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NEOPLASIA
From the Institutes of Hematology, Infectious Diseases,
and Pathology, Università Cattolica del Sacro Cuore, Rome, Italy;
the Department of Onco-Hematology, Division of Hematology, Casa
Sollievo della Sofferenza, S. Giovanni Rotondo, Italy; and the
Institute of Hematology Seragnoli, University of Bologna, Bologna,
Italy.
The receptor for hepatocyte growth factor (HGF) is a
transmembrane tyrosine kinase that is encoded by the
proto-oncogene c-met. Recently, c-MET was
detected in Reed-Sternberg (RS) cells from Epstein-Barr
virus-positive (EBV+) Hodgkin disease
(HD). The c-MET, EBER-1, and LMP-1 expression in 45 lymph node biopsies and 12 bone marrow biopsies obtained from patients
with HD was analyzed. In addition, HGF levels in serum samples from 80 healthy individuals and 135 HD patients in different phases of disease.
In all 45 lymph node and 12 bone marrow samples examined, RS
cells expressed c-MET but not HGF+. These results were
independent of the EBV infection. Interestingly, several
HGF+ dendritic-reticulum cells were found scattered around
c-MET+ RS cells. The mean ± SEM serum HGF levels in HD
patients at diagnosis and at the time of relapse were 1403 ± 91
(95% confidence interval [CI], 1221-1585) and 1497 ± 242 pg/mL
(95% CI, 977-2017), respectively. HGF values were significantly higher
than those of healthy individuals (665 ± 28 pg/mL; 95% CI, 600-721;
and P < .001 for both groups of patients) and of HD
patients in remission (616 ± 49 pg/mL; 95% CI, 517-714; and
P < .001 for both groups of patients). A significant
correlation was found between serum HGF levels and B symptoms at
diagnosis (P = .014). In conclusion, this study indicates
that HGF and c-MET constitute an additional signaling pathway between
RS cells and the reactive cellular background, thereby affecting
adhesion, proliferation, and survival of RS cells. Furthermore, the
serum concentration of HGF in HD patients may be a useful tool in
monitoring the status of disease.
(Blood. 2001;97:1063-1069) Hepatocyte growth factor (HGF) is produced by
various cells of mesenchymal origin and has pleiotropic functions in
several cell types and organs.1-3 HGF is produced as a
single-chain precursor, which is activated by proteolytic cleavage in
pathologic conditions such as liver, lung, or kidney
injuries.4 The active form is constituted by a
disulfide-linked heterodimer consisting of a heavy subunit that is
responsible for binding to the HGF receptor (c-MET) and a light subunit
that contains a serine-protease-like structure similar to that
of enzymes of the coagulation/fibrinolytic system.5
Although first discovered as a liver-regeneration inducing
factor,6 it has been shown that HGF acts on several cell
types, particularly those of epithelial as well as endothelial origin.2,3
All the activities of HGF are mediated by binding to its receptor, a
tyrosine kinase encoded by the proto-oncogene
c-met.7 The HGF receptor, c-MET, is composed of
an In the hematopoietic system, HGF is produced by stromal bone
marrow cells and synergizes with other growth factors (eg,
granulocyte-macrophage colony-stimulating factor, interleukin 3 [IL-3], and erythropoietin), thereby inducing the proliferation and
differentiation of a subset of CD34+/c-MET-expressing
cells.15-18 The presence of HGF and/or HGF receptor has
been extensively investigated in hematological malignancies. Myeloma
cell lines and primary myeloma cell samples express c-MET and produce
HGF,19,20 and a possible role for HGF has been suggested
in the pathogenesis of osteolytic lesions.21 Furthermore, HGF promotes the proliferation and migration of myeloid leukemic cells.22,23 The c-MET/HGF network plays an important role
in the lymphoid microenviroment as well by regulating the
integrin-mediated adhesion of antigen-driven B cells to the germinal
center.24,25 Weimar et al26 have
recently demonstrated that c-MET is expressed by activated centroblasts
in lymph nodes from healthy individuals and from patients with
lymphoma. HGF was also shown to activate the Among non-Hodgkin lymphomas, c-MET has been primarily detected in
follicular lymphomas and CD30+ large B-cell
lymphomas.26,27 In Hodgkin disease (HD), Weimar et
al26 found c-MET expression only in Epstein-Barr
virus-positive (EBV+) HD. However, another study on the
expression of HGF and c-MET in several leukemia and lymphoma cell lines
found that 5 of 6 Hodgkin lymphoma cell lines were c-MET+
and that all 6 cell lines were also HGF+.28
Although these studies of c-MET expression in HD are not in complete
concordance, they raise the intriguing hypothesis that in this disease,
the growth of c-MET+ Reed-Sternberg (RS) cells could be
triggered or sustained by the autocrine or paracrine production of HGF.
To further elucidate the role of EBV infection in modulating c-MET
expression in HD, we evaluated the expression of HGF and its receptor
in lymph node and bone marrow biopsies from patients with either
EBV+ or EBV Immunohistochemistry
Neoplastic samples.
This study was based on 57 samples of HD. The tumor panel included
lymph node and bone marrow biopsies obtained from patients at the time
of diagnosis or relapse. Altogether, 45 lymph node and 12 bone marrow
biopsies were evaluated. Of these biopsies, 2 lymph node and 3 bone
marrow samples were from human immunodeficiency virus (HIV)-infected
patients. All samples were obtained as part of the diagnostic
procedures, and in all patients a serum sample was collected for HGF
level evaluation. Tissues were fixed in neutral-buffered formalin. In
most cases a portion of unfixed tissue was snap-frozen in liquid
nitrogen and stored at c-MET protein. The c-MET protein was detected by the C-28 rabbit pAb raised against a peptide corresponding to the carboxy terminus of c-MET p140 of human origin (Santa Cruz Biotechnology, Santa Cruz, CA). Blocking peptides at 10-fold excess by weight relative to C-28 (sc-161 P, Santa Cruz) were used as competing compounds to assess the specificity of immunolabeling. Immunostaining for c-MET was performed on frozen sections and/or formalin-fixed, paraffin-embedded tissue sections using the alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP) method or the ABC-px method as previously described.31 In selected cases, the reactivity pattern of the C-28 rabbit pAb was compared with that of 8F-11, a mAb raised against the human c-MET protein (Novocastra Laboratories, Newcastle, England). HGF protein. Antihuman HGF is a goat antiserum developed using recombinant human HGF as the immunogen. This antiserum shows no cross-reactivity with other cytokines (antihuman HGF ALP01; R&D Systems, Minneapolis, MN). Antihuman HGF was applied only to frozen sections because of its lack of reactivity in paraffin-embedded tissue sections. Briefly, 6-µm-thick cryostat sections were fixed for 10 minutes at room temperature (RT) in 4% paraformaldehyde and treated for 20 minutes with 0.3% hydrogen peroxide (H2O2) in methanol to block endogenous peroxidase activity. Sections were then incubated at 4°C overnight with antihuman HGF at a 1:40 final dilution, washed, and incubated with biotinylated horse antigoat immunoglobulin G (IgG) (Vector Laboratories, Burlingame, CA). Indirect immunostaining was achieved using the ABC-px method, Dako LSAB 2. Endogenous biotin was saturated by a biotin blocking kit (Vector). The peroxidase was developed with a DAB substrate kit (Vector). Two-color staining In selected HD cases, double-immunohistochemical stains were performed to detect (1) c-MET and HGF; (2) c-MET and one of the following antigens: CD30, 4 1 integrin (CD49d/VLA-4 [clone
15A8, Ylem]), or 51 integrin (CD49e/VLA-5 [clone SAM-1,
Ylem]); or (3) HGF and one of the following antigens: CD3, macrophage
(HAM 56, Dakopatts), CD20, CD21, and CD30. To detect c-MET and HGF, cryostat sections were first incubated at 4°C overnight with
antihuman HGF goat antiserum and then immunostained with the ABC-px
method developed with a DAB substrate kit (Vector) to produce a brown color. Subsequently, sections were incubated for 1 hour with c-MET rabbit pAb at RT and immunostained by the APAAP method using
naphthol AS-MX phosphate along with fast-red TR salt (Sigma
Chemical Co, St Louis, MO) for the development of alkaline phosphatase
in order to produce a red color. To further assess
coexpression of (1) CD30, CD49d, and CD49e and c-MET and (2) HGF and
CD3, HAM 56, CD20, CD21, and CD30, double-immunofluorescence staining
was also performed. Briefly, after incubation with antihuman HGF goat
antiserum or with c-MET rabbit pAb, serial sections were first
immunostained using rabbit antigoat or goat antirabbit
tetraethylrhodamine isothiocyanate (Dakopatts). The same sections were
subsequently incubated with CD3, HAM 56, CD20, CD21, CD30, CD49d, and
CD49e and immunostained with horse antimouse fluorescein
isothiocyanate. The specimens were observed and digitalized by a
fluorescence Zeiss Axioskop (Zeiss; Jena, Germany) equipped with an
intensified CCD camera system (series 200, Macintosh configuration;
Photometrics, Tucson, AZ).
Analysis of viral infection All HD samples included in this study were analyzed for EBV infection. In-situ hybridization of EBV-encoded small RNAs (EBERs) was performed using a cocktail of fluorescein-isothiocyanate-labeled oligonucleotides complementary to the 2 nuclear EBER (1/2) RNAs according to the manufacturer's instructions (Dakopatts). In all samples immunostaining for LMP1 was also performed with an LMP1-specific antibody (Dakopatts) on formalin-fixed, paraffin-embedded tissue sections as previously described.32Serum HGF evaluation Patients.
Serum samples were collected from 135 HD patients. Informed consent was
obtained from all patients. Results from the patient samples were
recorded between May 1995 and June 2000 at 3 different hematology
centers in Italy: the Division of Hematology, Catholic University of
Rome, Rome, Italy (66 patients); the Division of Hematology, Casa
Sollievo della Sofferenza of S. Giovanni Rotondo, Italy
(54 patients); and the Institute of Hematology Seragnoli, University of
Bologna, Bologna, Italy (15 patients). Forty patients were studied at
different phases of their disease. We evaluated 255 serum samples: 80 samples from healthy blood donors (43 males and 37 females; median age,
37 years; age range, 19-65 years); 106 samples from HD patients at the
time of diagnosis; 15 samples from relapsing or resistant HD patients;
and 54 samples from HD patients in remission. Five patients observed at
the time of diagnosis were HIV-infected. Clinical findings and HD
histotypes at diagnosis were balanced among the 3 groups of patients
(Table 1).
HGF enzyme-linked immunosorbent assay. Serum HGF was measured using the Quantikine Human HGF immunoassay (R&D Systems) according to the manufacturer's instructions. In brief, standard dilutions or serum samples were incubated for 2 hours at RT in 96-well microplates coated with a mAb against HGF. Following incubation, samples were aspirated, and wells were carefully washed 4 times. Horseradish peroxidase-conjugated anti-HGF pAb was added to each well, and after a 2-hour incubation, the wells were washed 4 times, and a mixture of substrate solution (constituted by equal amounts of stabilized H2O2 and tetramethylbenzidine) was added. After a 30-minute incubation, reaction was stopped by adding 2 N sulfuric acid solution, and the optical density was determinated within 30 minutes at 450 nm. All samples were evaluated in duplicate. Statistic methods Because serum HGF levels were not normally distributed, results are expressed both as the mean ± SE and median (range). Serum HGF values were compared by the Kruskal-Wallis test, the Mann-Whitney test, and the paired t test when appropriate. In HD patients at diagnosis, serum HGF values were related to clinical and laboratory features both in univariate (Mann-Whitney test) and multivariate regression analyses: All evaluated variables were dichotomized, while HGF was evaluated as a continuous variable. Missing data were dealt with by excluding from particular analysis those patients lacking data for the required variable. Clinical findings in the different groups of HD patients were compared by the 2 test.
Detection of EBV infection in lymph node and bone marrow biopsies The overall incidence of EBV infection in this series of patients was 30%. As expected, EBV+ HD resulted in both EBER+ at ISH and LMP-1+ at immunohistochemistry. EBER transcripts and LMP-1 viral protein were detected in all HIV+ HD cases studied independent of nodal or bone marrow involvement. In cases of HD occurring in the general population, 7 nodal biopsies and all bone marrow biopsies involved by tumor were found to be both EBER-1+ and LMP-1+.Detection of c-MET and HGF in lymph node and bone marrow biopsies RS cells and their variants expressed c-MET in all cases of HD, both in HIV-infected and immunocompetent patients. These cases were representative of the entire pathologic spectrum of common HD. The pattern of c-MET immunoreactivity in RS cells was both cytoplasmic and membranous, and its intensity varied from moderate to strong. The specificity of immune reaction with the C-28 antibody was demonstrated by competitive inhibition with the blocking peptide (Figure 1A,B). Other than vascular endothelial cells and plasma cells, which appeared c-MET+, no c-MET+ elements were detected in the reactive cellular background. When residual germinal centers were present, they displayed weak c-MET positivity. Finally, there was no difference in the pattern of c-MET immunoreactivity between EBV+ and EBV samples. To confirm our results, we compared the
reactivity of the C-28 pAb with that of the 8F-11 mAb in 6 EBV and 6 EBV+ samples. Both antibodies
stained RS cells in both EBV+ and EBV HD,
confirming that c-MET expression in RS cells is independent of EBV
infection.
Double-staining experiments on frozen sections demonstrated the
presence of several HGF+ elements with a dendritic
appearance scattered around the c-MET+ RS cells (Figure
1C). To simultaneously demonstrate the presence of 2 antigens, we used
a double-immunofluorescence staining technique. These experiments
showed that CD30+ RS cells coexpress c-MET but not HGF
(Figure 1D and data not shown). In addition, we found that
c-MET+ RS cells coexpress HGF serum levels in HD patients Serum HGF values in healthy individuals and the different groups of HD patients are shown in Table 2. No difference was found between HD patients in remission and controls (P = .1). In contrast, patients at diagnosis and in relapse showed higher HGF levels (P < .001) than healthy individuals and patients in remission. Notably, HGF levels were similar in patients studied at the time of diagnosis and in relapse (P = .62). Moreover, in 35 patients whose serum samples were collected at diagnosis and in remission, a significant decrease in HGF levels was observed at the time of remission (mean ± SEM: 678 ± 77 pg/mL; 95% CI, 520-837; and 1220 ± 107 pg/mL; 95% CI, 1000-1441, respectively; P = .0009). No differences were found in the HGF values of HIV-infected and immunocompetent patients (data not shown) or EBV+ and EBV patients
(Table 3). We correlated HGF levels with
disease characteristics at the time of diagnosis (Table
4): The HGF value was evaluated as a
continuous variable, while all the other variables were dichotomized. The cut-off level for each variable was chosen on the basis of its
prognostic value, as reported by Hasenclever and Diehl.34 Histological subtypes were grouped by "good" or "poor"
prognosis: The former group consisted of lymphocyte-rich (LR) and NS I
subtypes, and the second group consisted of NS II, mixed cellularity
(MC), and lymphocyte-depletion (LD) subtypes. As shown in Table 4, in
univariate analysis, HGF levels closely correlated with low levels of
hemoglobin (P = .007) and with increased ESR
(P = .0002). Moreover, although no differences were found
between early and advanced stages, patients with B symptoms presented
with higher levels of HGF compared to patients without symptoms
(P < .0001). Multivariate analysis of these parameters
(Table 5) demonstrated that only the
presence of B symptoms was independently associated with high HGF
values at diagnosis (P = .014).
Serial evaluation of HGF levels during follow-up Fourteen patients with high HGF levels at diagnosis were further evaluated after the completion of chemotherapy and during follow-up (Figure 2). All 14 patients achieved complete remission after chemotherapy, and all but 2 patients had normal HGF levels at this time and during follow-up. Whereas all 12 patients who had normal HGF values after chemotherapy remain in complete remission (mean follow-up, 16 months; follow-up range, 8-52 months), the 2 patients with high HGF levels after chemotherapy relapsed at 3 and 5 months, respectively.
Hodgkin disease is characterized by the presence of malignant RS
cells, which constitute only 1% to 2% of total tumor cell mass. Most
of the neoplastic tissue consists of reactive elements including
lymphocytes, histiocytes, eosinophils, plasma cells, and stromal cells.
Despite this, RS cells evade immunosurveillance, in part due to the
interaction between malignant and reactive components of HD that
promote their survival in a potentially hostile
environment.35 Typically, members of the tumor necrosis factor receptor (TNFR) and of the TNF ligand superfamilies play an
important role in RS cell survival, proliferation, and cytokine production.36,37 In this study we demonstrated that an
additional possible mechanism of signaling between RS cells and the
reactive milieu may involve the c-MET/HGF pathway. We found that in all HD cases evaluated, RS cells showed a clear expression of c-MET, while
several dendritic-reticulum cells from the reactive cellular background
produced HGF. Moreover, we showed that c-MET+RS cells
coexpress The proto-oncogene c-met plays an important role in the
regulation of adhesion and migration of normally activated B cells. In
normal lymphatic tissues (ie, lymph node, tonsil, or spleen), c-MET is
expressed in activated centroblasts of germinal centers and, to a
lesser extent, in B cells from the marginal zone of secondary
follicles, which reflects the interaction of these cells with
antigen-specific T lymphocytes.24,25 Different mechanisms have been demonstrated to elicit c-MET expression in B cells. van der
Voort et al24 demonstrated that the ligation of CD40 by
CD40 ligand induces a transient up-regulation of c-MET expression, in
particular when concomitant B-cell receptor activation occurs. Furthermore, Weimar et al26 found that circulating B
lymphocytes, c-MET The role of the c-MET/HGF pathway in the interaction between stromal
cells and hematopoietic progenitors has been highlighted in the
hematopoietic microenvironment.16-18 Although it is not clear which of the stromal elements (fibroblasts, endothelial cells,
or adipocytes) produces HGF, it has been shown that
stromal-derived HGF promotes adhesion, proliferation, and survival of
hematopoietic progenitors.9,16-18 Similarly, our findings
that c-MET+ RS cells expressing Previous studies have shown that HGF serum values in patients with
multiple myeloma are significantly related to the status of the
disease. Similarly, we found that serum level values of HGF are
significantly higher in HD patients with active disease compared to
patients in remission. Among patients observed at the time of
diagnosis, higher serum HGF levels were associated with the presence of
B symptoms, typically reflecting the immune activation induced by the
disease more than the extent or burden of disease (advanced stage and
bulky disease). Many clinical and laboratory features of HD, such as
fever, weight loss, and alteration of inflammatory parameters, have
been typically ascribed to enhanced cytokine secretion. We hypothesize
that HGF/c-MET interaction stimulates cytokine release by
c-MET+ RS cells, as recently shown in multiple myeloma
where IL-11 secretion is induced by c-MET+
osteoblasts.21 Alternatively, cytokines such as IL-1 and
IL-6, transforming growth factor Our findings show that HGF levels, high at diagnosis, significantly decrease after chemotherapy in patients achieving clinical remission, whereas persistent high HGF values after chemotherapy predict early relapse. Although these observations are obtained from a small number of patients, they suggest that the serial determination of serum HGF levels could represent an important clinical tool in monitoring the response to chemotherapy. A longer follow-up might assess whether serum HGF level at diagnosis could represent a new prognostic factor in HD. In conclusion, c-MET/HGF interaction may constitute an additional pathway of signaling between RS cells and the reactive cellular background in Hodgkin disease and, like the TNF ligand/TNFR family members, HGF and its receptor c-MET may be important elements in the unbalanced cytokine network typical of HD.
The authors thank Dr Raffaella Urbano, Alessandro Rinelli, and Rosella Matera for excellent technical assistance and Dr Maurizio Martini and Dr Maria Luigia Vigliotti for the useful suggestions.
Submitted April 24, 2000; accepted October 24, 2000.
Supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro, Milan, Italy, and by grant RF 1999 ICS120.5/RF99.98 from the Ministero della Sanità Rome, Rome, Italy.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Luigi Maria Larocca, Institute of Pathology, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy; e-mail: llarocca{at}rm.unicatt.it.
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Abstract
Introduction
80°C.
