic immunoreactivity (arrows) for the latency-associated peptide (LAP) of TGF-ß1.

 


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  		Fig. 3. Reed-Sternberg (R-S) cells and their variants in nodular sclerosing Hodgkin’s disease (diaminobenzidine chromogen, panels A,B,C,D; all original magnifications x788). Panel A: plasmalemmal and paranuclear (Golgi) immunoreactivity for CD30 antigen. Panel B: moderate (2+) intranuclear immunoreactivity for c-Jun protein. Panel C: plasmalemmal and cytoplasmic immunopositivity for c-kit (CD117) protein in mast cells (arrowheads). Panel D: mild (1+) immunoreactivity for transforming growth factor-ß receptor II in occasional R-S cells (arrow R-S).

 
Proteomic analysis by immunohistochemistry and scoring by bright-field microscopy gave the following results in the NS subtype: c-kit protein (CD117 antigen) was either absent (0) or only faintly (±) expressed in the cytoplasm of R-S and Hodgkin’s cells in the majority of cases; however, scores of 1+, 1+, and 2+ positivity, respectively, were noted in 3 cases (companion cells, eg, frequent mast cells and, on occasion, fibroblasts, exhibited 3+ positivity [Fig. 3Go, panel C]); the chromogenic signal for PDGFR-{alpha}antigen was strong (2 to 3+) in R-S and Hodgkin’s cells (Fig. 1Go, panel B) in all cases. Variable and generally weaker reactivity was noted in companion lymphocytes, endothelial cells, and histocytes, except for dendritic cells, which showed 3+ immunopositivity in an occasional case. Overall, immunopositivity in companion cells appeared to be upregulated relative to reactive lymphoid tissue in the concurrently run control.

Components of the angiotensin system demonstrated a consistent pattern of immunoreactivities with a general absence of cathepsin D and ACE from the R-S and Hodgkin’s cells, but with strong (3+) expression of cathepsin D in companion dendritic cells (Fig. 2Go, panel A), of ACE on endothelial and histiocytic/dendritic cells (Fig. 2Go, panel B) and of AT1 receptor in the cytoplasm of R-S and Hodgkin’s cells in all cases at a range of 1 to 3+ positivity.



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  		Fig. 2. Reed-Sternberg (R-S) cells and their variants in nodular sclerosing Hodgkin’s disease (diaminobenzidine chromogen, panels A,B,C,D; all original magnifications x788). Panel A: cytoplasmic immunoreactivity for cathepsin D protein in companion dendritic cells. Panel B: plasmalemmal immunoreactivity for angiotensin-converting enzyme (ACE) protein in companion dendritic cells, some of which are contiguous. Panel C: moderate cytoplasmic immunoreactivity (2+) for angiotensin II type 1 (AT1) receptor protein in both R-S (arrow R-S) and small, possible progenitor cells (arrowhead). Panel D: strong (3+) intranuclear immunoreactivity for Ki-67 protein (arrow R-S) and also in companion lymphoid cells.

 
Immunopositivity was also found in smaller (possible progenitor R-S) cells (Fig. 2Go, panel C); the intranuclear expressions of Ki-67 and c-Jun proteins were 2 to 3+ in all but 1 case (Fig. 2Go, panel D and Fig. 3Go, panel B, respectively). TGF-ß1 (LAP) was consistently and strongly expressed (2+ to 3+) in R-S and Hodgkin’s cells in all cases. The companion lymphocytes and adjacent stromal cells also showed generally strong chromogenic signals (Fig. 1Go, panel D), but the range of immunopositivity for TGF-ßRII was broader (0 to 3+) and averaged 1.0 in the 10 cases (Fig. 3Go, panel D). Intranuclear immunoreactivity for p-JNK was variable within and among cases, ranging from ± to 2+ (Fig. 1Go, panel C).

In R-S cells from the 4 cases of the LP subtype of Hodgkin’s disease, the analyges gave the following immunoreactivities, compared to their counterparts in the NS subtype: less detectable c-kit and PDGFR-{alpha} antigens with mean scores of 0 and 1.5, respectively; essentially no intranuclear c-Jun protein expression (0 to ±); similar immunopositivities for cathepsin D, ACE, AT1 receptor, p-JNK, Ki-67, and TGF-ß1 (LAP); but greater immunoreactivity for TFG-ßRII (range 1 to 3+; mean 2.5). The mean scores for the protein analytes in the cases of NS and LP subtypes are listed in Table 1Go.


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  		Table 1. Molecular profile of Reed-Sternberg (R-S) cells, based on proteomic analysis by immunohistochemistry.
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, proteomic analysis has provided insights into molecular pathways that may explain the genesis and proliferation of R-S cells. The results suggest a pathogenetic sequence for Hodgkin’s disease and suggest opportunities for therapeutic intervention.

Pinto et al [7] detected c-kit (CD 117) antigen in R-S cells and their mononuclear variants from 11 of 21 cases of Hodgkin’s disease. This observation coincides with our finding of c-kit (CD117) expression in 3 of 10 cases of the NS subtype. Since the ligand for c-kit is stem cell factor and the c-kit gene is expressed in hematopoietic stem cells [7,9,10], it is possible that the R-S cells in cases of the NS subtype are derived from pluripotential progenitor cells. Such a histogenesis would reconcile the variable phenotypic and genotypic findings of the R-S cells in this subtype. Alternatively, because expression of c-kit antigen has been associated with a majority of CD30+ anaplastic large cell lymphomas in one series [7], CD30-associated activation may possibly be responsible for c-kit expression in the NS subtype of Hodgkin’s disease.

Immunodetection of PDGFR-{alpha} in R-S cells in all of the cases in this study is consistent with the cytokine milieu in Hodgkin’s disease. Because interferon-{gamma} and interleukin-1ß upregulate PDGFR-{alpha} expression at the mRNA level [11–13] and because interferon-{gamma} and interleukin-1ß have been detected in Hodgkin’s disease and in R-S cells [14–17], the expression of PDGFR-{alpha} in R-S cells in this study is not surprising. Its expression in R-S cells suggests a molecular pathway leading to proliferation of these cells and their progenitors through tyrosine kinase-mediated signal transduction.

In general, the signaling pathway for PDGFR-induced mitogenesis incorporates ligand-dependent activation, downstream signal transduction following activation (via JAK kinases) of the signal transducer and activator of transcription protein, Stat3, and in turn of mitogen-activated protein kinase (MAPK) pathways, and, finally, expression of c-Myc leading to DNA synthesis and mitogenesis [18–26]. In the context of Hodgkin’s disease, several reports provide molecular concomitants that support such a pathway in the R-S cell. These include the report by Kube et al [27] that Stat3 is constitutively activated in the majority of Hodgkin cell lines, that this activation is independent of interleukin (IL)-6, and that it can be blocked by a Janus kinase (JAK) inhibitor, AG490. Moreover, genomic and proteomic evidence suggests that c-myc oncogene and c-Myc protein are expressed in R-S cells [4,28–30]. The proteomic concomitant of DNA synthesis and mitogenesis, which was detected in R-S cells in this and previous studies, is the intranuclear expression of Ki-67 antigen [31–34]. Parenthetically, IL-9 could contribute to the activation of Stat3, the expression of c-Myc, and to cell proliferation in some cases of the NS subtype of Hodgkin’s disease [2,4,35,36]. Similarly, DNA synthesis in CD30+ R-S cells of the NS subtype may be stimulated by interactions with the relatively numerous CD30 ligand (CD30L)-positive mast cells [37–39].

In addition, co-expression of the AT1 receptor in the R-S cell in all cases in our study lends support to PDGFR-{alpha} signaling, since the angiotensin system serves as a transactivator of this molecular pathway [40,41]. Commonalities between angiotensin II-induced signaling and PDGFR-signaling support such transactivation. These include: involvement of the Src family of tyrosine kinases and phospholipase C isozyme, PLC-{gamma} [18–20,26,42]; activation of Stat3 [22,26,43]; activation of MAPK and JNK pathways [24,44–47]; and induction of c-Myc [23,26,48,49] and c-Jun [50,51] expressions. Although some of these commonalities have already been considered in the context of Hodgkin’s disease (see above), there are other relevant observations. These include the detection of Src oncogene expression in R-S cells [4], our detection of p-JNK in R-S cells in this study, the report of Knecht et al [52] that activation of the JNK signaling pathway is important in the formation of R-S cells, and the correlation of c-jun expression with histiocytic differentiation in Hodgkin’s R-S cells [53]. Finally, the close proximity of dendritic/histocytic cells containing cathepsin D and ACE antigens, as noted in this study, points to paracrine stimulation of this transactivator through the catalytic generation of angiotensin I from angiotensinogen and in turn angiotensin II from angiotensin I [54,55].

As a potential brake on these mitogenic pathways in R-S cells, there are proapoptotic/growth inhibitors. Principal among these are the latency-associated peptide (LAP) of TGF-ß1, as seen in this study, a high molecular weight TGF-ß in Hodgkin’s disease of the NS subtype [56–58], and TGF-ß1 expressed in Hodgkin’s R-S cells and by reactive T lymphocytes in Hodgkin’s disease [59,60]. The angiotensin system has a potential role in the induction of the latent and active forms of TGF-ß1 in R-S cells [61]. A rate limiting factor in the apoptotic and growth inhibitory effects of TGF-ß1 appears to be the amount of TGF-ß receptor expression in the R-S cells, which in the case of the NS-derived, L428 cell line has been quantified as <500 TGF-ß receptor sites per R-S cell [57]. The variable immunohistochemical expression and relatively low score for TGF-ßRII in R-S cells in the NS subtype, compared to those in the LP subtype, portends relative resistance to the apoptotic and antiproliferative effects of TGF-ß1 [62–65] in nodular sclerosing Hodgkin’s disease, unless the receptor can be up-regulated.

The molecular profile of the R-S cells that we have developed through proteomic analysis suggests some new therapeutic options for controlling the proliferation of R-S cells. Specifically, STI571 ("Gleevec") has been shown to inhibit both c-kit and PDGFR-mediated signaling for tyrosine kinase [25]. ACE inhibitors (eg, captopril [66]) and AT1 receptor inhibitors (eg, losartan [67]) could moderate transactivation. Retinoids (eg, all-trans retinoic acid), by converting the abundant latent TGF-ß1 to its active form, by up-regulating the synthesis of TGF-ß1 and TFG-ßRII, and by inhibiting JNK and the expression of c-Jun [68–76], could curtail proliferation of RS cells.

Retinoids and STI571 appear to be a logical therapeutic combination since the retinoic acid receptor (RAR)-{alpha} is stabilized by STI571 and since these agents in combination show greater efficacy in promoting maturation and differentiation of leukemic cell lines [77]. Similar cytodifferentiation has been achieved in cultured R-S cells using retinoic acid as one of the inducing agents [78–79]. These molecular pathways and their implications for therapeutic intervention are diagrammed in Fig. 4Go.



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  		Fig. 4. Cartoon of Reed-Sternberg cell in nodular sclerosing Hodgkin’s disease illustrating the findings in this study and from the literature. The molecular pathways created by functional grouping of these proteins provides a pathogenetic sequence (red color) for the growth of the R-S cell. This involves: (1) activation of platelet-derived growth factor receptor (PDGFR)-{alpha} by its ligand, PDGF (presumably from endothelial and histiocytic cells [80,81]); (2) stimulation of angiotensin (Ang) II type 1 receptor (AT1R), following catalytic conversion of angiotensinogen and Ang I by cathepsin D and angiotensin-converting enzyme (ACE) in companion dendritic/histiocytic cells; (3) AT1R-induced transactivation (+) of PDGFR-{alpha} via Src; (4) activation (+) of Stat3 by PDGFR-{alpha} (noting a potential role for interleukin [IL]-9); and (5) downstream signaling (+) by effector molecules, including mitogen-activated protein kinases (MAPK), c-Jun N-terminal kinase (JNK), c-Jun, and c-Myc, leading to DNA synthesis as evidenced by Ki-67 expression with a contributing role by CD30 ligand (CD30L)-bearing mast cells. Opportunities for therapeutic intervention (shown in blue) include: (a) STI571 to inhibit (-) PDGFR-{alpha} and c-kit signaling in R-S and mast cells, and to enhance (+) the effect of retinoids via the stabilization of retinoic acid receptor (RAR)-{alpha}; (b) losartan, an AT1R inhibitor; and (c) retinoids to downregulate (-) JNK, to facilitate (+) the activation of the latency-associated peptide (LAP) of transforming growth factor (TGF)-ß1 and to upregulate (+) TGF-ß receptor (R) II synthesis, leading to suppression (-) of c-Jun and cell cycling, and eventually to apoptosis.

 
In summary, proteomic analysis by immunohistochemistry has characterized the R-S cell in both NS and LP subtypes of Hodgkin’s disease as possessing molecular pathways that incorporate PDGFR-{alpha} tyrosine kinase-mediated signaling and angiotensin transactivation. Differences in the two subtypes may be explained, at least in part, by the more consistent and stronger expression of TGF-ßRII in the LP subtype. These observations suggest opportunities for specific therapeutic interventions.


   Acknowledgments
 
The authors are grateful to Mr Glen Kauwell for technical assistance in immunohistochemistry, to Ms Tina Fahy for secretarial support, and to Ms Diane Latranyi for help with the graphics.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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