Blood, Vol. 94 No. 11 (December 1), 1999:
pp. 3653-3657
The Insulin-Like Growth Factor System in Normal and Malignant
Hematopoietic Cells
By
Walter Zumkeller and
Stefan Burdach
From the Department of Hematology/Oncology, Children's Hospital
Medical Center and BioCenter, Martin-Luther-University,
Halle-Wittenberg, Halle, Germany.
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INTRODUCTION |
PROLIFERATION OF hematopoietic cells is
controlled by a coordinated hierarchy of growth factors and their
inhibitors. These growth factors form complex signaling networks either
by stimulating or inhibiting cell proliferation and differentiation. They govern all growth stages of blood cells that emerge from a small
common pool of ancestral stem cells. In addition, biologic effects are
altered by the interaction of different growth factors, which adds
another magnitude of complexity. Insulin-like growth factors
(IGFs) are part of a number of growth factors and
cytokines responsible of burst-like growth of early erythroid
progenitor cells in vitro and may play a role in the ontogeny of marrow
development. IGFs may not be considered as classical hematopoietic
growth factors, but nonetheless their involvement in abberant
hematopoietic growth regulation is intriguing. The complexity of the
IGF system should be a challenge for conducting more research on this
topic rather than a hurdle. This review aims to unravel the biological
significance of IGFs in normal and malignant hematopoiesis as well as
to stimulate further research in this rapidly expanding field.
IGFs constitute a family of peptides capable of stimulating various
cellular responses, including cell proliferation and
differentiation.1 Both IGF-I and -II are mitogenic factors
that are secreted by malignant cells as well.2 A steadily
increasing number of IGF-binding proteins (IGFBP-1 to -6) and
IGFBP-related proteins (IGFBP-rP1 to 4) are part of the IGF system.
These IGFBPs either enhance or inhibit the IGF-mediated effects. The
IGFBP-related proteins (IGFBP-rPs) are newly described factors that
appear to be implicated in tumorigenesis.3 The type I
(IGF-I-R) and type II (IGF-II-R) IGF receptor bind IGFs and mediate
their effects (Figs 1, 2, and 3). IGF-I-R is of particular interest because of its
antiapoptotic role,4 and novel anticancer therapies may be
designed aiming at this receptor.5
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| Fig 1.
Schematic representation of the insulin-like growth
factor axis: IGFs, IGFBPs, and IGF receptors.
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| Fig 2.
Signal pathway of receptor-activated tyrosine kinase
receptors. Cytokines, growth factors, and insulin activate
receptor-linked tyrosine kinases that induce receptor
autophosphorylation. The GRB2 and son of sevenless (SOS) guanine
nucleotide-releasing protein is recruited to the plasma membrane. SOS
activates raf kinase, which initiates a phosphorylation cascade
resulting in effects on metabolism and growth.
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IGFs are also of importance for blood formation.6 They
stimulate both myeloid and lymphoid cells in culture.7,8
Since epidemiologic studies have indicated that high birthweight is associated with an increased risk of infant leukemia,9 it
has been postulated that IGF-I may both produce a larger baby and contribute toward leukemogenesis.10
| |
INSULIN-LIKE GROWTH FACTORS |
IGF-I and -II stimulate erythroid and myeloid
progenitors.11-13 IGF-I induces granulopoiesis in human
bone marrow culture granulocyte-monocyte colony-forming units (GM-CFU),
and the effect is inhibited by monoclonal antibodies against the type I
IGF receptor.14 IGF-II promotes GM colony formation of both
normal and leukemic hematopoietic cells in vitro15 and was
shown to function as a B-cell growth-promoting factor.16
Bone marrow cells enriched for CD34+ cells and placed in
liquid cultures supplemented with interleukin-3 (IL-3) and IGF-II
showed an enhanced proliferation of granulocytes, macrophages, and
erythroid cells.8 Infusion of human recombinant IGF-I
stimulated erythropoiesis in hypophysectomized rats, evidenced by iron
incorporation into red blood cells and an increase in reticulocyte
numbers.11 Erythroid colony-forming cells stimulated with
IGF-I, in addition to erythropoietin, showed an enhanced heme
synthesis, cellular proliferation, and greatly enhanced nuclear condensation as well as enucleation in late
erythroblasts.17 CD4+ T cells and splenic B
cells increased in mice treated with IGF-I, indicating its likely role
in augmenting the immune response.18,19 Both IGF-I and
IGF-II were found to enhance T-cell proliferation 3-fold in the early
activation process.7
Circulating erythroid progenitors in polycythemia vera (PV) are
hypersensitive to IGF-I with respect to erythroid burst formation in
serum-free medium and independent of erythropoietin.20 In peripheral blood mononuclear cells from PV patients, an increased basal
tyrosine phosphorylation of the IGF-I receptor 
-subunit and a
hypersensitive receptor with respect to tyrosine phosphorylation was
found.21 Elevated levels of IGFBP-1 were found in
these patients and the effect of IGFBP-1 in the presence of IGF-I
stimulated erythroid burst formation.22 Thus, these data
indicate that IGFs are implicated in the pathogenesis of polycythemia vera.
Both insulin and IGF-I induce proliferation of the promyelocytic
leukemia HL-60 cells in a dose-dependent manner.23-25 Both serum anti-IGF-I25 and antibodies directed against the
type I IGF receptor23 abrogates the growth-promoting effect
of IGF-I. IGF-I stimulates thymidine incorporation in K562
erythroleukemia cells26 and increases bone marrow blast
colony numbers in patients with acute myeloid leukemia.27
Murine ELM erythroleukemia cells underwent clonal
extinction when serially cloned in IGF-I and became IGF-I-independent
during long-term growth in IGF-I.28 IGF-I and IGF-II
increase cell proliferation of AML-193 cells 4-fold and 2-fold,
respectively. A synergistic effect of IGFs and GM colony-stimulating
factor (GM-CSF) has been found in these cells.29 Casein
kinase II, a key enzyme involved in the regulation of cell growth, is
activated in human myeloblastic leukemia cell line ML-1 only when
exposed to both IGF-I and transferrin.30 IGF-I and
transferrin stimulate the expression of the c-myb and c-ets-1
proto-oncogenes which, as transcription factors, are involved in the
regulation of cell proliferation and differentiation.31
Genomic imprinting is a non-Mendelian form of gene regulation resulting
in differential allelic gene expression that plays a pivotal role in
the transcriptional repression of developmental genes associated with
normal growth. Relaxation of IGF-II genomic imprinting occurs in many
different tumors and may represent a novel epigenetic mechanism.
Loss of imprinting (LOI) of IGF-II was found in all 12 informative samples from acute myeloid leukemia (AML)
patients, whereas both blood from normal individuals and 3 types of
hematopoietic progenitor cells showed monoallelic expression. The fact
that LOI of IGF-II was present in the earliest stage of disease (ie,
myelodysplastic syndrome) and did not correlate with
French-American-British (FAB) classification implies that LOI of IGF-II
are both early and general epigenetic events in leukemogenesis.32 The significance of LOI of IGF-II lies in the upregulation of this autocrine growth factor during the development of leukemia.
Recently, loss of imprinting of the IGF-II gene has been found to be
associated with disease progression in chronic myelogenous leukemia
(CML). Whereas the importance of the Philadelphia chromosome translocation in CML has been recognized nearly 2 decades ago, factors
that cause progression to blast crisis at a molecular level remain
largely to be identified. LOI of IGF-II in accelerated phase and blast
crisis but not in stable CML indicate a novel type of genetic
alteration in CML related to disease progression and, thus, adverse
prognosis.33 Abnormal DNA methylation at other loci such as
calcitonin has been described in CML progression.34 Furthermore, aberrant methylation has recently been shown in the major
breakpoint cluster region (M-bcr) in CML where most Philadelphia chromosome breakpoints are located.35 Thus, the imbalance
in DNA methylation may play a role in the progression of genetic instability characteristic for the advancing stages of CML.
IGF-I was found to increase the blast colony numbers in bone
marrow of B-cell acute lymphoblastic leukemia (ALL)
patients.27 However, neither a proliferative response nor
clonal growth was induced by IGF-I in B-cell precursor
ALL.36 Leukemic cells from patients with B-ALL do not
require IGF-I for proliferation, which does not rule out the
acquisition of an autocrine secretion.37 A possible role of
IGF-I in etiology of bovine leukemia virus (BLV) infection and
progression has also been suggested.38 Diet reduction
appears to modulate mononuclear cell leukemia progression in Fischer
rats via suppression of the GH:IGF-I axis and enhancement of host
defences against tumor cells.39
Apoptosis or programmed cell death is a physiological process that
eliminates damaged cells. Both anti-apoptotic proteins (Bcl-2, Bcl-xL
and Bcl-w) and pro-apoptotic proteins (Bax, Bad, and Bcl-xS) are
involved in the control of apoptosis. IGF-I was identified as an
essential factor for R-Ras-induced suppression of cell death in the
BaF3 pro-B cell line.40 IGF-I activated the extracellular
signal-regulated kinase (ERK) and R-Ras and IGF-I cooperatively induced
Bcl-xL expression in this cell line.41 The combination of
IGF-I and IL-7 stimulates proliferation of pro-B cells42
and cell survival may be a result of R-Ras activation by these factors.
IGF-I stimulates the proliferation of T-cell lymphoma lines that have
phenotypic characteristics of thymic pre-T cells and may inhibit cell
differentiation, which could be of importance in early lymphoma
tumorigenesis.43 The in vitro proliferation of the murine
lymphoid T-cell leukemia LB cells was enhanced by insulin but not IGF-I
or IGF-II.44
Recombinant IGF-I stimulated the expression of immunoglobulin µ-heavy
chain genes and potentiated the proliferative stimulus provided by
IL-7, indicating a pivotal role for IGF-I in regulating primary B
lymphopoiesis.45 Responsiveness to insulin and IGF-I was
found to be less developed in 3 Epstein-Barr virus (EBV)-immortalized B-lymphoblastoid cell lines, in the Burkett lymphoma cell line Ramos,
and in the non-EBV lymphoblastoid cell line HS Sultan as compared with
human multiple myeloma cell lines.46 IGF-I causes a
significant increase in proliferation of Burkitt's lymphoma cells,
which could be blocked by antiserum against IGF-I.25
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IGF RECEPTORS |
Specific receptors for IGFs are detectable on human
erythrocytes47 as well as monocytes, B lymphocytes, and a
marginal number of T lymphocytes.48 IGF-II exerts its
effects on developmental regulation of human marrow erythroid
progenitors via pathways involving the IGF-I-R.42 Type I
and II IGF receptors are expressed on resting human T cells and are
increased on activated T cells.49 It was found that
expression of the type I IGF receptor after activation is skewed
between CD4+ and CD8+ T-cell
subpopulations.7 Relatively high numbers of the type I IGF
receptor were found on monocytes, natural killer cells, and
CD4+ T-helper cells.50 Jurkat T cells possess
specific IGF-I-R and IGF-I induces phosphorylation of tyrosine kinase,
which supports the notion that this receptor is involved in the
induction of T-cell activation.51
Type I IGF receptors were found on the human promyelocytic leukemia
cell line HL-60 and their number decreases while differentiating to
macrophage-like cells.52 The treatment of the
erythropoietin (EPO)-dependent cell line, F-36P, with a combination of
EPO and IGF-I enhanced EPO-induced tyrosine phosphorylation of STAT5
and mRNA expression of c-CIS, which is a target molecule of STAT5. It
was therefore concluded that IGF-I may augment EPO-induced proliferation by enhancing tyrosine phosphorylation of STAT5 and that
Ras may be involved in this process.53 It was suggested that IGF-I-R is either not expressed or expressed at low levels on
normal hematopoietic progenitor cells but was easily detectable in more
differentiated cells derived from day 6 burst-forming unit-erythroid
(BFU-E) and CFU-GM colonies.54 IGF-I-R are
present on K562 erythroleukemia cells and IGF-I binding sites decrease in the course of differentiation.26 A novel human ryk
tyrosine kinase cDNA originally identified as a polymerase chain
reaction (PCR)-amplified cDNA fragment in K 562 cells55 was
shown to possess homology to the IGF-I-R tyrosine kinase.56
Receptors for insulin, IGF-I, and IGF-II are present on T- and
B-lymphoblasts.57 Several T-cell lines infected with human T-lymphotropic virus (HTLV)-I and -II showed significantly higher type
I IGF receptor mRNA transcripts as compared with uninfected cells,
suggesting that deregulation of this receptor contributes toward
proliferation and transformation in HTLV-I and -II infected cell
lines.58 High numbers of type I IGF receptors (IGF-I-R) were found in immature (stage I) as well as pre-B ALL cell lines, and
cross-linking revealed IGF-I-R 
-subunits of 135 and 116 kD in the
HSB2 T-ALL cell line.59 The IGF-I-R appears to mediate the
IGF-I effect in early differentiated T-cell lines HSB2 and HUT78 as
well as the B-cell line REH, whereas both the IGF-I-R and IGF-II-R seem
to be involved in the proliferation of the differentiated T-ALL Jurkat
and JMP cell lines.60 The presence of EBV in Burkitt's lymphoma cells causes a reduction of the IGF-I-R number but an increase
of insulin receptors in these cells.61
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IGF-BINDING PROTEINS |
Malignant cells synthesize IGF-binding proteins and these peptides have
been found to be useful tumor markers.1 Human leukemic B
lymphoblasts synthesize IGFBP-2 and -4 but not IGFBP-1 and
-3.62 High amounts of IGFBP-2 as determined by
radioimmunoassay were detectable in culture supernatant of T-cell lines
and promyelocytic HL-60 cells, whereas normal B cells secreted only
small amounts of IGFBP-2.63 The addition of IGF-II, and to
a lesser extent IGF-I, to leukemic T cells increased IGFBP-2 secretion
significantly.64 Thus, IGFBPs may modulate the biology of
leukemic cells conferring either a growth-enhancing or
growth-inhibitory effect upon them.
In children with leukemia and non-Hodgkin's lymphoma (NHL), serum
concentrations of IGF-I, IGF-II, and IGFBP-3 were significantly decreased whereas IGFBP-2 levels were elevated.65 After
hematological remission, all 4 parameters had normalized, which is a
further indication that IGFBP-2 levels may directly relate to the
proliferation of lymphoblasts.66 Thus, IGFBP analysis could
be of relevance for the surveillance of remission and/or early
diagnosis of disease relapse.
In conclusion, future research should therefore provide us with a more
profound insight into the role of IGFs for the proliferation and
differentiation of hematological malignancies. Above all, novel
therapeutic approaches that target the IGF system may be designed,
which should improve the outcome of malignant hematological disease.
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FOOTNOTES |
Submitted March 11, 1999; accepted July 28, 1999.
Supported by Grants Bu 10-0361 from the Deutsche Krebshilfe, BioRegio
0311661 TP5 and TP10 from the Bundesministerium für Bildung und
Forschung, and the Elterninitiative Kinderkrebsklinik e.V.
Address reprint requests to Walter Zumkeller, MD,
Department of Hematology/Oncology, Martin-Luther-University
Halle-Wittenberg, Children's Hospital Medical Center, 06097 Halle,
Germany; e-mail: walter.zumkeller{at}medizin.uni-halle.de.
| |
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TOP
INTRODUCTION
INSULIN-LIKE GROWTH FACTORS
