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University of Texas Health Science Center, San Antonio, Texas, USA3 i# @3 I5 |7 \. Q% I* `
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Key Words. Myeloma ? Mobilization ? SDF-1/CXCR4 ? VLA4
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Yair Gazitt, Ph.D., Department of Medicine/Hematology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284, USA. Telephone: 210-567-4848; Fax: 210-567-1956; e-mail: gazitt@uthscsa.edu& r. y* z! m) U$ S
* U4 a+ w+ j2 u) }( iABSTRACT
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/ t- j( m5 V4 DMobilization of hematopoietic stem cells (HSC) can be achieved by the administration of chemotherapy, by administration of hematopoietic growth factors such as G-CSF or GM-CSF, or by chemotherapy plus hematopoietic growth factor . The molecular events and signaling molecules involved in HSC mobilization have been extensively studied. Thus, downregulation of adhesion molecules and desensitization of the CXCR4/stromal cell-derived factor (SDF-1) chemotaxis are critical events in growth factor-induced and/or chemotherapy-induced mobilization of HSC . Comobilization of tumor cells following chemotherapy or growth factor has also been documented for hematological malignancies and for solid tumors .0 U# d) U/ ]- F; W0 C$ [) n; B4 M
3 s3 U; Y/ M# F% |; mRecent studies revealed that adhesion molecules are similar to HSC in their homing and release of cancer cells. In particular, the involvement of very late activation antigen (VLA)-4 and VLA-5 in adhesion of myeloma cells to stromal cells and the resulting drug resistance has been extensively studied . SDF-1/CXCR4 signaling is also active in all cancer cells studied , in solid tumors , and in hematological malignancies, including chronic lymphocytic leukemia , non-Hodgkin’s lymphoma , chronic myelogenous leukemia , and acute leukemias . The role of SDF-1/CXCR4 signaling in the adhesion of myeloma cells to fibronectin and stromal cells has also been studied . Hideshima et al. have shown that SDF-1 promotes proliferation, induces migration, and protects against dexamethasone-induced apoptosis through the mitogen-activated protein (MAP)/Akt pathway in myeloma cells, but these effects were only modest. Also, SDF-1 upregulated the secretion of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) in bone marrow (BM) stromal cells, resulting in proliferation and partial resistance to dexamethasone-induced apoptosis . In addition, the expression and role of various chemokines and chemokine receptors in myeloma cells was studied recently by Moller et al. . They reported that cells derived from myeloma cell lines and primary myeloma cells express functional chemokine receptors CCR1, CXCR3, and CXCR4 and migrate in response to the CCR1 ligands RANTES, macrophage inflammatory protein-1 (MIP-1), and SDF-1 . We have studied the role of MIP-1 in the regulation of myeloma cell adhesion in vitro and myeloma cell growth in vivo in a xenograft mouse model . Blocking of MIP-1 resulted in decreased survival of myeloma cells and decreased bone disease in mice engrafted with ARH-77 myeloma cells transfected with anti-sense MIP-1-expressing vector .) t/ d( x* R' o6 M# b
+ n5 ]- P% Y" ^ wFurther support of the general role of SDF-1/CXCR4 signaling in the survival, homing, and mobilization of cancer cells was obtained from several recent studies demonstrating that blocking of CXCR4 by specific antibodies or by the CXCR4-blocking peptides, such as T140, results in mobilization of tumor cells and blocking of human lymphoma, and leukemia cell growth in xenograft mouse models .
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! G. v0 S" \' k7 b B& A% d4 iIn this communication, we report the involvement of adhesion molecules and SDF-1/CXCR4 signaling in the mobilization of myeloma cells. We report a decrease in plasma levels of SDF-1 and a decrease in surface expression of VLA-4 and CXCR4 in mobilized myeloma cells compared with premobilization BM myeloma cells. We also observed a concomitant decrease in adhesion and trans-stromal migration of mobilized myeloma cells. Preliminary results from this work were presented at the 94th Annual Meeting of the American Association of Cancer Research .1 \9 E8 D# }, s7 p
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MATERIALS AND METHODS
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8 l$ t4 a" j" z2 k6 cAdhesion molecules and CXCR4 signaling were implicated in mobilization of HSC and various cancer cells. However, the expression of adhesion molecules and CXCR4 on mobilized myeloma cells was not studied. We first studied the expression of VLA-4, VLA-5, and CXCR4 on CD38 CD138 myeloma cells in the blood of mobilized myeloma patients compared with premobilization BM myeloma cells. An example is shown in Figure 1. A marked decrease in the expression of CXCR4 and VLA-5 was observed in the apheresis collections obtained from all patients studied, relative to steady-state BM (Fig. 1).
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Figure 1. Three-color immunofluorescence staining of myeloma cells expressing CXCR4, VLA4, and VLA5. An example staining of BM myeloma cells (BM) and day-1 apheresis collection (PBSC1) for CXCR4, VLA4, and VLA5 is shown. Mononuclear cells were stained with PE-anti-CD38, APC-anti-CD138 (syndican-1), FITC-conjugated anti-CXCR4, anti-VLA4, and anti-VLA5. Region was set on CD38 CD138 cells (R1 R2) and the fluorescence in the FITC channel was determined in R3 for the three FITC-conjugated antibodies. Immunofluorescence staining was performed as described in the Materials and Methods section. Dot plots represent immunoglobulin isotype control (upper left) and staining for CD49d (lower right). Results were quantitated by CellQuest software. At least 50,000 cells were analyzed. Dotted lines are isotype-matched controls, and solid lines represent staining with specific antibodies. Note the decrease in expression of CXCR4 and VLA4 and the slight decrease in VLA5 in the apheresis sample versus the BM sample of the same patient. Note also the relatively low expression of VLA5 compared with the high expression of VLA4 and CXCR4 in BM and apheresis samples of myeloma cells.8 g, ?' I' o8 X' [7 F0 g
# w2 _8 n# c2 a7 m& FThe cumulative results in mobilized blood obtained from 12 myeloma patients are depicted in Figure 2. The mean expression of VLA-4 and CXCR4 on mobilized myeloma cells was significantly decreased compared with premobilization myeloma cells in all apheresis collections. In contrast, expression of VLA-5 was low and was not significantly decreased (Fig. 2A). Concomitant with a decrease in the proportion of myeloma cells expressing VLA-4 and CXCR4, we observed a statistically significant decrease in the mean fluorescence intensity (MFI) of VLA-4 and CXCR4 on mobilized myeloma cells compared with premobilization BM myeloma cells. In contrast to VLA-4 and CXCR4, no decrease in MFI was observed for VLA-5. The data obtained from 12 patients are presented in Figure 2B.) x S1 L, W. s9 r7 v# Y1 J
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Figure 2. Decreased expression of CXCR4 and VLA4 in mobilized myeloma cells. Cell staining and analysis of stained cells were performed as described in the Materials and Methods section. A) BM myeloma cells were compared with four consecutive apheresis collections (d1 to d4). The results are depicted as percent myeloma cells expressing CXCR4, VLA-4, or VLA-5 of the total number of cells analyzed (absolute percentage). Bars represent mean ± SD of each apheresis collection obtained from 12 myeloma patients. Asterisks represent significant (p 2 ]( l: ^! `1 P+ U, {- f
' e+ \2 @3 k3 E+ _4 lWe also studied the plasma levels of SDF-1 in the apheresis collections and in premobilization BM samples. We observed a significant decrease (~50%) in plasma SDF-1 in each of the apheresis collections compared with premobilization BM. The results are depicted in Figure 3.! O0 `& X9 Q! S4 S. o+ B
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Figure 3. Decrease in plasma SDF-1 in the apheresis collections of mobilized myeloma patients. Changes in plasma levels of SDF-1 in mobilized blood (day 1 to day 4) compared with BM plasma before mobilization. Determination of SDF-1 levels by ELISA was carried out as described in the Material and Methods section. BM = bone marrow before mobilization; d1 to d4 = apheresis collections at day 1 to day 4. Results were derived from 12 myeloma patients. Bars represent mean ± SD. Asterisks represent significant differences (p ' `* ?4 e3 K2 | _" g2 f
6 f0 v0 U2 m& s) kIn addition we studied cell adhesion and trans-stromal migration of myeloma cells in response to SDF-1 derived from the apheresis collections compared with that of premobilization BM myeloma cells. The results are depicted in Figure 4. We observed about a 50% decrease in SDF-1-dependent adhesion and trans-stromal migration of purified myeloma cells derived from day-1 apheresis collections compared with premobilization BM myeloma cells. Furthermore, preincubation of myeloma cells with antibodies to VLA-4 (V4) or CXCR4, but not with anti-VLA-5 (c), resulted in abrogation of cell adhesion and trans-stromal migration of myeloma cells. Most importantly, incubation of myeloma cells for 24 hours with 100 ng/ml of IL-3 and 50 ng/ml SCF resulted in varying degrees of restoration of cell adhesion and trans-stromal migration of myeloma cells, with best results obtained with IL-6. The results for IL-6 presented in column R in Figure 4 demonstrate full restoration of SDF-1-dependent cell adhesion and trans-stromal migration. Very small (
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7 k/ m2 w. O0 L$ E& Q( B3 \Figure 4. Decrease in cell adhesion and trans-stromal migration of myeloma cells derived from mobilized blood of MM patients. CD38 CD138 myeloma cells were purified by flow cytometry from premobilization BM and from day-1 apheresis collections (A1) of myeloma patients mobilized with cyclophosphamide and GM-CSF. C = control BM with no SDF-1; BM = bone marrow 50 ng/ml SDF-1; A = apheresis (day-1 collection 50 ng/ml SDF-1); V4 and V5 = same 2 μg/ml of anti-VLA-4 or anti-VLA-5 antibodies, respectively; C = same 2 μg/ml of anti-CXCR4 antibodies; R = myeloma cells from apheresis collections (A1) incubated for 24 hours with 50 ng/ml IL-6 and assayed for adhesion and trans-stromal migration with 50 ng/ml of SDF-1. Error bars are ± SD derived from 12 patients. Asterisks represent significant (p
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, |. r& U: @' @These results strongly suggest that mobilization of myeloma cells requires downregulation of VLA-4 and disruption of SDF-1/CXCR4 signaling, and thus myeloma cells follow the same requirement for mobilization as was described for HSC.+ T9 ]2 a8 _ X( M- L; \8 ^8 E
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In order to delineate the mechanism for the observed reversal of cell adhesion and trans-stromal migration of myeloma cells, we tested the effect of a 24-hour incubation of myeloma cells with 100 ng/ml IL-3 or 50 ng/ml IL-6, or 50 ng/ml SCF on the re-expression of CXCR4, VLA-4, and VLA-5 in myeloma cells derived from apheresis collections of three different MM patients. The results are presented in Figure 5A (percent positive cells) and 5B (MFI).
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Figure 5. Growth factors induce re-expression of CXCR4 and VLA-4 on the surface of myeloma cells derived from mobilized blood of MM patients. CD38 CD138 myeloma cells were purified by flow cytometry from day-1 apheresis collections of 3 patients mobilized with cyclophosphamide and GM-CSF. F = fresh myeloma cells. Myeloma cells were cultured for 24 hours with 50 ng/ml of IL-6 or 50 ng/ml SCF, or 100 ng/ml IL-3. Error bars are ± SD derived from apheresis collections of 3 different patients. Cells were stained for CXCR4 and VLA-4 and analyzed by flow cytometry as described in the Materials and Methods section. A) depicts percent positive cells relative to Ig-isotype controls. B) depicts increase in MFI relative to Ig-isotype controls. Asterisks represent significant (p 5 h7 N6 `2 B/ A' ]9 q6 ]
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Hence, myeloma cells incubated for 24 hours with various growth factors exhibited a marked increase in surface expression of both CXCR4 and VLA-4, with best results obtained with IL-6 (70%–80% positive cells, Fig. 5A). Concomitantly, a substantial (> threefold) increase in the fluorescence intensity of CXCR4 and VLA-4 was also observed following treatment with IL-6 (Fig. 5B). No similar increase in the expression of VLA-5 was observed with any of the growth factors used (results not shown). Interestingly, a slight increase in the expression of CXCR4 and VLA-4 was observed following 24-hour incubation in medium (RPMI1640 plus 15% FCS) without growth factors added, compared with fresh, uncultured myeloma cells.( O, p4 u2 v* p( F/ \0 Y8 l( O( h1 }
0 g! e( N5 H+ J) \7 H8 NDISCUSSION
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% t2 W5 P: r5 U6 F! aWe would like to thank Dr. Cesar Freytes and Dr. Natalie Callander for enrolling patients on this mobilization protocol. We also would like to thank Mr. Charles Thomas and the Institutional Flow Cytometry Laboratory for performing the cytofluorometric analyses.
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发表于 2009-3-5 10:22
发表于 2015-7-27 13:18
