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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2908-2913
Primary Myeloma Cells Growing in SCID-hu Mice: A Model for
Studying the Biology and Treatment of Myeloma and Its
Manifestations
By
Shmuel Yaccoby,
Bart Barlogie, and
Joshua Epstein
From the Myeloma and Transplantation Research Center, Arkansas Cancer
Research Center, University of Arkansas for Medical Sciences, Little
Rock, AR.
 |
ABSTRACT |
Progress in unraveling the biology of myeloma has suffered from lack
of an in vitro or in vivo system for reproducible growth of myeloma
cells and development of disease manifestations. The SCID-hu mouse
harbors a human microenvironment in the form of human fetal bone.
Myeloma cells from the bone marrow of 80% of patients readily grew in
the human environment of SCID-hu mice. Engraftment of myeloma cells was
followed by detectable human Ig levels in the murine blood.
Myeloma-bearing mice had high levels of monotypic human Igs, high blood
calcium levels, increased osteoclast activity, and severe resorption of
the human bones. The human microenvironment was infiltrated with
Epstein-Barr virus-negative monoclonal myeloma cells of the same
clonality as the original myeloma cells. Active angiogenesis was
apparent in areas of myeloma cell infiltration; the new endothelial
cells were of human origin. We conclude that the SCID-hu mouse is a
favorable host for studying the biology and therapy of myeloma and that
a normal bone marrow environment can support the growth of myeloma
cells.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
THERE HAS BEEN a recent explosion in data
related to the biology of myeloma. However, most of these advances,
potentially of major importance to our understanding of the development
of myeloma and to its management, remain of uncertain importance due to
the lack of in vitro and in vivo systems allowing reproducible growth
of primary myeloma cells or the development of myeloma clinical
manifestations. Our inability to positively identify the proliferative
compartment in myeloma, to discern the role of circulating clonal B
lymphocytes in maintaining the disease,1-5 to determine the
role of pre-switch and isotypically diverse clonal cells in the
development of myeloma,6,7 or to determine the importance
of Kaposi's sarcoma associated herpes virus (KSHV) in
myelomagenesis8,9 is attributable primarily to the lack of
a biological read out system.
Human myeloma cell lines readily grow in SCID mice.10-16
However, success has been limited when primary myeloma cells were used,17 resulting in growth patterns more compatible with
lymphoma than with myeloma. The difficulty in growing primary myeloma
cells in SCID mice probably reflects the dependence of myeloma cells on
environmental stimuli that cannot be replaced by the murine host.
We have inoculated fresh bone marrow cells obtained from patients with
myeloma into SCID-hu mice.18-20 We report here that the
SCID-hu mice provide a hospitable environment for reproducible growth
of primary myeloma cells. Mice inoculated with bone marrow cells from
patients with myeloma develop typical manifestations of the disease
such as plasmacytosis, high levels of monoclonal Igs, and severe bone
resorption.
| |
MATERIALS AND METHODS |
Myeloma cells.
Heparinized bone marrow aspirates were obtained from patients with
active myeloma during scheduled clinic visits. Signed informed consents
were obtained and are kept on record. Relevant patient information is
provided in Table 1. The samples were
separated using ficoll hypaque centrifugation (Histopaque; Pharmacia,
Uppsala, Sweden). The proportion of myeloma cells in the
light-density cell preparations (specific gravity  1.077 g/mL)
was determined using CD38/CD45 flow
cytometry.4,21 When indicated, myeloma cells were sorted on
the basis of CD38/CD45 expression.4,21 The myeloma clone in
each sample was characterized by CDRIII polymerase chain reaction
(PCR).4,22
SCID-hu system.
CB.17/ICr-SCID mice were obtained from Harlan Sprague
Dawley and were housed and monitored in our animal facility. All
experimental procedures and protocols had been approved by the
Institutional Animal Care and Use Committee. SCID-hu mice were
generated as reported.23 Before inoculation of myeloma
cells, the mice were exposed to 150 rad X-irradiation, using a model
143-45 Irradiator 137Cesium source, at a rate of 125 rads/min. Light-density bone marrow cells (1.5 to
10 × 106) were injected directly into the human bone in
the SCID-hu mice in a final volume of 25 to 50 µL of
phosphate-buffered saline (PBS). An increase in the levels of
circulating monotypic human Ig (hIg) of the M protein isotype was used
as an indicator of myeloma cell growth.
Determination of hIg levels.
Levels of human IgG, IgA,  , and  light chains were determined by
enzyme-linked immunosorbent assay (ELISA). Antibodies were purchased from The Binding Site (San Diego, CA). Plates
were coated with 50 µL/well of primary antihuman and (5 µg/mL) and antihuman IgA and IgG (10 µg/mL) and incubated overnight
at 4°C. The plates were washed three times in PBS containing 0.5%
(vol/vol) of Tween 20 and washed one more time with blocking buffer
containing 4% bovine serum albumin (BSA) in PBS. Serial dilution of
samples in PBS-containing 1% BSA (50 µL/well) were incubated at room
temperature for 2 hours. Standards consisting of each purified Ig were
added to the appropriate plates at concentrations ranging from 0.4 to 300 ng/mL. After washing three times with PBS/Tween, plates were incubated with 50 µL/well of biotinylated Ab (affinity-purified antihuman and light chains at 0.5 µg/mL and antihuman IgA and
IgG at 0.2 µg/mL) for 1 hour. Fifty microliters per well of streptavidin-horseradish peroxidase were added to each well after washing and allowed to bind for 1 hour. After a final washing, 50 µL/well of OPD solution (DAKO, Carpinteria, CA)
containing 3% H2O2 was added. Absorbance at
450 nm was determined on a Auto-Reader II ELISA reader (Ortho
Diagnostic Systems, Raritan, NJ).
Methods of analysis.
Tissues and organs recovered from SCID-hu mice were processed as
reported.24 Myeloma cells were identified morphologically by immunohistochemical staining for cytoplasmic Ig (cIg;
DAKO immunoperoxidase kit) and their clonality was
determined by in situ hybridization with patient-specific probes
(ASO-ISH). Changes in bone remodeling were identified by
x-radiography and by increased osteoclast activity as demonstrated by
immunohistochemical staining for tartarate-resistant acid phosphatase
(TRAP; Sigma, St Louis, MO). Immunohistochemical staining with a
monoclonal antibody to CD34 (Cell Marque, Austin, TX) was
used to demonstrate neo-vascularization as an indicator for the
presence of a human microenvironment in areas of myeloma cell growth.
Determination of calcium.
Calcium levels were determined using a calcium determination kit (Sigma
Diagnostics) according to the manufacturer's recommendations.
In situ hybridization.
Clonality of the tumor cells grown in SCID mice was demonstrated by in
situ hybridization using an adaptation of published methods.25,26 Antisense oligonucleotide sequences (24-32 bp) complementary to CDR III regions of the myeloma clone of each patient were biotinylated during synthesis (Life Technologies, Rockville, MD). Tissue sections were dewaxed in xylene,
defatted in chloroform, and then rehydrated. The sections were treated with proteinase K (10 µg/mL in Tris-HCl buffer at 37°C for 1 hour). Hybridization mixture containing 50% formamide, 10% dextran, 4 × SSC (SSC is 150 mmol/L NaCL, 15 mmol/L trisodium citrate, pH 7), 25 mg/mL herring sperm DNA, and biotinylated probe (1 to 2 µg/mL) was
applied to each section. The sections were covered with Parafilm and
incubated in a humidified chamber overnight at 37°C. After
hybridization, the slides were washed twice with 1 × SSC at room
temperature and twice with 1 × SSC at 37°C to 42°C (depending on
the size of the probe). Signals were visualized using an in situ
hybridization kit (DAKO). Specificity was determined by using
irrelevant patient probes and sections from different patients.
Screening for Epstein-Barr virus.
Myeloma cells recovered from SCID-hu mice were analyzed for the
presence of EBV sequences by PCR.27 All samples were
negative.
| |
RESULTS |
Bone marrow cells from 15 patients were studied in the SCID-hu system.
Mice inoculated with cells from 12 patients had detectable circulating
hIg 2 to 19 weeks after inoculation. Two mice had no detectable hIg
even at 23 and 29 weeks, and one mouse, inoculated with cells from a
patient with nonsecretory myeloma, also had no detectable circulating
hIg (Table 1). In these 3 cases, myeloma growth could not be detected
by histological and immunohistochemical examinations. With two
exceptions, the circulating hIg was identical to the M protein isotype
in terms of both the heavy and light Ig chains; for 1 patient with IgA
myeloma, all 4 isotypes were expressed at 15 weeks (patient no.
10), and in 1 patient with nonsecretory myeloma, IgG was found at 3 weeks (patient no. 15). In this latter patient, the original myeloma
cells contained IgG cytoplasmic Ig (data not shown). The kinetics
of the increase of hIg levels varied among patients; examples are
presented for 3 of these patients in Fig 1.
Although the number of patients studied is too small to draw firm
conclusions, there was no apparent correlation between the time to
detection of hIg and the number of myeloma cells inoculated, marrow
plasmacytosis, or any other patient characteristic, whether analyzed
for the whole group or only for the 6 patients with IgG myeloma
(Table 1).
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| Fig 1.
hIg levels in SCID-hu mice. The mice were bled at the
indicated time point after inoculation of myeloma cells, and the levels
of Ig heavy and light chains were determined by ELISAs. Three examples
are presented. (A) IgG myeloma (patient no. 1). (B) IgA myeloma
(patient no. 2). (C) light chain myeloma (patient no. 6).
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Further analysis is available only for the 8 patients for whom the
experiments have been completed. Histological examination of
decalcified sections of the human bone showed extensive infiltration of
plasma cells (Fig 2). The cells uniformly
contained monotypic clg (Fig 3),
coexpressed Ig heavy and light chains, and reacted homogeneously and
exclusively with the patient's specific ASO (Fig
4), indicating their clonal identity with
the original patient's myeloma cells. In all cases, myeloma
plasma cells were found only in the human bone. Neither
myeloma cells nor any other human cells were detected in any of the
murine organs, bone marrow, or blood, as determined histologically, and
by CD38/CD45 and HLA-ABC flow cytometry.
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| Fig 2.
Myeloma cell infiltrate in the human bone of a
SCID-hu mouse. Photomicrograph of a 5-µm section of decalcified human
bone recovered from SCID-hu mouse (patient no. 4). Hematoxylin and
eosin staining, 10× objective.
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| Fig 3.
cIg expression in the SCID-hu mouse. 20× objective
photomicrograph of a 5-µm section of decalcified human bone recovered
from SCID-hu mouse reacted with monoclonal antibody to human light
chain (patient no. 4).
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| Fig 4.
Clonality of myeloma cells in the SCID-hu mouse.
Decalcified human bone section was hybridized with patient-specific ASO
(patient no. 4). (Insert) Control section hybridized with the ASO probe
to the myeloma clone from patient no. 2. 20× objective.
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Growth of the myeloma cells was associated with increased blood Ca
levels (summarized in Fig 5), suggesting
anomalies in bone remodeling. Immunohistochemical examination of the
kidneys showed varying amounts of light chain deposits (not shown).
Decalcified bone sections stained for TRAP showed markedly increased
osteoclast activity (Fig 6). Severe loss in
human bone density was readily visible upon x-ray examination in all
cases. Although density loss was severe in all mice, the degree of
human bone resorption varied. An example depicting a moderate level of
density loss is presented in Fig 7.
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| Fig 5.
Blood calcium levels in a myeloma-bearing SCID-hu
mouse. Ca levels were measured at the end of the experiments. Results
for 8 age-matched control SCID-hu mice and the 6 myeloma-bearing
mice are given. Ca levels for mice inoculated with cells from
patients no. 5 and 8 were within control range. Results are
presented as the mean ± SEM.
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| Fig 6.
Osteoclast activity in myeloma-bearing SCID-hu mouse.
Photomicrograph of a TRAP-stained decalcified human bone section.
Multinucleated osteoclasts (cells with red cytoplasm) surround and
excavate cancellous (A) and trabecular (B) bone. Patient no. 4, 20×
objective.
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| Fig 7.
Loss in density of human bone in myeloma-bearing SCID-hu
mouse as seen by x-radiography. Human bones are visible in the
right-hand side. The highly contrasted devices visible in the bottom
left corner are implant transponders used to identify the mice. (A)
Myeloma-bearing mouse (patient no. 6): (B) Age-matched control SCID-hu
mouse.
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Expression of the endothelial cell antigen CD34 in a decalcified
section of the human bone is demonstrated in Fig
8. An active vascularization process is
readily visible. In all cases, neo-vascularization was restricted to
areas infiltrated with myeloma cells and was not visible in the human
bones of control SCID-hu mice, suggesting that vascularization occurred
in response to the presence of myeloma cells.
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| Fig 8.
Neo-vascularization in myeloma bearing SCID-hu mouse.
Decalcified human bone sections immunostained with a mouse monoclonal
antibody to human CD34. Proliferative endothelial cells are stained
brown. Patient no. 4, 10× objective.
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| |
DISCUSSION |
Primary myeloma cells, hitherto considered not capable of sustained
proliferation when removed from the patient, readily grew in the human
bone of SCID-hu mice. Interestingly, no other human hematopoietic cells
were detectable in the murine bone marrow and blood. Growth of myeloma
cells was restricted to the human environment, similar to reports with
primary leukemic cells23 and very different from myeloma
cell lines that readily grow in SCID mice and disseminate out of the
human bone microenvironment in the SCID-hu system.28
Myeloma growth was accompanied by increased osteoclast activity and
resorption of the human bone, a typical manifestation of
myeloma.24 Increases in osteoclasts were also observed in the murine bones (femurs and vertebrae; data not shown). However, loss
in density of murine bones was not discernible on x-radiograms.
As in other malignancies, vascularization is an important part of
myeloma growth.29-31 In the SCID-hu system, newly formed blood vessels were made of human cells and were visible only in areas
infiltrated with myeloma cells. These endothelial cells could originate
from dormant stem cells in the implanted human bone or, alternatively,
from the myeloma patients' bone marrow. Because primary myeloma cells
cannot grow in SCID mice (23 failed attempts, including some samples
that grew in the SCID-hu system; data not shown), it appears that a
normal human bone environment can support the growth of primary myeloma
cells from bone marrow aspirates of patients with myeloma. Studies are
underway to determine the source of the endothelial and other cells
that constitute the human microenvironment in the SCID-hu mice and
whether purified myeloma plasma cells will also engraft in this model.
The SCID-hu mouse provides a favorable host environment for
reproducible growth of primary myeloma cells. This system is a suitable
model for studying the biology of myeloma, its treatment, and
manifestations.
| |
FOOTNOTES |
Submitted April 7, 1998;
accepted June 14, 1998.
Supported in part by Grant No. CA-55819 from the National Cancer
Institute.
Address reprint requests to Joshua Epstein, DSc, MTRC, UAMS, 4301 W
Markham, Slot #776, Little Rock, AR 72205; e-mail:
jepstein{at}life.uams.edu.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
REFERENCES |
1.
Pilarski LM,
Belch AR:
Circulating monoclonal B cells expressing P glycoprotein may be a reservoir of multidrug-resistant disease in multiple myeloma.
Blood
83:724,
1994[Abstract/Free Full Text]
2.
Pilarski LM,
Jensen GS:
Monoclonal circulating B cells in multiple myeloma. A continuously differentiating, possibly invasive, population as defined by expression of CD45 isoforms and adhesion molecules [Review].
Hematol Oncol Clin North Am
6:297,
1992[Medline]
[Order article via Infotrieve]
3.
Bergui L,
Schena M,
Gaidano G,
Riva M,
Caligaris-Cappio F:
Interleukin 3 and interleukin 6 synergistically promote the proliferation and differentiation of malignant plasma cell precursors in multiple myeloma.
J Exp Med
170:613,
1989[Abstract/Free Full Text]
4.
Chen BJ,
Epstein J:
Circulating clonal lymphocytes in myeloma constitute a minor subpopulation of Bb cells [see comments].
Blood
87:1972,
1996[Abstract/Free Full Text]
5.
Kay NE,
Leong T,
Kyle RA,
Greipp P,
Billadeau D,
Van Ness B,
Bone N,
Oken MM:
Circulating blood B cells in multiple myeloma: Analysis and relationship to circulating clonal cells and clinical parameters in a cohort of patients entered on the Eastern Cooperative Oncology Group phase III E9486 clinical trial.
Blood
90:340,
1997[Abstract/Free Full Text]
6.
Billadeau D,
Ahmann G,
Greipp P,
Van Ness B:
The bone marrow of multiple myeloma patients contains B cell populations at different stages of differentiation that are clonally related to the malignant plasma cell.
J Exp Med
178:1023,
1993[Abstract/Free Full Text]
7.
Corradini P,
Boccadoro M,
Voena C,
Pileri A:
Evidence for a bone marrow B cell transcribing malignant plasma cell VDJ joined to C mu sequence in immunoglobulin (IgG)- and IgA-secreting multiple myelomas.
J Exp Med
178:1091,
1993[Abstract/Free Full Text]
8.
Rettig MB,
Ma HJ,
Vescio RA,
Pold M,
Schiller G,
Belson D,
Savage A,
Nishikubo C,
Wu C,
Fraser J,
Said JW,
Berenson JR:
Kaposi's sarcoma-associated herpesvirus infection of bone marrow dendritic cells from multiple myeloma patients [see comments].
Science
276:1851,
1997[Abstract/Free Full Text]
9.
Said JW,
Rettig MR,
Heppner K,
Vescio RA,
Schiller G,
Ma HJ,
Belson D,
Savage A,
Shintaku IP,
Koeffler HP,
Asou H,
Pinkus G,
Pinkus J,
Schrage M,
Green E,
Berenson JR:
Localization of Kaposi's sarcoma-associated herpesvirus in bone marrow biopsy samples from patients with multiple myeloma.
Blood
90:4278,
1997[Abstract/Free Full Text]
10.
Cattan AR,
Douglas E:
The C.B. 17 scid mouse strain as a model for human disseminated leukaemia and myeloma in vivo.
Leuk Res
18:513,
1994[Medline]
[Order article via Infotrieve]
11.
Tong AW,
Huang YW,
Zhang BQ,
Netto G,
Vitetta ES,
Stone MJ:
Heterotransplantation of human multiple myeloma cell lines in severe combined immunodeficiency (SCID) mice.
Anticancer Res
13:593,
1993[Medline]
[Order article via Infotrieve]
12.
Bellamy WT,
Odeleye A,
Finley P,
Huizenga B,
Dalton WS,
Weinstein RS,
Hersh EM,
Grogan TM:
An in vivo model of human multidrug-resistant multiple myeloma in SCID mice.
Am J Pathol
142:691,
1993[Abstract]
13.
Huang YW,
Richardson JA,
Tong AW,
Zhang BQ,
Stone MJ,
Vitetta ES:
Disseminated growth of a human multiple myeloma cell line in mice with severe combined immunodeficiency disease.
Cancer Res
53:1392,
1993[Abstract/Free Full Text]
14.
Suzuki H,
Yasukawa K,
Saito T,
Goitsuka R,
Hasegawa A,
Ohsugi Y,
Taga T,
Kishimoto T:
Anti-human interleukin-6 receptor antibody inhibits human myeloma growth in vivo.
Eur J Immunol
22:1989,
1992[Medline]
[Order article via Infotrieve]
15.
Huang YW,
Richardson JA,
Vitetta ES:
Anti-cd54 (icam-1) has antitumor activity in scid mice with human myeloma cells.
Cancer Res
55:610,
1995[Abstract/Free Full Text]
16.
Bellamy WT,
Mendibles P,
Bontje P,
Thompson F,
Richter L,
Weinstein RS,
Grogan TM:
Development of an orthotopic SCID mouse-human tumor xenograft model displaying the multidrug-resistant phenotype.
Cancer Chemother Pharmacol
37:305,
1996[Medline]
[Order article via Infotrieve]
17.
Feo-Zuppardi FJ,
Taylor CW,
Iwato K,
Lopez MH,
Grogan TM,
Odeleye A,
Hersh EM,
Salmon SE:
Long-term engraftment of fresh human myeloma cells in SCID mice.
Blood
80:2843,
1992[Abstract/Free Full Text]
18.
Kaneshima H,
Baum C,
Chen B,
Namikawa R,
Outzen H,
Rabin L,
Tsukamoto A,
McCune JM:
Today's SCID-hu mouse.
Nature
348:561,
1990[Medline]
[Order article via Infotrieve]
19.
Namikawa R,
Weilbaecher KN,
Kaneshima H,
Yee EJ,
McCune JM:
Long-term human hematopoiesis in the SCID-hu mouse.
J Exp Med
172:1055,
1990[Abstract/Free Full Text]
20.
DiGiusto D,
Chen S,
Combs J,
Webb S,
Namikawa R,
Tsukamoto A,
Chen BP,
Galy AH:
Human fetal bone marrow early progenitors for T, B, and myeloid cells are found exclusively in the population expressing high levels of CD34.
Blood
84:421,
1994[Abstract/Free Full Text]
21.
Hata H,
Xiao H,
Petrucci MT,
Woodliff J,
Chang R,
Epstein J:
Interleukin-6 gene expression in multiple myeloma: A characteristic of immature tumor cells.
Blood
81:3357,
1993[Abstract/Free Full Text]
22.
Billadeau D,
Blackstadt M,
Greipp P,
Kyle RA,
Oken MM,
Kay N,
Van Ness B:
Analysis of B-lymphoid malignancies using allele-specific polymerase chain reaction: A technique for sequential quantitation of residual disease.
Blood
78:3021,
1991[Abstract/Free Full Text]
23.
Namikawa R,
Ueda R,
Kyoizumi S:
Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice.
Blood
82:2526,
1993[Abstract/Free Full Text]
24.
Alsina M,
Boyce B,
Devlin RD,
Anderson JL,
Craig F,
Mundy GR,
Roodman GD:
Development of an in vivo model of human multiple myeloma bone disease.
Blood
87:1495,
1996[Abstract/Free Full Text]
25.
Pringle JH,
Primrose L,
Kind CN,
Talbot IC,
Lauder I:
In situ hybridization demonstration of poly-adenylated RNA sequences in formalin-fixed paraffin sections using a biotinylated oligonucleotide poly d(T) probe.
J Pathol
158:279,
1989[Medline]
[Order article via Infotrieve]
26.
Brown R,
Luo XF,
Gibson J,
Morley A,
Sykes P,
Brisco M,
Joshua D:
Idiotypic oligonucleotide probes to detect myeloma cells by mRNA in situ hybridization.
Br J Haematol
90:113,
1995[Medline]
[Order article via Infotrieve]
27.
Miyashita EM,
Yang B,
Lam KM,
Crawford DH,
Thorley-Lawson DA:
A novel form of Epstein-Barr virus latency in normal B cells in vivo.
Cell
80:593,
1995[Medline]
[Order article via Infotrieve]
28.
Urashima M,
Chen BP,
Chen S,
Pinkus GS,
Bronson RT,
Dedera DA,
Hoshi Y,
Teoh G,
Ogata A,
Treon SP,
Chauhan D,
Anderson KC:
The development of a model for the homing of multiple myeloma cells to human bone marrow.
Blood
90:754,
1997[Abstract/Free Full Text]
29.
Vacca A,
Ribatti D,
Roncali L,
Dammacco F:
Angiogenesis in B cell lymphoproliferative diseases. Biological and clinical studies [Review].
Leuk Lymphoma
20:27,
1995[Medline]
[Order article via Infotrieve]
30.
Vacca A,
Di LM,
Ribatti D,
Di SR,
Gadaleta-Caldarola G,
Iodice G,
Caloro D,
Dammacco F:
Bone marrow of patients with active multiple myeloma: Angiogenesis and plasma cell adhesion molecules LFA-1, VLA-4, LAM-1, and CD44.
Am J Hematol
50:9,
1995[Medline]
[Order article via Infotrieve]
31.
Vacca A,
Ribatti D,
Roncali L,
Ranieri G,
Serio G,
Silvestris F,
Dammacco F:
Bone marrow angiogenesis and progression in multiple myeloma.
Br J Haematol
87:503,
1994[Medline]
[Order article via Infotrieve]
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July 15, 2008;
112(2):
374 - 382.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Rozemuller, E. van der Spek, L. H. Bogers-Boer, M. C. Zwart, V. Verweij, M. Emmelot, R. W. Groen, R. Spaapen, A. C. Bloem, H. M. Lokhorst, et al.
A bioluminescence imaging based in vivo model for preclinical testing of novel cellular immunotherapy strategies to improve the graft-versus-myeloma effect
Haematologica,
July 1, 2008;
93(7):
1049 - 1057.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Huff and W. Matsui
Multiple Myeloma Cancer Stem Cells
J. Clin. Oncol.,
June 10, 2008;
26(17):
2895 - 2900.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Wang, L. Zhang, X. Han, J. Yang, J. Qian, S. Hong, P. Lin, Y. Shi, J. Romaguera, L. W. Kwak, et al.
A Severe Combined Immunodeficient-hu In vivo Mouse Model of Human Primary Mantle Cell Lymphoma
Clin. Cancer Res.,
April 1, 2008;
14(7):
2154 - 2160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Yang, V. MacLeod, Y. Dai, Y. Khotskaya-Sample, Z. Shriver, G. Venkataraman, R. Sasisekharan, A. Naggi, G. Torri, B. Casu, et al.
The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy
Blood,
September 15, 2007;
110(6):
2041 - 2048.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yaccoby, W. Ling, F. Zhan, R. Walker, B. Barlogie, and J. D. Shaughnessy Jr
Antibody-based inhibition of DKK1 suppresses tumor-induced bone resorption and multiple myeloma growth in vivo
Blood,
March 1, 2007;
109(5):
2106 - 2111.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Dalton and K. C. Anderson
Synopsis of a Roundtable on Validating Novel Therapeutics for Multiple Myeloma.
Clin. Cancer Res.,
November 15, 2006;
12(22):
6603 - 6610.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Tassone, P. Neri, J. L. Kutok, O. Tournilhac, D. D. Santos, E. Hatjiharissi, V. Munshi, S. Venuta, K. C. Anderson, S. P. Treon, et al.
A SCID-hu in vivo model of human Waldenstrom macroglobulinemia
Blood,
August 15, 2005;
106(4):
1341 - 1345.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Moreaux, F. W. Cremer, T. Reme, M. Raab, K. Mahtouk, P. Kaukel, V. Pantesco, J. De Vos, E. Jourdan, A. Jauch, et al.
The level of TACI gene expression in myeloma cells is associated with a signature of microenvironment dependence versus a plasmablastic signature
Blood,
August 1, 2005;
106(3):
1021 - 1030.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ferrone and G. Sconocchia
A clinically relevant mouse model of human multiple myeloma?
Blood,
July 15, 2005;
106(2):
388 - 389.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Tassone, P. Neri, D. R. Carrasco, R. Burger, V. S. Goldmacher, R. Fram, V. Munshi, M. A. Shammas, L. Catley, G. S. Jacob, et al.
A clinically relevant SCID-hu in vivo model of human multiple myeloma
Blood,
July 15, 2005;
106(2):
713 - 716.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. O. Oyajobi, C. M. Shipman, and G. R. Mundy
Recent Insights into Myeloma Bone Disease
IBMS BoneKEy,
May 1, 2005;
2(5):
17 - 25.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Yin
Chondroitin Synthase 1 Is a Key Molecule in Myeloma Cell-Osteoclast Interactions
J. Biol. Chem.,
April 22, 2005;
280(16):
15666 - 15672.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Podar and K. C. Anderson
The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications
Blood,
February 15, 2005;
105(4):
1383 - 1395.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson
Advances in biology of multiple myeloma: clinical applications
Blood,
August 1, 2004;
104(3):
607 - 618.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Trudel, S. Ely, Y. Farooqi, M. Affer, D. F. Robbiani, M. Chesi, and P. L. Bergsagel
Inhibition of fibroblast growth factor receptor 3 induces differentiation and apoptosis in t(4;14) myeloma
Blood,
May 1, 2004;
103(9):
3521 - 3528.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yaccoby, M. J. Wezeman, A. Henderson, M. Cottler-Fox, Q. Yi, B. Barlogie, and J. Epstein
Cancer and the Microenvironment: Myeloma-Osteoclast Interactions as a Model
Cancer Res.,
March 15, 2004;
64(6):
2016 - 2023.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Johrer, K. Janke, J. Krugmann, M. Fiegl, and R. Greil
Transendothelial Migration of Myeloma Cells Is Increased by Tumor Necrosis Factor (TNF)-{alpha} via TNF Receptor 2 and Autocrine Up-Regulation of MCP-1
Clin. Cancer Res.,
March 15, 2004;
10(6):
1901 - 1910.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Mahtouk, M. Jourdan, J. De Vos, C. Hertogh, G. Fiol, E. Jourdan, J.-F. Rossi, and B. Klein
An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti-IL-6 antibody-induced apoptosis
Blood,
March 1, 2004;
103(5):
1829 - 1837.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-Y. Huang, H.-F. Tien, F.-H. Su, and S.-M. Hsu
Nonirradiated NOD/SCID-Human Chimeric Animal Model for Primary Human Multiple Myeloma: A Potential in Vivo Culture System
Am. J. Pathol.,
February 1, 2004;
164(2):
747 - 756.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. S. Mitsiades, N. S. Mitsiades, R. T. Bronson, D. Chauhan, N. Munshi, S. P. Treon, C. A. Maxwell, L. Pilarski, T. Hideshima, R. M. Hoffman, et al.
Fluorescence Imaging of Multiple Myeloma Cells in a Clinically Relevant SCID/NOD in Vivo Model: Biologic and Clinical Implications
Cancer Res.,
October 15, 2003;
63(20):
6689 - 6696.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. C. Platanias
Map kinase signaling pathways and hematologic malignancies
Blood,
June 15, 2003;
101(12):
4667 - 4679.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. L. Bergsagel
Prognostic Factors in Multiple Myeloma: It's in the Genes
Clin. Cancer Res.,
February 1, 2003;
9(2):
533 - 534.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yaccoby, C. L. Johnson, S. C. Mahaffey, M. J. Wezeman, B. Barlogie, and J. Epstein
Antimyeloma efficacy of thalidomide in the SCID-hu model
Blood,
December 1, 2002;
100(12):
4162 - 4168.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Yang, S. Yaccoby, W. Liu, J. K. Langford, C. Y. Pumphrey, A. Theus, J. Epstein, and R. D. Sanderson
Soluble syndecan-1 promotes growth of myeloma tumors in vivo
Blood,
June 28, 2002;
100(2):
610 - 617.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-W. Peng, G. J. Ahmann, L. Pham, P. R. Greipp, R. Cattaneo, and S. J. Russell
Systemic therapy of myeloma xenografts by an attenuated measles virus
Blood,
October 1, 2001;
98(7):
2002 - 2007.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. N. Pearse, E. M. Sordillo, S. Yaccoby, B. R. Wong, D. F. Liau, N. Colman, J. Michaeli, J. Epstein, and Y. Choi
Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression
PNAS,
September 13, 2001;
(2001)
201394498.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Podar, Y.-T. Tai, F. E. Davies, S. Lentzsch, M. Sattler, T. Hideshima, B. K. Lin, D. Gupta, Y. Shima, D. Chauhan, et al.
Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration
Blood,
July 15, 2001;
98(2):
428 - 435.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Li, M. Bendandi, Y. Deng, C. Dunbar, N. Munshi, S. Jagannath, L. W. Kwak, and H. K. Lyerly
Tumor-specific recognition of human myeloma cells by idiotype-induced CD8+ T cells
Blood,
October 15, 2000;
96(8):
2828 - 2833.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Dankbar, T. Padro, R. Leo, B. Feldmann, M. Kropff, R. M. Mesters, H. Serve, W. E. Berdel, and J. Kienast
Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma
Blood,
April 15, 2000;
95(8):
2630 - 2636.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Pilarski, G. Hipperson, K. Seeberger, E. Pruski, R. W. Coupland, and A. R. Belch
Myeloma progenitors in the blood of patients with aggressive or minimal disease: engraftment and self-renewal of primary human myeloma in the bone marrow of NOD SCID mice
Blood,
February 1, 2000;
95(3):
1056 - 1065.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Singhal, J. Mehta, R. Desikan, D. Ayers, P. Roberson, P. Eddlemon, N. Munshi, E. Anaissie, C. Wilson, M. Dhodapkar, et al.
Antitumor Activity of Thalidomide in Refractory Multiple Myeloma
N. Engl. J. Med.,
November 18, 1999;
341(21):
1565 - 1571.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yaccoby and J. Epstein
The Proliferative Potential of Myeloma Plasma Cells Manifest in the SCID-hu Host
Blood,
November 15, 1999;
94(10):
3576 - 3582.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Aoki, E. S. Jaffe, Y. Chang, K. Jones, J. Teruya-Feldstein, P. S. Moore, and G. Tosato
Angiogenesis and Hematopoiesis Induced by Kaposi's Sarcoma-Associated Herpesvirus-Encoded Interleukin-6
Blood,
June 15, 1999;
93(12):
4034 - 4043.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Vacca, D. Ribatti, M. Presta, M. Minischetti, M. Iurlaro, R. Ria, A. Albini, F. Bussolino, and F. Dammacco
Bone Marrow Neovascularization, Plasma Cell Angiogenic Potential, and Matrix Metalloproteinase-2 Secretion Parallel Progression of Human Multiple Myeloma
Blood,
May 1, 1999;
93(9):
3064 - 3073.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. N. Pearse, E. M. Sordillo, S. Yaccoby, B. R. Wong, D. F. Liau, N. Colman, J. Michaeli, J. Epstein, and Y. Choi
Multiple myeloma disrupts the TRANCE/ osteoprotegerin cytokine axis to trigger bone destruction and promote tumor progression
PNAS,
September 25, 2001;
98(20):
11581 - 11586.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Abstract
Introduction
Abstract