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Clinical Cancer Research Vol. 12, 6973-6977, December 1, 2006
© 2006 American Association for Cancer Research

Human Cancer Biology

Tumor Angiogenesis Is Associated with Plasma Levels of Stromal-Derived Factor-1{alpha} in Patients with Multiple Myeloma

Sally K. Martin1, Andrea L. Dewar1, Amanda N. Farrugia1, Noemi Horvath2, Stan Gronthos3, L. Bik To2 and Andrew C.W. Zannettino1

Authors' Affiliations: 1 Myeloma and Mesenchymal Research Group, Matthew Roberts Foundation Laboratory, Division of Haematology, Institute of Medical and Veterinary Science, The Hanson Institute, and the Department of Medicine, University of Adelaide; 2 Division of Haematology, The Institute of Medical and Veterinary Science; and 3 Mesenchymal Research Laboratory, Division of Haematology, Institute of Medical and Veterinary Science, The Hanson Institute, and University of Adelaide, Adelaide, Australia

Requests for reprints: Andrew C.W. Zannettino, Myeloma and Mesenchymal Research Group, Matthew Roberts Foundation Laboratory, Division of Haematology, Institute of Medical and Veterinary Science, P.O. Box 14, Rundle Mall, Adelaide 5000, Australia. Phone: 61-8-8222-3455; Fax: 61-8-8222-3139; E-mail: andrew.zannettino{at}imvs.sa.gov.au.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Multiple myeloma is an incurable hematologic malignancy characterized by increased bone marrow angiogenesis and extensive lytic bone disease. We have previously shown that elevated levels of stromal-derived factor-1{alpha} (SDF-1{alpha}) in peripheral blood plasma are associated with osteolysis in multiple myeloma patients. We have now examined whether SDF-1{alpha} levels also correlate with angiogenesis.

Experimental Design: We examined the contribution of multiple myeloma plasma cell–derived SDF-1{alpha} in the stimulation of in vitro angiogenesis using a tube formation assay. We also collected trephine and peripheral blood plasma samples from patients with multiple myeloma to analyze microvessel density and SDF-1{alpha} levels, respectively.

Results: We show that multiple myeloma plasma cell line–derived conditioned medium containing SDF-1{alpha} stimulates in vitro angiogenesis. In addition, in a large cohort of patients with multiple myeloma and its precursor condition monoclonal gammopathy of undetermined significance, we confirm previous findings that plasma cell burden correlates with both angiogenesis and plasma levels of SDF-1{alpha}. We now extend these observations and show the novel finding that peripheral blood plasma levels of SDF-1{alpha} positively correlate with the degree of bone marrow angiogenesis in multiple myeloma and monoclonal gammopathy of undetermined significance patients.

Conclusions: High levels of SDF-1{alpha} produced by multiple myeloma plasma cells promote osteolysis and bone marrow angiogenesis. Therefore, we propose that inhibition of SDF-1{alpha} may be an effective mechanism by which angiogenesis and osteolysis can be reduced in multiple myeloma patients.

Angiogenesis, or the process of blood vessel formation from preexisting vasculature, plays an important role in the pathology of multiple myeloma in a manner similar to that observed in solid tumors (1). In particular, it has been shown that bone marrow microvessel density (MVD), a surrogate marker of angiogenesis, is elevated in patients with active multiple myeloma compared with those in remission or those with monoclonal gammopathy of undetermined significance (MGUS), a clinical precursor to multiple myeloma (2, 3). Importantly, increased bone marrow MVD is associated with a decreased overall survival in multiple myeloma patients (4–6).

Although the precise molecular mechanisms underlying the progressive increase in angiogenesis in multiple myeloma remain unclear, a number of multiple myeloma plasma cell–derived angiogenic growth factors, cytokines, and chemokines have been implicated (7, 8). In particular, the chemokine stromal-derived factor-1{alpha} (SDF-1{alpha}; also known as CXCL12) has recently been shown to stimulate physiologic angiogenesis (9, 10). However, a role for SDF-1{alpha} in pathologic angiogenesis, as seen in multiple myeloma, has not been established.

SDF-1{alpha}, expressed by bone marrow stroma, vascular endothelial cells, and multiple myeloma plasma cells, is involved in many aspects of multiple myeloma biology through interactions with its G-protein–coupled receptor CXCR4. These actions include the mobilization and adhesion of multiple myeloma plasma cells to stroma (11), the proliferation and migration of multiple myeloma plasma cells (12), the recruitment of osteoclasts to the bone marrow (13), and, most recently, the enhancement of osteoclastic bone resorption (14, 15). In this study, we determined whether multiple myeloma plasma cell–derived SDF-1{alpha} could stimulate angiogenesis in vitro and examined whether SDF-1{alpha} promotes angiogenesis in multiple myeloma patients.


   Materials and Methods
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Results
 Discussion
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Patients. A cohort of newly diagnosed multiple myeloma and MGUS patients, who fulfilled standard diagnostic criteria (16) and had yet to receive any treatment, and age-matched healthy subjects were used in this study. As detailed in Table 1 , the age, sex, bone marrow plasma cell burden, the presence or absence of radiologically detectable lytic bone lesions, bone marrow MVD, and peripheral blood plasma levels of SDF-1{alpha} were registered for patients and healthy age-matched donors at diagnosis, where possible. Studies were done with approval from the Institutional Ethics Review Committee of the Institute of Medical and Veterinary Science, Royal Adelaide Hospital, and University of Adelaide, following written informed consent.


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  		Table 1. Patient and control subject information

 
Determination of bone marrow MVD in patient bone marrow trephine biopsies. Sections (3 µm) of mercuric chloride–fixed paraffin-embedded biopsy specimens were obtained from the posterior iliac crest of multiple myeloma and MGUS patients and healthy age-matched subjects. The sections were immunostained using a monoclonal antibody against CD34, as previously described (2, 6). The MVD for each biopsy was determined by counting the number of individually stained microvessels (capillaries and small venules not exceeding 10 µm) at x200 magnification in three areas of highest vessel density according to the accredited "hotspot" method, as previously described (17). Areas of staining with no discrete breaks were counted as a single vessel, and the presence of a lumen was not required. To limit subjectivity, all assessments of bone marrow MVD were done in a blinded manner by two investigators. MVD analysis was not done in circumstances where diagnostic trephine biopsies were not available or the quality of the specimen was poor. Similarly, due to ethical considerations, bone marrow trephine biopsies were not obtained from healthy subjects. Rather, MVD analysis was done on trephine specimens collected from individuals who underwent bone marrow biopsies but were subsequently found to be hematologically normal.

Determination of SDF-1{alpha} levels in patient-derived plasma. SDF-1{alpha} levels in multiple myeloma and MGUS patient-derived peripheral blood plasma and plasma from healthy age-matched donors were determined using a commercial SDF-1{alpha}-specific immunoassay (Human SDF-1{alpha} Quantikine Colorimetric Sandwich ELISA, R&D Systems, Minneapolis, MN), as previously described (15). As peripheral blood plasma samples were not collected at the time of diagnosis for some patients, measurement of SDF-1{alpha} levels in these patients was not possible.

Tube formation assays. Growth factor–reduced Matrigel (80 µL; BD Biosciences, San Jose, CA) was pipetted into 6-mm-diameter tissue culture wells (96-well plate) and left to polymerize for 30 minutes at 37°C. Human umbilical vein endothelial cells were treated with or without 50% conditioned medium from the multiple myeloma plasma cell line RPMI-8226 (collected at 1 x 106/mL), or various concentrations of recombinant human SDF-1{alpha} (Peprotech, Rocky Hill, NJ) and plated onto the Matrigel at a density of 2.5 x 104 per well in 100 µL M199 medium. Where indicated, the cells were preincubated in the presence 5 µmol/L of the CXCR4 inhibitor T140 (kindly provided by Profs. N. Fujii and H. Tamamura) for 30 minutes before plating. Each dose of control or test compound was assayed in triplicate. Cultures were incubated in a humidified environment at 37°C in the presence of 5% CO2. Tubes were defined as cellular extensions linking cell masses or branch points. After 21 hours, the cultures were photographed (x40), and total tube length was quantitated from digital photographs using Scion image analysis software (Scion Image for Windows 2000, Scion Corp., Frederick, MD).

Statistical analyses. Statistical analyses were done using the Mann-Whitney rank sum test or Pearson product moment correlation test on the SigmaStat 3.0 software package (SPSS, Inc., Chicago, IL). In all cases, P < 0.05 was considered statistically significant.


   Results
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 Results
Discussion
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SDF-1{alpha} produced by myeloma cells increases in vitro angiogenesis, which is inhibited by the CXCR4 inhibitor, T140. To show that multiple myeloma cell–derived SDF-1{alpha} could stimulate angiogenesis, we examined the effect of conditioned medium from the multiple myeloma plasma cell line RPMI-8226 on human umbilical vein endothelial cell tube formation (Fig. 1 ). RPMI-8226 was selected from a number of multiple myeloma cell lines as it was found to express levels of SDF-1{alpha} mRNA and protein most similar to that found in patient-derived CD38+ cells (15). Human umbilical vein endothelial cells were also treated with various concentrations of recombinant human SDF-1{alpha}, which stimulated in vitro tube formation at physiologically achievable concentrations. Importantly, treatment of human umbilical vein endothelial cells with 50% conditioned medium increased tube formation 2.9-fold compared with untreated controls. This increase was inhibited by the addition of T140, a specific, potent, and biostable inhibitor of the SDF-1{alpha}/CXCR4 interaction (18–20).


Figure 1
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  		Fig. 1. SDF-1{alpha} produced by multiple myeloma plasma cell increases in vitro angiogenesis, which is inhibited by the CXCR4 inhibitor T140. The contribution of SDF-1{alpha} produced by the multiple myeloma plasma cell line RPMI-8226 on in vitro tube formation was investigated using an antagonist directed against SDF-1{alpha} receptor CXCR4. The antagonist was also added to cells treated with various concentrations of recombinant SDF-1{alpha} and to untreated cells as a negative control measure. The addition of 50% conditioned medium (CM) increased tube formation 2.9-fold relative to controls, and this effect was reduced in the presence of T140 (5 µmol/L; P < 0.001, Mann-Whitney rank sum test). Columns, mean from replicate wells of a representative experiment of three; bars, SD.

 
Bone marrow plasma cell burden positively correlates with MVD and systemic SDF-1{alpha} levels in multiple myeloma and MGUS patients. It is well established that the transition from MGUS to advanced multiple myeloma is associated with an increase in bone marrow plasma cell burden (16). In this study, we confirmed previous findings (21) that there is a strong correlation between bone marrow angiogenesis and plasma cell infiltration (Fig. 2A ; rs = 0.76, P < 0.001, Pearson product moment). Furthermore, using a larger cohort of patients, we confirmed our previous finding (15) that plasma cell burden correlates with plasma levels of SDF-1{alpha} in multiple myeloma and MGUS patients (Fig. 2B; rs = 0.35, P < 0.01, Pearson product moment), and that SDF-1{alpha} levels in multiple myeloma patients (2952 ± 118 pg/mL, mean ± SE; n = 38) are elevated compared with either MGUS patients (2,583 ± 109 pg/mL, n = 19) or healthy age-matched controls (2,216 ± 120 pg/mL, n = 24; Table 1).


Figure 2
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  		Fig. 2. Bone marrow plasma cell burden correlates with MVD (A) and plasma levels of SDF-1{alpha} (B) in multiple myeloma and MGUS patients. Bone marrow MVD data and plasma levels of SDF-1{alpha} were collected from multiple myeloma (bullet; A, n = 40; B, n = 37) and MGUS ({circ}; A, n = 24; B, n = 18) patients at diagnosis and plotted with reference to their respective bone marrow plasma cell burden. A positive correlation between plasma cell burden and both bone marrow MVD and plasma SDF-1{alpha} levels were confirmed in our patient cohort of MGUS and multiple myeloma patients.

 
Bone marrow MVD positively correlates with systemic levels of SDF-1{alpha}. Because SDF-1{alpha} plays a role in physiologic angiogenesis (9, 10), and because multiple myeloma plasma cell infiltration correlates with SDF-1{alpha} levels (15), we investigated whether elevated levels of SDF-1{alpha} in peripheral blood plasma also correlate with an increase in bone marrow angiogenesis in multiple myeloma and MGUS patients (Fig. 3 ). We have made the novel observation that elevated levels of SDF-1{alpha} are associated with bone marrow MVD in multiple myeloma and MGUS patients (Fig. 3; rs = 0.34, P < 0.02, Pearson product moment), suggesting that in addition to promoting osteolysis (15), elevated levels of SDF-1{alpha} are associated with increased bone marrow angiogenesis in multiple myeloma.


Figure 3
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  		Fig. 3. MVD positively correlates with systemic SDF-1{alpha} levels in multiple myeloma and MGUS patients and control subjects. In patients where both peripheral blood plasma and suitable bone marrow trephine specimens were available, peripheral blood plasma SDF-1{alpha} levels in multiple myeloma (bullet, n = 33) and MGUS ({circ}, n = 15) patients and control subjects (Figure 3, n = 5) were plotted with reference to their respective MVD. Increasing levels of SDF-1{alpha} were positively associated with an increase in bone marrow MVD.

 

   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
Multiple myeloma plasma cell express numerous angiogenic cytokines, including vascular endothelial growth factor, basic fibroblast growth factor, and hepatocyte growth factor, which have been collectively implicated in angiogenesis in multiple myeloma (7, 8). Although the chemokine SDF-1{alpha} has also recently been shown to play an important role in the stimulation of physiologic angiogenesis (22), and although multiple myeloma plasma cell produce SDF-1{alpha} (15), no direct evidence has been provided to show that multiple myeloma plasma cell–derived SDF-1{alpha} can stimulate angiogenesis. Using conditioned media from the multiple myeloma plasma cell line RPMI-8226, we have shown that multiple myeloma plasma cell–derived SDF-1{alpha} directly stimulates in vitro angiogenesis. Although conditioned medium is a source of numerous growth factors, cytokines, and chemokines, the increase in angiogenesis was directly attributable to SDF-1{alpha}, as the addition of T140, a specific and biostable inhibitor of the SDF-1{alpha}/CXCR4 interaction, abrogated the conditioned medium-mediated increase in angiogenesis. The magnitude of T140 inhibition on tube formation in the presence of conditioned medium can be attributed to the fact that in addition to directly acting on endothelial cells, multiple myeloma–derived factors, such as vascular endothelial growth factor and basic fibroblast growth factor, act, in part, by up-regulating expression of CXCR4 on endothelial cells (9).

Previous studies have reported a positive correlation between bone marrow MVD and peripheral blood plasma levels of hepatocyte growth factor (23), but no correlation between other important angiogenic cytokines, such as vascular endothelial growth factor, interleukin-6, basic fibroblast growth factor, and SDF-1{alpha} (23, 24). Given that SDF-1{alpha} plays a role in physiologic angiogenesis (9, 10), and multiple myeloma plasma cell infiltration positively correlates with SDF-1{alpha} levels in multiple myeloma and MGUS patients (15), we next investigated whether elevated levels of SDF-1{alpha} in the peripheral blood of these patients also correlate with an increase in bone marrow angiogenesis in vivo. First, however, we confirmed a direct correlation between plasma cell burden and both angiogenesis and SDF-1{alpha} levels in our patient cohort, in accord with previously published results (15, 21).

When SDF-1{alpha} levels in peripheral blood plasma from newly diagnosed MGUS and multiple myeloma patients and healthy age-matched subjects were measured and correlated with their respective bone marrow MVD, we made the novel and important observation that bone marrow angiogenesis positively correlates with plasma levels of SDF-1{alpha}.

Taken together with our previous findings that show a role for SDF-1{alpha} in the promotion of osteolysis (15), the results presented here raise the intriguing possibility that SDF-1{alpha} may indirectly promote osteolysis in multiple myeloma patients by increasing angiogenesis, thereby increasing the recruitment of osteoclast precursors to sites of multiple myeloma plasma cell infiltration. Conversely, SDF-1{alpha}-mediated osteolysis, through the release of proangiogenic cytokines and growth factors from within the bone matrix, may also precede the increase in bone marrow angiogenesis. Although beyond the scope of the present communication, we are currently investigating whether there is an in vivo association between pathologic angiogenesis and the transition to an osteolytic phenotype in multiple myeloma.

In conclusion, we have shown that SDF-1{alpha} plays a key role, not only in the promotion of osteoclast activity (15), but also in the elevated angiogenesis observed in multiple myeloma patients. These results suggest that inhibition of SDF-1{alpha} may be an effective strategy for the treatment of multiple myeloma bone disease, through reducing both angiogenesis and osteoclast activity. However, as multiple myeloma–associated angiogenesis is a complex process that involves a multitude of cytokines and growth factors, further studies are required to investigate the relationship between SDF-1{alpha} and other angiogenic factors in the bone marrow microenvironment.


   Acknowledgments
 
We thank the technical assistance of Jim Manavis and Peter Gilham for their help with CD34 immunohistochemistry and Profs. Hirokazu Tamamura (Tokyo Medical and Dental University, Tokyo, Japan) and Nobutaka Fujii (Kyoto University, Kyoto, Japan) for providing the T140 used in this study.


   Footnotes
 
Grant support: National Health and Medical Research Council of Australia (A.C.W. Zannettino, L.B. To, and A.N. Farrugia), Cancer Council of South Australia (A.L. Dewar, A.C.W. Zannettino, and S. Gronthos), and Australian Postgraduate Award (S.K. Martin).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 2/ 9/06; revised 6/22/06; accepted 8/ 4/06.


   References
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