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Experimental Therapeutics |
Divisions of Hematology-Oncology [F. B., C. D., P. M., C. R., A. B., G. M.], Experimental Oncology-IFOM Institute of Molecular Oncology [S. M., A. G.], and Pathology [G. P.], European Institute of Oncology, 20141 Milan, Italy
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the present study, we evaluated a panel of malignant lymphoid cell lines and primary NHL cells, and found CXCR4 expression in the large majority of malignant cells. CXCR4 neutralization by monoclonal antibodies had profound in vitro effects on NHL cells including inhibition of transendothelial/stromal migration, enhanced apoptosis, decreased proliferation, and inhibition of pseudopodia formation. In preclinical models, CXCR4 neutralization demonstrated remarkable efficacy in either tumor challenge and therapy trials in the absence of overt short- or long-term toxicity. Furthermore, CXCR4 neutralization increased the number of lymphoma cells circulating 24 h after i.v. injection, suggesting a crucial role of CXCR4 in tumor cell extravasation. Taken together, our data indicate that the CXCR4-CXCL12/SDF-1 circuitry may be an useful target for NHL therapy.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Detection of Chemokine Receptors and CXCL12/SDF-1 mRNA.
CXCR1, 2, 3, and 4, and CCR1, 2, 3, 4, and 5 mRNA expression was evaluated by multiplex RT-PCR. Total RNA was isolated from cell lines and primary cells by QIAamp RNA kit (Quiagen, Hilden, Germany), and treated with a reverse transcriptase enzyme (SuperScript II; Life Technologies, Inc., Gaithersburg, MD). The cDNA generated following this approach was amplified by multiplex PCR using commercially available kits Cytoexpress hCXCR and hCCR (Biosource, Camarillo, CA) according to manufacturer’s instructions. PCR-amplified products were stained with ethidium bromide and evaluated by 2% agarose-gel electrophoresis. The Quantikine colorimetric assay (R&D, Minneapolis, MN) was used according to manufacturer’s instructions for quantitative evaluation of CXCL12/SDF-1 mRNA. Positive controls (Cytoexpress) and reagents to generate a calibrator curve (Quantikine) were obtained by manufacturers, and the appropriate null control reactions always remained negative.
Flow Cytometry Studies.
The expression of CXCR4 on the surface of cell lines and primary NHL cells was evaluated by four-color flow cytometry using a FACScalibur (BD, Mountain View, CA), anti-CD45, -CD19, -
, -
, and -CXCR4 monoclonal antibodies (BD), annexin V, and 7AAD to depict apoptotic or dead cells as described previously (7)
.
In Vitro Studies.
Sodium azide-free monoclonal antibodies anti-CXCR4 (clones MAB171 from R&D and 12G5 from BDPharMingen, San Diego, CA) and polyclonal anti-SDF-1 (R&D) were used to neutralize the CXCR4-CXCL12/SDF-1 circuitry. Appropriate irrelevant antibodies (sodium azide-free 2007OD and anti-CD19; BDPharMingen) were used as control in vitro and in vivo. After 5-h culture in RPMI-10% FBS at 37°C, the extent of cell proliferation was evaluated by a standard MTT assay (Sigma, St. Louis, MO) and by cell proliferation reagent WST-1 (Boehringer Mannheim, Mannheim, Germany; Ref. 8
), and cell viability measured by flow cytometry. Apoptosis was investigated by flow cytometry and commercially available multiplex RT-PCR kits (Biosource) able to detect caspases, Fas, FasL, FLICE, FADD, and TRADD.
We used an approach similar to Burger et al. (5) and Poznansky et al. (9) with slight modifications to study the effect of CXCR4 neutralization in NHL cell transendothelial/stromal migration in transwell (diameter, 6.5 mm; pore, 5 µm; Costar, Cambridge, MA) culture. A layer consisting of 2 x 104 human microvascular endothelial cells (Cascade Biologics, Portland, OR) or bone marrow-derived stromal cell lines L87/4 and L88/5 (10) was seeded in the upper chamber and cultured for 48 h in RPMI-10% FBS. A total of 2 x 105 Namalwa NHL cells were preincubated for 30 min in 100 µl migration buffer containing different concentrations of neutralizing anti-CXCR4 monoclonal antibodies or control antibodies. Cells were seeded in the upper chambers coated with endothelial or stromal cells. After 30-min incubation at 4°C, chambers were transferred to wells containing medium with or without CXCL12/SDF-1 (125 ng/ml; R&D) as a chemoattractant and incubated for 2 h at 37°C. Cells that migrated to the lower chamber were counted in triplicates by flow cytometry.
Pseudopodia formation in Namalwa and Granta 519 cells was evaluated as described by Muller et al. (3) . Cells were incubated at 37°C in RPMI supplemented with 125 ng/ml CXCL12/SDF-1 (or CX3CL1/fractalkine as negative control) in the presence of anti-CXCR4, anti-CD19, or control (irrelevant) antibodies. After a 20-min culture, cells were fixed by paraformaldehyde, and pseudopodia formation was observed and enumerated by microscopy.
In Vivo Studies.
CXCR4- and CXCL12/SDF-1 neutralization were evaluated in a model of human NHL generated in our laboratory by transplanting Namalwa cells in NOD/SCID mice (11
, 12)
. This NHL cell line was found to be the most aggressive one in terms of efficiency of engraftment, speed of engraftment, and tumor size in a panel of lymphoid malignant cell lines tested in i.p. (11
, 12)
or s.c. (13)
xenotransplants. To generate a disease similar to human high-grade B-cell NHL, we transplanted NOD/SCID mice i.p. rather than s.c., and Namalwa cells generated measurable i.p. tumors in the injection site in 100% of injected animals. Tumor volume was measured by calipers and the formula [width2 x length x 0.52] applied for approximating the volume of a spheroid (12)
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In a first tumor-challenge trial, 2 x 105 Namalwa cells were preincubated with 10 µg of sodium azide-free anti-CXCR4, anti-CXCL12/SDF-1, or control antibodies before i.p. injection (n = 6/study group). In a second tumor-challenge trial, mice were injected i.v. with 2 x 105 Namalwa cells preincubated with 10 µg of sodium azide-free anti-CXCR4, anti-CXCL12/SDF-1, or control antibodies (n = 12/study group). In both tumor-challenge trials, tumor cells were washed before injection.
To investigate the therapeutic potential of CXCR4-neutralization, mice injected i.p. with 2 x 105 Namalwa cells (not preincubated by anti-CXCR4) were treated in a site different from tumor injection with 3 weekly i.p. injections of 100 µg of sodium azide-free anti-CXCR4 or control antibodies. Animals (n = 12/study group, in two replicate trials involving a total of 12 treated animals and 12 controls) were treated on days 3, 10, and 17 after tumor injection.
Tumor-bearing mice were sacrificed by CO2 inhalation, and tumor engraftment confirmed by histology, immunohistochemistry, and flow cytometry. Tumor weight was evaluated after complete removal of the i.p. tumor bulk. For histology and immunohistochemistry evaluation, tumor samples were fixed in 10% formalin and embedded in paraffin. Sections (4 µm-thick) were stained with H&E and Giemsa for conventional histology. For immunohistochemistry, sections were immunostained with the anti-CD10 and -CD20 monoclonal antibodies by DAKO (Glostrup, Denmark). In flow cytometry, tumor expression of human CD19 and CD20 antigens was evaluated by BD monoclonal antibodies.
In separate studies (n = 6), Namalwa cell extravasation was evaluated in vivo injecting NOD/SCID mice i.v. with 2 x 105 Namalwa cells preincubated with 10 µg of sodium azide-free anti-CXCR4 or control antibodies. Mice were sacrificed 24 h after injection, and the frequency and viability of Namalwa cells circulating in the peripheral blood evaluated by flow cytometry. A minimum of 100,000 circulating cells were evaluated.
All of the procedures involving animals were done in accordance with national and international laws and policies.
Statistical Analysis.
Statistical comparisons were performed using the t test and ANOVA when data were normally distributed, and the nonparametric analyses of Spearman and Mann-Whitney when data were not normally distributed. All of the Ps were two-sided and considered statistically significant at <0.05.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, other chemokine receptors were less frequently expressed in cell lines and primary NHL cells. Flow cytometry studies confirmed CXCR4 expression in all of the RT-PCR-positive NHL lines and in primary cells, and indicated high levels of CXCR4 expression when compared with other normal lymphoid cells (Fig. 1)
.
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; P < 0.01). When compared with NHL cell lines, the amount of CXCL12/SDF-1 mRNA expressed by bone marrow-derived stromal cell lines L87/4 and L88/5 was slightly increased but not significantly higher.
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). When compared with control antibodies, mean inhibition ranged from 7% (1 µg anti-CXCR4 in 100 µl culture medium and endothelial cell layers) to 61% (10 µg anti-CXCR4 in 100 µl culture medium and stromal cell layers). In four independent experiments, the addition of 10 µg anti-CXCR4 in 100 µl culture medium significantly enhanced Namalwa cell apoptosis (evaluated by flow cytometry enumeration of annexin V-positive cells; Fig. 2c
) from 2.0 ± 0.9% (i.e., 1.8, 3.2, 0.9, and 2.1% apoptosis) to 6.8 ± 1.1% (i.e., 6.7, 7.1, 5.3, and 8.0% apoptosis; P = 0.005). Moreover, mRNA expression of death-domain- related proteins FADD and TRADD significantly enhanced in CXCR4-neutralized cells (Fig. 2c)
. As expected, anti-CXCR4 also reduced the mean channel of CXCR4-related fluorescence (Fig. 2c)
.
Using MTT and WST-1 assays (8)
, we observed that the addition of 1–10 µg anti-CXCR4 or neutralizing anti-CXCL12/SDF1 antibodies to Namalwa cell culture inhibited cell proliferation (n = 4/group; Fig. 2d
). When compared with controls, mean inhibition of cell proliferation ranged from 2% (1 µg anti-CXCL12/SDF1) to 32% (10 µg anti-CXCR4), and data from the MTT and WST-1 assays were superimposable.
As showed in Fig. 3
, culture in the presence of CXCL12/SDF1 (but not in the presence of CX3CL1/fractalkine used as a negative control) was associated with distinct pseudopodia formation in 20–30% of Namalwa cells (expressing high levels of CXCR4 mRNA) as well as in Granta 519 cells (expressing low levels of CXCR4 mRNA). In both cell lines, CXCR4 neutralization by monoclonal antibodies inhibited pseudopodia formation (Fig. 3)
.
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). Furthermore, mean tumor weight was significantly reduced by 32% (anti-CXCL12/SDF-1) and 48% (anti-CXCR4; Fig. 4b
). In a second tumor-challenge trial, mice were injected i.v. with Namalwa cells (n = 12/study group). All of the control mice died of neoplasia by day 36, all of the mice injected with NHL cells preincubated with 10 µg anti-CXCL12/SDF-1 died of neoplasia by day 60, and, remarkably, 83% of mice injected with NHL cells incubated with 10 µg anti-CXCR4 were still alive and disease-free >150 days after transplant (P < 0.0001; Fig. 4c
).
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, CXCR4 neutralization had profound effects in NHL cell extravasation. In fact, circulating Namalwa cells were found 24 h after i.v. injection in mice given CXCR4-neutralized cells but not in mice given cells preincubated with control antibodies. Interestingly, 32–47% of CXCR4-neutralized Namalwa cells circulating 24 h after injection expressed the apoptosis marker annexin V (Fig. 5d)
. Variance in the percentage of apoptotic cells reflects results of several independent experiments. Increased apoptosis in circulating cells was clearly attributable to CXCR4 neutralization, because annexin V staining was not observed in normal mouse cells.
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). In tumor-challenge and therapy trials, no toxicity was observed in long-term survivor mice. At autopsy, liver, kidney, bladder, stomach, gut, lung, heart, brain, spleen, or bone marrow toxicity was not observed.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Cell migration along chemokine gradients involves a number of steps including establishment of cell polarity, directional cell locomotion through cytoskeletal rearrangements, and adhesive interactions with extracellular matrix (16) . Breast cancer cell migration and metastasis usually follows a distinct pattern involving regional lymph nodes, bone marrow, lung, and liver. This pattern shares relevant similarities with leukocyte trafficking and seems to be mediated through CXCR4 or CCR7 signaling (3 , 17) . Similarly, the CXCR4-CXCL12/SDF-1 circuitry seems to be involved in migration of chronic lymphocytic leukemia (5) and acute lymphoblastic leukemia B cells (6) . Regarding NHL, CXCL12/SDF-1 has been found recently to enhance migration of follicular NHL cells but not of their normal counterpart, germinal center B cells (4) . Moreover, Sei et al. (18) reported recently increased CXCL12/SDF-1 mRNA levels in circulating mononuclear cells from AIDS-related NHL pediatric patients.
In the present study we observed that CXCR4 neutralization significantly impairs transendothelial/stromal NHL cell migration. Moreover, CXCR4 neutralization enhanced NHL cell apoptosis and reduced NHL cell proliferation. Because quantitative studies indicated that CXCL12/SDF-1 mRNA was frequently expressed by NHL cells at levels significantly higher than normal lymphocytes, enhanced apoptosis and reduced proliferation in the presence of anti-CXCR4 or -CXCL12/SDF-1 might be because of inhibition of an autocrine loop. Burger et al. (19) have described recently a novel antiapoptotic role of the CXCR4-CXCL12/SDF-1 circuitry in B-cell chronic lymphocytic leukemia. In this disease, CXCL12/SDF-1 seems to provoke an antiapoptotic effect on malignant cells through a novel population of blood-derived nurse-like cells. We are currently investigating whether a similar pattern also exists in different NHL types. Along this line, our finding that neutralization of the CXCR4-CXCL12/SDF-1 circuitry results in some degrees of inhibition of Namalwa cell proliferation fits well with the original identification of CXCL12/SDF-1 as a B-cell progenitor growth factor (20) . We have observed distinct pseudopodia formation in NHL cells stimulated by CXCL12/SDF-1. Previous studies in lymphoma cells have demonstrated that pseudopodia formation is crucial for tissue invasion and metastases formation (21) . Again, CXCR4 neutralization dramatically inhibited pseudopodia formation in cells stimulated by CXCL12/SDF-1.
These in vitro observations, together with reports of impaired human hematopoietic stem cell engraftment in immunodeficient mice treated with anti-CXCR4 antibodies (2) , prompted us to study the effect of CXCR4 neutralization in a preclinical NHL model developed in our laboratory by injecting Namalwa cells in NOD/SCID mice. When compared with a panel of lymphoid malignant cells, this line was the most aggressive in terms of efficiency of engraftment, speed of engraftment, and tumor size (11, 12, 13) . In NHL tumor-challenge trials, CXCR4 neutralization of i.p.-injected Namalwa cells delayed tumor growth and reduced tumor weight. The effect of CXCR4-neutralization of i.v.-injected Namalwa cells was particularly remarkable, because all of the controls died of NHL within day 36, whereas 83% of mice injected with cells incubated with anti-CXCR4 were still alive and disease-free >150 days after transplant.
To better elucidate the role of CXCR4 neutralization in NHL cell extravasation, we enumerated tumor cells circulating in the peripheral blood of mice injected i.v. with Namalwa cells. The day after tumor injection, in recipients of Namalwa cells preincubated with control antibodies, circulating tumor cells were below the sensitivity threshold of the flow cytometry procedure. Conversely, in mice injected with CXCR4-neutralized Namalwa cells the frequency of circulating tumor cells was always >0.5%. Taken together with the observation of impaired transendothelial/stromal Namalwa cell migration after CXCR4 neutralization, our data suggest a pivotal role of the CXCR4-CXCL12/SDF-1 circuitry in NHL cell extra- and intravasation.
In additional preclinical trials, we investigated the therapeutic effect of anti-CXCR4 antibodies in mice bearing NHL cells (not preincubated by anti-CXCR4) injected 3 days before. CXCR4 neutralization had a clear therapeutic potential, because tumor growth was abrogated in the majority of mice, and tumor growth was significantly delayed in the remaining group. As already reported by Muller et al. (3) , no cytotoxicity for either anti-CXCR4 antibodies (or control antibodies) could be detected in vitro. The evidence that CXCR4 neutralization by monoclonal antibodies is active in vivo against human NHL despite a severely B-cell-, T-cell-, natural killer-cell-, myeloid cell-, and complement-deficient host mice (22) is of particular interest. In fact, it suggests that most of anti-CXCR4-induced biological responses may not be because of antibody-dependent cellular cytotoxicity or complement-dependent cell lysis. We are now investigating whether this therapeutic effect of CXCR4 neutralization is mostly because of impaired NHL cell trafficking, in vivo NHL cell apoptosis, targeting of nurse cell activity, decreased angiogenesis, or other, still unknown mechanisms. In the meantime, it is interesting to note that despite the wide spectrum of CXCL12/SDF-1 and CXCR4 expression in different tissues and organs (14) , mice given anti-CXCR4 antibodies showed no major short- or long-term toxicity.
In conclusion, present data on CXCR4 expression in most NHL primary cells, in vitro effects of CXCR neutralization in NHL cells, and the efficacy of anti-CXCR4 antibodies observed in either tumor-challenge and therapy preclinical NHL trials indicate that the CXCR4-CXCL12/SDF-1 circuitry is a very attractive target for NHL therapies. Because the HIV-1 virus may use CXCR4 as a coreceptor (23) , a number of CXCR4 antagonists have been discovered and are entering clinical trials for AIDS patients (24, 25, 26) . Our data suggest that these novel molecules, together with anti-CXCR4 antibodies, might be considered for clinical trials in NHL patients.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported in part by AIRC (Associazione Italiana per la Ricerca sul Cancro) e FIRC (Fondazione Italiana per la Ricerca sul Cancro). F. B. is a scholar of the United States National Blood Foundation. 
2 To whom requests for reprints should be addressed, at Division of Hematology-Oncology European Institute of Oncology via Ripamonti 435, 20141 Milan Italy. Phone: 39-02-57489535; Fax: 39-02-57489537; E-mail: francesco.bertolini{at}ieo.it
3 The abbreviations used are: NHL, non-Hodgkin’s lymphoma; NOD/SCID, nonobese diabetes/severe combined immunodeficiency; RT-PCR, reverse transcription-PCR; 7AAD, 7-Aminoactinomycin D; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; FADD, Fas-associated death domain; CI, confidence interval.
Received 7/30/01. Accepted 3/28/02.
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