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Angiogenic Factors
Angiogenic Factors
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Angiogenic factors and chronic lymphocytic leukaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1. VEGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2. bFGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3. PDGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4. Leptin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5. G-CSF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6. Follistatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7. Ang1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8. ANG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.9. MK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.10. PTN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.11. PGRN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.12. PLF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.13. Angiogenic factors and macrophages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.13.1. PlGF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.13.2. Del-1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Authorship and responsibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Abstract
The role of angiogenesis in haematological malignancies such as chronic lymphocytic leukaemia (CLL) is difficult to envision, because
leukaemia cells are not dependent on a network of blood vessels to support basic physiological requirements. Regardless, CLL cells secrete
Corresponding author: Department I of Internal Medicine, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Tel.: +49 221 478 97626;
fax: +49 221 478 97627.
E-mail addresses: luis.aguirre-palma @uk-koeln.de (L.M. Aguirre Palma), Iris.Gehrke@cancercare.mb.ca (I. Gehrke), karl-anton.kreuzer@uni-koeln.de
(K.-A. Kreuzer).
1 Department I of Internal Medicine, University of Cologne, Kerpener Strasse 62, 50937 Cologne, Germany. Tel.: +49 221 478 97384;
fax: +49 221 478 97383.
2 Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, 675 McDermot, Canada MB R3E 0T3. Tel.+1 204 787 8776.
http://dx.doi.org/10.1016/j.critrevonc.2014.10.007
1040-8428/ 2014 Elsevier Ireland Ltd. All rights reserved.
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high levels of major angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and
platelet derived growth factor (PDGF). Nonetheless, it remains unclear how most angiogenic factors regulate accumulation and delayed
apoptosis of CLL cells. Angiogenic factors such as leptin, granulocyte colony-stimulating factor (G-CSF), follistatin, angiopoietin-1
(Ang1), angiogenin (ANG), midkine (MK), pleiotrophin (PTN), progranulin (PGRN), proliferin (PLF), placental growth factor (PIGF),
and endothelial locus-1 (Del-1), represent novel therapeutic targets of future CLL research but have remained widely overlooked. This review
aims to outline our current understanding of angiogenic growth factors and their relationship with CLL, a still uncured haematopoietic
malignancy.
2014 Elsevier Ireland Ltd. All rights reserved.
Keywords: Angiogenesis; Angiogenic factors; Microenvironment; Chronic lymphocytic leukaemia (CLL); Pathological angiogenesis
1. Introduction
Angiogenesis, the development of new blood vessels,
is highly active during embryogenesis and development,
but in adult life only occurs during wound healing, menstrual cycles [1], and in heart and skeletal muscles from
strenuous exercise [2]. The complexity of angiogenesis is
illustrated by the interplay between a plethora of molecular and cellular elements, all of which regulate the
microenvironmental stability. In the bone marrow (BM)
microenvironment, T-cells, B-cells, osteocytes, stromal cells,
adipocytes, white blood cells, fibroblasts, and endothelial
cells (EC) live in an angiogenically-balanced microenvironment (Fig. 1a). This angiogenic balance is dependent on
the efficient molecular communication mediated by angiogenic factors (i.e. pro-angiogenic or angiogenic growth
factors), angiogenic inhibitors (i.e. anti-angiogenic factors),
cytokines, chemokines and accessory proteins, all of which
act in combinatorial manner to achieve optimal cellular
behaviour and tissue stability. Nevertheless, the aberrant
expression of the above-mentioned groups of molecules disturbs the angiogenic balance of organisms, turning on
the so-called angiogenic switch inducing pathological
angiogenesis.
Besides a molecular imbalance of factors, a persistent
and aberrant proliferation of EC is the outmost characteristic attributed to pathological angiogenesis. In addition to
sustaining uncontrolled growth and proliferation of solid neoplasms, pathological angiogenesis also supports leukaemia
[1]. Similarly to cells comprising solid neoplasms, malignant haematopoietic cells excessively secrete angiogenic
factors, among many other molecules, to the extra cellular
space, or better known as the microenvironment, to support
growth and proliferation [3]. In the case of CLL, angiogenesis is a permanent and dynamic subject of study in its
infancy.
CLL is a prevalent and incurable haematological malignancy among the adult population in Western societies [4]. It
is characterized by the clonal expansion of malignant CD5+
B-lymphocytes and because these fail to undergo timely apoptosis, they excessively accumulate in peripheral blood (PB),
BM (Fig. 1b), and LN. The overexpression and exorbitant
secretion of angiogenic factors disrupts the angiogenically
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Fig. 1. Comparison of the BM and PB microenvironment between a healthy and CLL state. In the BM of healthy individuals (a), there is a balance
between angiogenic growth factors and inhibitors. B-lymphocytes numbers remain low and the ECL remains quiescent. The bone marrow environment is a rich
cellular entity hosting adipocytes, fibroblasts, stromal cells, osteocytes, endothelial cells, basophils, and white blood cells including B- and T- lymphocytes. In
CLL patients (b), malignant B-cells accumulate disproportionately in BM and PB and the excessive secretion of angiogenic factors could in return compromise
the ECL, allowing the infiltration of CLL lymphocytes. Platelets were omitted from this model. ECL, endothelial cell layer; PB, peripheral blood; BM, bone
marrow.
on CLL cells showed the efficiency of this monoclonal antibody in inducing apoptosis of leukaemia cells [13]. Whilst
many studies highlight the importance of VEGF as target
of research in CLL angiogenesis [7,11,1317], we are still
refining our understanding of the VEGF family in the CLL
context.
After detecting the expression of VEGF in CLL cells
[18], researchers observed a correlation between serum levels
of VEGF, risk of disease progression, and progression free
survival (PFS) [19]. The sensitivity of CLL cells to VEGF
ligands is illustrated by their expression of the three VEGF
receptors [14]. Two co-receptors of VEGFR-1 and VEGFR-2,
neuropilin-1 and -2 (NRP1/2) [20], regulate angiogenesis, tumour development, and immunological responses [7].
Recently Piechnik et al. reported higher NRP1 expression
on leukemic lymphocytes when compared to healthy Blymphocytes in a cohort that included 114 CLL patients
[7]. Furthermore, they detected an increase in NRP1 expression upon VEGF stimulation. In addition, regulatory T cells
(Tregs) and plasmacytoid dendritic cells (PDCs), essential
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Table 1
Roles associated with angiogenic factors and the pathways/factors they regulate.
VEGF
bFGF
PDGF
Leptin
G-CSF
Follistatin
Ang1
ANG
MK
PTN
PGRN
PLF
PIGF
Del-1
Associated roles
Downstream targets
Abbreviations: ABIN-2, A20-binding inhibitor of NFB-2; ANG, angiogenin; Ang1, angiopoietin 1; Ang2, angiopoietin 2; bFGF, basic fibroblast growth factor;
c SRC, proto-oncogene tyrosine-protein kinase Src; Del-1, developmental endothelial locus-1; Dok-R, dock protein-R; ERK1/2, extracellular signal-regulated
kinase 1/2; FAK, focal adhesion kinase; FLRG, follistatin related gene; G-CSF, growth colony-stimulating factor; HPSC, hematopoietic stem/progenitor cells;
JAK, Jak2 tyrosine kinase; JAK-STAT, Janus kinase- signal transducer and activator of transcription; MAPK, mitogen activated protein kinase; MAPK/ERK,
mitogen-activated protein kinases/extracellular signal-regulated kinase; MK, midkine; NF-B, nuclear factor kappa-light-chain-enhancer of activated B cells;
p38, a mitogen-activated protein kinase pathway; PC1, phospholipase C gamma-protein; PDGF, platelet-derived growth factor; PDGF-B, platelet-derived
growth factor-B; PGRN, progranulin; PI3K-AKT, Phosphatidylinositide 3-kinase-AKT; PIGF, placental derived growth factor; PKB-AKT, protein kinase B/AKT
pathway; PLF, Proliferin; FGF, fibroblast growth factor; PTN, pleiotrophin; RAS-MAPK, RAS-mitogen-activated protein kinase; STAT, signal transducers and
activators of transcription; VEGF, Vascular endothelial factor growth factor; SAPK-JNK, stress-activated protein kinase/Jun-amino-terminal kinase.
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2.8. ANG
Angiogenin (ANG) is a powerful angiogenic factor
produced by neoplastic cells and cells from the cancer microenvironment [68]. The increased levels of ANG
in malignancies is associated with tumour initiation and
development [69]. Acute myeloid leukaemia (AML) and
myelodysplastic syndrome (MS), and a variety of other
malignancies display ANG upregulation [70]. This upregulation also correlates to poor prognosis in patients of myeloid
leukaemia and myelodysplastic syndromes [68].
Evidence linking CLL and ANG comes from a study
including 77 CLL cases of untreated patients on Binet stage
A [71]. In spite of reporting only a minor difference of ANG
levels, the 5-year progression-free survival was 85% for
patients with ANG above the median (300 ng/ml), against
51.5% for those with values lower than the median when taking into consideration the cut-off ANG concentration [71].
Additionally, the levels of ANG could be integrated into Rai
substages [71]. Previously, Pavlov et al. suggested ANG as
a possible prognostic marker and potential target of antiangiogenic therapy [72]. Notably, ANG is capable of directly
binding follistatin without the help of interacting pattern,
not even activin a, suggesting a follistatin/ANG synergy
[73]. Concomitantly with bFGF and VEGF downregulation
is overexpression of ANG and Ang2 in CLL upon lenalidomide administration [29]. Possibly ANG actively interacts
with Ang2, bFGF, VEGF, and follistatin to regulate survival
and quiescent in the cancer microenvironment.
2.9. MK
Upregulation of MK correlates with poor prognosis in
neuroblastomas, astrocytomas, pancreatic head carcinomas,
gastrointestinal stromal tumours, and blood malignancies
[7476]. This factor has been remarkably associated with
unregulated cell growth [75]. CLL patients present an
elevated level of MK secretion as detected by serum measurements [74]. A similar expression pattern of MK expression
is observed in other haematopoietic malignancies [77]. The
singularity of MK resides in its ability to activate a mechanism that regulates survival and homeostasis of peripheral
mature B-cells and CLL cells [74].
MK triggers angiogenesis by binding to receptor protein
tyrosine phosphatase zeta (RPTP), inducing Bcl-2 expression and inhibiting caspase-3/-7 [76] without compromising
caspase-8 activity [78]. Interaction of MK and the receptor RPTP modulate signal transduction events that lead to
survival advantage [74]. Blocking the interaction between
MK and RPTP results in CLLs apoptosis and inhibition of
MIF/CD74 signal transduction [74]. Due to its proapoptotic
effect on CLL cells, MK appears as a potential therapeutic
development, however, even when efficient, blocking of the
RPTP is not complete [74]. MK is a novel angiogenic factor and further studies will provide an integral understanding
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2.13.1. PlGF
PlGF is secreted as a glycosylated homodimer that
stimulates angiogenesis by binding to VEGFR1 [2].
Outstandingly, PlGF recruits and activates macrophages indirectly through VEGFR1 signalling [93]. Blocking PIGF
inhibits macrophage recruitment, preventing initiation of
the angiogenic rescue program [96]. In addition, PIGF
expression is associated with inflammation processes that
accompany pathological angiogenesis [2]. As well, PIGF
strongly supports tumour burden and EC proliferation [97].
Remarkably, carcinoma-associated fibroblasts are strong
secretors of PIGF [97]. Utilization of monoclonal antibodies against PIGF showed an evident effect against tumour
development in human tumour xenographs [98]. Interestingly, employing PIGF siRNA induces a reduction of NRP1
expression, yet no changes in VEGF and VEGFR-1 are
detected [97]. Possibly PIGF and NRP1 synergize to confer stronger prosurvival signal and probably to regulate ECs
in the CLL microenvironment. Even if CLL themselves
do not express PIGF, NRP1 could be regulated by externally secreted PIGF in a paracrine fashion. Besides, PIGF
present in the CLL microenvironment is likely to regulate the
macrophage population and therefore the CLL-macrophage
interaction.
2.13.2. Del-1
Del-1 is essential during embryogenesis and the gene is
silenced in adult life [99]. Tumours expressing Del-1 show
an increased capillary density and accelerated growth rate
in vivo [100]. Del-1 is capable of increasing the number
of blood vessels and inducing proliferation of ECs [101].
Interestingly, Del-1 is secreted by activated macrophages
and recognizes phosphatidylserine, a phospholipid detected
on the outer cellular membrane of apoptotic cells [92].
Expression of Del-1 is detected in macrophages populating
the BM, indicating a tight control of the microenvironment [92]. The increased microvessel density observed in
BM sections [5,102] could possibly be linked to abnormal expression of Del-1 in the CLL microenvironment.
Nevertheless, the expression patterns of Del-1 in CLL
microenvironments and the effect on CLL cell apoptosis must
be elucidated.
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3. Conclusion
The prominent functions of angiogenic factors reside in
their ability to regulate cell proliferation, migration, survival,
tumour genesis, and tissue repair (Table 1).
It is plausible to believe that high levels of angiogenic factors secreted by CLL cells and surrounding accessory cells
compromise the stability of the ECL. This would facilitate
CLL cell infiltration and trafficking to and from the microenvironmental niche. Notably, Cinamon et al. argued that apical
chemokines on vessel endothelia attract lymphocytes, allowing their migration through ECL by a process denominated
transendothelial migration (TEM) [103]. If CLL cells are
capable of undergoing TEM, they may transiently undergo
co-option before reaching their niches. Co-option is the process in which, without inducing development of new blood
vessels, tumour cells profit from close proximity to blood
capillaries [104]. Upon compromising the ECL, CLL cells
could undergo TEM, remaining transiently and closely associated with the ECL whilst profiting from co-option (Fig. 2).
By further secreting angiogenic factors, or by interacting
with those available at their surroundings ECL, it is possible to infer that CLL cells modulate their surroundings, thus
facilitating their transport, proliferation, and evasion from
apoptosis and treatment.
Whilst VEGF, bFGF, and PDGF are among the most relevant angiogenic factors in CLL, others such as leptin, G-CSF,
follistatin, Ang1, ANG, MK, PTN, and PGRN are emerging novel factors that regulate angiogenic related process
that determine the fate of CLL molecular physiology. The
nature of PLF, Del-1, and PIGF on CLL pathophysiology is
not understood, but further studies will clarify the extent in
which they modulate survival, proliferation and escape from
apoptosis.
Certainly, the integral molecular understanding of molecular communication between angiogenic factors and their
influence on CLL pathophysiology will help develop effective treatments against CLL. Only then will we be able
to develop drugs that exclusively and only modulate the
Reviewers
Prof Eric Eldering: Meibergdreef 9, Amsterdam, The
Netherlands.
Prof Krzysztof Giannopoulos: Medical University of
Lublin, Chodzki 4a, Lublin, Poland.
Acknowledgements
We are deeply grateful to Mr. Kearnan Welch, MS (Touro
University California), for his critical comments on this
manuscript. This work was kindly supported by a grant (No.
2011.101.02) from the Wilhelm Sander-Foundation, Munich,
Germany.
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Biography
Karl-Anton Kreuzer studied medicine at the University
of Bonn and the Technical University of Munich, as well as in
Pittsburgh, PA, USA, and Zurich, Switzerland. He furthered
his scientific training at the Wistar Institute in Philadelphia,
PA, USA and the Weizmann Institute of Science in Rehovot,
Israel. Under the supervision of Prof. Dr. Dieter Huhn he
underwent his residency at the Rudolf Virchow University
Clinic of Charit, Berlin. Since 2004 he focuses in haematology, oncology, internal medicine research, and diagnostics at
the Department of Internal Medicine I at University Clinic of
Cologne. In addition, Prof. Kreuzer is one of the directors of
the Interdisciplinary Oncology Project of Acute Leukaemia
and Myelodysplastic Syndromes of the Centre for Integral
Oncology of Cologne-Bonn (CIO). Currently he directs the
Laboratory of Molecular Haematology and Oncology at the
Clinic of the University of Cologne, a laboratory focused on
haematological diagnostics comprising cytogenetics, molecular genetics, flow cytometry, morphology, and a research
facility focusing on understanding angiogenesis and cellular
stress in chronic lymphocytic leukaemia (CLL). As member of several internationally renowned medical societies,
Prof. Kreuzer serves as consultant to international research
institutions and is author and co-author of multiple publications in the fields of haematology, oncology, and internal
medicine.