Introduction: In multiple myeloma, there is an increase in bone marrow microvascular density and enhanced renal lymphangiogenesis. Increased levels of the proangiogenic protein growth differentiation factor-15 (GDF15) have previously been reported to be associated with poor prognosis in myeloma. A possible association between GDF15 and the soluble forms of vascular endothelial growth factor receptors (sVEGFR) 1 and 2 has not yet been investigated, and a role for these receptors in pathological angiogenesis in myeloma is still to be defined. Methods: Plasma levels of GDF15 and sVEGFR1 and 2 were determined by ELISA in patients with smouldering multiple myeloma (sMM), patients with symptomatic multiple myeloma (abbreviated as MM), and healthy controls. The levels were compared between the three groups, and correlation coefficients were calculated, as were Kaplan-Meier curves for GDF15 and sVEGFR1 and sVEGFR2. Results: Levels of GDF15 were significantly higher in MM than in both patients with sMM and controls. A gradual decrease in mean sVEGFR1 concentration was observed, with MM > sMM > controls. Mean sVEGFR2 was lower in patients with MM than in controls. There was a positive correlation between GDF15 and sVEGFR1, and GDF15 correlated negatively with sVEGFR2. High GDF15 (>3 ng/mL) was associated with poor prognosis. Conclusion: In multiple myeloma, increased expression of GDF15 correlates positively with sVEGFR1 and negatively with sVEGFR2. It is possible that the altered levels of sVEGFR1 and 2 contribute to the increased angio- and lymphangiogenesis observed in myeloma.

1.
Kazandjian
D
.
Multiple myeloma epidemiology and survival: a unique malignancy
.
Semin Oncol
.
2016
;
43
:
676
81
. .
2.
Rajkumar
SV
.
Multiple myeloma: 2020 update on diagnosis, risk-stratification and management
.
Am J Hematol
.
2020
;
95
:
548
67
. .
3.
Alexandrakis
MG
,
Passam
FJ
,
Ganotakis
E
,
Dafnis
E
,
Dambaki
C
,
Konsolas
J
,
Bone marrow microvascular density and angiogenic growth factors in multiple myeloma
.
Clin Chem Lab Med
.
2004
;
42
(
10
):
1122
6
.
4.
Zimmer
JK
,
Dahdal
S
,
Mühlfeld
C
,
Bergmann
IP
,
Gugger
M
,
Huynh-Do
U
.
Lymphangiogenesis is upregulated in kidneys of patients with multiple myeloma
.
Anat Rec
.
2010
;
293
:
1497
505
. .
5.
Apte
RS
,
Chen
DS
,
Ferrara
N
.
VEGF in signaling and disease: beyond discovery and development
.
Cell
.
2019
;
176
:
1248
64
. .
6.
Stacker
SA
,
Williams
SP
,
Karnezis
T
,
Shayan
R
,
Fox
SB
,
Achen
MG
.
Lymphangiogenesis and lymphatic vessel remodelling in cancer
.
Nat Rev Cancer
.
2014
;
14
:
159
72
. .
7.
Bowler
E
,
Oltean
S
.
Alternative splicing in angiogenesis
.
Int J Mol Sci
.
2019
;
20
(
9
):
2067
. .
8.
Kumar
S
,
Witzig
TE
,
Timm
M
,
Haug
J
,
Wellik
L
,
Fonseca
R
,
Expression of VEGF and its receptors by myeloma cells
.
Leukemia
.
2003
;
17
:
2025
31
.
9.
Corre
J
,
Hébraud
B
,
Bourin
P
.
Concise review: growth differentiation factor 15 in pathology–a clinical role?
Stem Cells Transl Med
.
2013
;
2
:
946
52
. .
10.
Ha
G
,
De Torres
F
,
Arouche
N
,
Benzoubir
N
,
Ferratge
S
,
Hatem
E
,
GDF15 secreted by senescent endothelial cells improves vascular progenitor cell functions
.
PLoS One
.
2019
;
14
(
5
):
e0216602
.
11.
Westhrin
M
,
Moen
SH
,
Holien
T
,
Kærsgaard Mylin
A
,
Heickendorff
L
,
Olsen
OE
,
Growth differentiaton factor 15 (GDF15) promotes osteoclast differentiation and inhibits osteoblast differentiation and high serum GDF15 levels are associated with multiple myeloma bone disease
.
Haematologica
.
2015
;
100
:
e511
4
.
12.
Corre
J
,
Labat
E
,
Espagnolle
N
,
Hébraud
B
,
Avet-Loiseau
H
,
Roussel
M
,
Bioactivity and prognostic significance of growth differentiation factor GDF 15 secreted by bone marrow mesenchymal stem cells in multiple myeloma
.
Cancer Res
.
2012
;
72
(
6
):
1395
406
.
13.
Song
H
,
Yin
D
,
Liu
Z
.
GDF-15 promotes angiogenesis through modulating p53/HIF-1α signaling pathway in hypoxic human umbilical vein endothelial cells
.
Mol Biol Rep
.
2012
;
39
:
4017
22
. .
14.
Rajkumar
SV
,
Dimopoulos
MA
,
Palumbo
A
,
Blade
J
,
Merlini
G
,
Mateos
M
,
International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma
.
Lancet Oncol
.
2014
;
15
:
e538
548
.
15.
Greipp
PR
,
San Miguel
J
,
Durie
BGM
,
Crowley
JJ
,
Barlogie
B
,
Bladé
J
,
International staging system for multiple myeloma
.
J Clin Oncol
.
2005
;
23
(
15
):
3412
20
.
16.
Palumbo
A
,
Avet-Loiseau
H
,
Olivia
S
,
Lokhorst
HM
,
Goldschmidt
H
,
Rosinol
L
,
Revised international staging system for multiple myeloma: a report from International Myeloma Working Group
.
J Clin Oncol
.
2015
;
33
(
26
):
2863
9
.
17.
Thulin
M
.
Modern statistics with R. Eos Chasma Press
;
2021
. ISBN 9789152701515.
18.
Tarkun
P
,
Atesoglu
EB
,
Mehtap
O
,
Muscul
MM
,
Hacihanefioglu
A
.
Serum growth differentiation factor 15 levels in newly diagnosed multiple myeloma patients
.
Acta Haematol
.
2014
;
131
:
173
8
.
19.
Botcoov
MR
,
Bauskin
AR
,
Valenzuela
SM
,
Moore
AG
,
Bansal
M
,
Yan He
X
,
MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGFβ-superfamily
.
Proc Natl Acad Sci
.
1997
;
94
:
11514
9
.
20.
Eling
TE
,
Baek
SJ
,
Shim
M
,
Ho Lee
C
.
NSAID activated gene (NAG-1), a modulator of tumorigenesis
.
J Biochem Mol Biol
.
2006
;
39
:
649
55
.
21.
Dong
G
,
Zheng
Q
,
Ma
M
,
Wu
S
,
Zhang
R
,
Yao
R
,
Angiogenesis enhanced by treatment damage to hepatocellular carcinoma through the release of GDF15
.
Cancer Med
.
2018
;
7
(
3
):
820
30
.
22.
Ambati
BK
,
Nozaki
M
,
Singh
N
,
Takeda
A
,
Jani
PD
,
Suthar
T
,
Corneal avascularity is due to soluble VEGF receptor-1
.
Nature
.
2006
;
443
(
26
):
993
7
.
23.
Kearney
JB
,
Ambler
CA
,
Monaco
KA
,
Johnson
N
,
Rapoport
RG
,
Bautch
VL
.
Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modulating endothelial cell division
.
Blood
.
2002
;
99
(
7
):
2397
407
. .
24.
Kappas
NC
,
Zeng
G
,
Chappell
JC
,
Kearney
JB
,
Hazarika
S
,
Kallianos
KG
,
The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching
.
J Cell Biol
.
2008
;
181
(
5
):
847
58
.
25.
Chappell
JC
,
Taylor
SM
,
Ferrara
N
,
Bautch
VL
.
Local guidance of emerging vessel sprouts requires soluble Flt-1 (VEGFR-1)
.
Dev Cell
.
2009
;
17
(
3
):
377
86
.
26.
Huh
SJ
,
Chung
CY
,
Sharma
A
,
Robertson
GP
.
Macrophage inhibitory Cytokine-1 regulates melanoma vascular development
.
Am J Pathol
.
2010
;
176
(
6
):
2948
57
. .
27.
Pavlakovic
H
,
Becker
J
,
Albuquerque
R
,
Wilting
J
,
Ambati
J
.
Soluble VEGFR-2: an anti-lymphangiogenic variant of VEGF receptors
.
Ann N Y Acad Sci
.
2010
;
1207
(
Suppl 1
):
E7
15
.
28.
Shibata
M
,
Ambati
J
,
Shibata
E
,
Albuquerque
R
,
Morimoto
J
,
Ito
Y
,
The endogenous soluble VEGF receptor-2 isoform suppresses lymph node metastasis in a mouse immunocompetent mammary cancer model
.
BMC Medicine
.
2010
;
8
:
69
.
29.
Becker
J
,
Pavlakovic
H
,
Ludewig
F
,
Wilting
F
,
Weich
HA
,
Albuquerque
R
,
Neuroblastoma progression correlates with downregulation of the lymphangiogenesis inhibitor sVEGFR-2
.
Clin Cancer Res
.
2010
;
16
:
1431
41
.
30.
Medinger
M
,
Halter
J
,
Heim
D
,
Buser
A
,
Gerull
S
,
Stern
M
,
Angiogenic markers in plasma cell myeloma patients treated with novel agents
.
Anticancer Res
.
2015
;
35
:
1085
90
.
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