ujms109_3.pdf


Upsala J Med Sci 109: 165–178, 2004

Development and possible clinical use of antagonists for
PDGF and TGF-�

Carl-Henrik Heldin

Ludwig Institute for Cancer Research, Box 595, Biomedical Center, S-751 24 Uppsala, Sweden

ABSTRACT

A free full-text copy of this article can be found at the web page of Upsala J Med Sci: 
http://www.ujms.se

Platelet-derived growth factor (PDGF) and transforming growth factor-� (TGF-�)
are examples of signaling molecules which control the growth, survival motility and
differentiation of cells. PDGF stimulates the growth mainly of connective tissue
cells, whereas TGF-� inhibits the growth of most cell types. PDGF and TGF-� exert
their cellular effects by vinding to receptors equipped with tyrosine and serine/thre-
onine kinase activities, respectively. Both factors have important roles e.g. during
the embryonal development and in wound healing.

Overactivity of PDGF or PDGF receptors contributes to the development of cer-
tain diseases characterized by excessive cell growth including fibrotic disorders,
atherosclerosis and malignancies. Overactivity of TGF-� also contributes to fibrotic
conditions, since TGF-� promotes accumulation of extracellular matrix molecules.
In cancer, TGF-� is initially a tumor suppressor due to its ability to inhibit cell
growth, however, at later stages of tumor progression TGF-� has tumor promoting
activity by enhancing the invasive properties of tumor cells and by suppressing the
immune system and promoting angiogenesis.

The involvement of PDGF in TGF-� in serious diseases makes clinically useful
antagonists highly desirable. A low molecular weight receptor kinase inhibitor of
the PDGF receptor kinase is now tested clinically, and TGF-� antagonists are under
development. The present review discusses the development and possible clinical
use of antagonsts for PDGF and TGF-�.

INTRODUCTION

The growth, survival, motility and differentiation of cells are regulated in part by
signals the cell receives from its environment. Such signals are important, e.g. dur-
ing embryonal development, wound healing, hematopoiesis and during the immune

165

Received 18 March 2004
Accepted 25 March 2004



response, and may come from interactions with other cells or the extracellular
matrix, or from stimulation by specific soluble growth regulatory factors.

Accumulating evidence suggest that the lack of growth control of tumor cells is due
to constitutive activation of components, which in the normal cell is controlled by
growth stimulatory factors, or by loss of functional activity of components in growth
inhibitory pathways. Modulation of signaling pathways involved in cell growth and
survival is therefore an interesting strategy to explore in the treatment of cancer.

The present review focuses on two important growth regulatory factors, i.e.
platelet-derived growth factor (PDGF), a major mitogen for connective tissue cells,
and transforming growth factor-� (TGF-�), which inhibits the growth of most cell
types. The possibility to use knowledge about the signaling mechanisms of these
factors in the development of drugs for the treatment of patients with cancer or oth-
er diseases, will be discussed.

PLATELET-DERIVED GROWTH FACTOR

Mechanism of action of PDGF

PDGF is a family of disulfide-bonded dimers of structurally similar polypeptide
chains, which occur as homodimers (PDGF-AA, -BB, -CC and -DD) or as a het-
erodimer (PDGF-AB) (reviewed in 1). The PDGF isoforms exert their cellular
effects by binding to structurally similar �- and �-tyrosine kinase receptors. Ligand
binding induces receptor dimerization which is a key event in the activation of the
receptors. Since the A-, B- and C-chains of PDGF bind to the �-receptor, whereas
the B- and D-chains bind to the �-receptor, different types of homo- and het-
erodimeric receptor complexes can be formed depending of the stimulating PDGF
isoform and depending on which of the receptors the target cell expresses (Fig. 1).

Ligand-induced receptor dimerization brings the intracellular parts of the receptors
close to each other, so that the kinase domain of one receptor can phosphorylate spe-
cific tyrosine residues in the other, and vice versa. The autophosphorylation serves
two important functions; phosphorylation of the activation loop of the kinase domain
enhances the kinase activity, and phosphorylation of tyrosine residues outside the
kinase domain creates specific docking sites for SH2-domain-containing signaling
molecules. About 10 different types of SH2-domain-containing proteins bind to the
PDGF receptors. The specificity in binding is determined by the amino acid residues
downstream of the phosphorylated tyrosine. The docking of the signaling molecules
activates a cascade of signaling pathways, which ultimately leads to initiation of
DNA synthesis and cell division, survival and migration (reviewed in 2).

Among the signaling pathways activated after PDGF stimulation of cells, phos-
phatidylinositol-3’-kinase (PI3-kinase) and phospholipase-C� (PLC�) are particu-
larly important for the motility effects of PDGF, and, in the case of PI3-kinase, for
the survival effect. Important mediators of the mitogenic effect of PDGF are Ras,
which is activated by the docking of the adapter Grb2 in complex with the exchange
factor Sos1 to the receptor and which activates the Erk MAP kinase pathway, and

166



Src, which induces the transcription factor c-Myc. It should be emphasized, howev-
er, that intracellular signaling occurs in a network of signaling components, with
extensive interactions between different signaling pathways.

In vivo function of PDGF

PDGF has important functions during the embryonal development. The ligand is
often produced by specific epithelial cells, and act on neighboring connective tissue
cells by paracrine stimulation. The specific functions of individual PDGF isoforms
and receptors have been elucidated by knock-out studies in the mouse. Thus, inacti-
vation of the genes for the PDGF B-chain (3) or the �-receptor (4), leads to severe
defects in the development of the kidneys due to a complete lack of mesangial cells.
Also blood vessel development is defect leading to bleedings at the time of birth,
which often is the direct cause of death; the reason is that in the absence of PDGF-B
or PDGF �-receptor, the vascular smooth muscle cells and pericytes do not develop
normally (5).

Knock-out of the A-chain leads to death of the mice at around the age of 3 weeks,

167

Fig. 1. Five PDGF isoforms induce the formation of three dimeric receptor complexes. The picture
schematically illustrates the binding specificities of PDGF isoforms. The �- and �-receptors for PDGF
each contains 5 immunoglobulin-like domains extracellularly, and a kinase domain intracellularly
which is split into two parts by an intervening sequence.



due to a defect development of alveolar smooth muscle cell progenitors (6). In addi-
tion, the mucosal lining of the gastrointestinal tract is defect with a decreased num-
ber of villus clusters (7). Knock-out of the �-receptor gives a severe phenotype with
cranial malformations and a deficiency in myotome formation (8).

In the adult, PDGF promotes wound healing. PDGF stimulates chemotaxis and
growth of many cell types involved in the healing process, including fibroblasts,
smooth muscle cells, neurotrophils and macrophages. Clinical studies have shown
that topical administration of PDGF stimulates wound healing in patients with decu-
bitus ulcers (9).

The importance of PDGF for the connective tissue compartment is also illustrated
by the fact that PDGF regulates the interstitial fluid pressure (10). The exact mecha-
nism involved is not known, but probably involves increased interactions between
fibroblasts of the connective tissue and matrix molecules, and a stimulation of con-
traction of fibroblasts through effects on the actin filament system of such cells.

PDGF in disease

Overactivity of PDGF has been implicated in several types of serious disorders,
including malignant diseases, as well as atherosclerosis and fibrotic diseases.

In atherosclerosis, injury to the endothelial cell layer leads to deposit of PDGF
from platelets, macrophages and other cells adhering to the injured site. PDGF then
stimulates migration of smooth muscle cells from the media into the intima of the
vessel, where they proliferate. This intimal thickening causes a narrowing of the
vessel lumen and is an early stage in the atherosclerotic process, which subsequent-
ly is followed by lipid deposition and plaque formation (11). 

Given the important role of PDGF for the growth and development of different
types of connective tissue cells, it is not surprising that overactivity of PDGF can
contribute to fibrosis. There are evidence for the involvement of PDGF in lung
fibrosis, glomerulonephritis, liver cirrhosis and myelofibrosis (reviewed in 12). 

In malignancies, PDGF has two principally different effects. On one hand, activa-
tion of PDGF receptors, by mutational events or by constitutive autocrine stimula-
tion by ligand, may drive the proliferation and survival of tumor cells. On the other
hand, PDGF produced in the tumor may act in a paracrine manner on the non-
malignant cells in the tumor, i.e. fibroblast-like cells in the stroma, and smooth mus-
cle cells, pericytes and, possibly, endothelial cells of blood vessels (reviewed in 13).

The first demonstration that autocrine stimulation by PDGF can have a trans-
forming effect, came through the discovery that the sis oncogene of simian sarcoma
virus is derived from the PDGF B-chain gene (14; 15). Subsequent studies have
demonstrated that production of PDGF by tumor cells that possess PDGF receptors
is common in glioblastoma (16) and sarcoma (17). Experimental proof that PDGF
overproduction can cause glioblastoma has come from studies showing that such
tumors are formed after intracranial injection of simian sarcoma virus into mar-
mosets (18), or a PDGF B-chain containing retrovirus into mice (19).

There are some examples of chromosomal translocations in patients which lead

168



to constitutive activation of PDGF receptors. Thus, the skin tumor dermatofibrosar-
coma protuberance (DFSP) is associated with a translocation which fuses the colla-
gen 1A1 gene with the PDGF B-chain gene (20). This results in the production of
large quantities of a fusion protein, which after processing to PDGF-BB causes
autocrine stimulation of growth and cell transformation (21; 22).

In the case of the rare disease chronic monomyelocytic leukemia (CMML), the
part of the �-receptor gene that encodes the kinase domain is fused to certain genes,
e.g. the Tel gene, that have in common that they encode proteins that can dimerize
(23–25). This results in constitutively dimerized and activated receptors, which dri-
ve tumor cell proliferation and survival. A similar situation prevails in the case of
hypereosinophilic syndrome (HES); in this disease the PDGF �-receptor gene has
been fused to the FIP1L1 gene, leading to constitutive dimerization and activation
of the receptor kinase activity (26). 

In the gastrointestinal stromal tumor (GIST), the �-receptor for PDGF often have
point mutations in the activation loop, or elsewhere, causing activation of the recep-
tor kinase which drives tumor cell growth and survival (27). Interestingly, GIST
alternatively can have mutations in the structurally related tyrosine kinase receptor
for stem cell factor (28). 

Finally, a subset of gliomas shows amplification of the �-receptor gene, leading
to an increased susceptibility to ligand stimulation or activation in the complete
absence of ligand (29; 30). 

Tumors of epithelial cell types generally do not express PDGF receptors. Howev-
er, PDGF produced in such tumors may stimulate non-tumor cells in blood vessels
and in the stroma, in a paracrine manner. Whereas PDGF does not have as potent
effect in the early stages of angiogenesis as the classical angiogenesis factors of the
vascular endothelial cell factor or fibroblast growth factor families, PDGF may
have important roles at later stages in vessel maturation through its effects on
smooth muscle cell development and pericyte recruitment (5; 31). Interestingly,
PDGF receptor-deficient melanoma cells transfected with PDGF-B or -D were
found to grow faster and to have an increased pericyte coverage of their vessels,
compared to untransfected melanoma cells (32).

Another important effect of paracrine PDGF stimulation relates to the regulation
of the interstitial fluid pressure (IFP) in tumors. Many solid tumors have increased
IFP (33), which is an obstacle in tumor treatment, since it leads to an inefficient
uptake of chemotherapeutical drugs from the circulation. There is evidence that
PDGF, through its action on stromal myofibroblasts, may be one of the factors caus-
ing the increased tumor IFP (34).

PDGF antagonists for clinical use

Given the involvement of PDGF overexpression in serious diseases, clinically use-
ful PDGF antagonists are highly warranted. Among the different antagonists that
have been developed are molecules that prevent ligand activation of receptors,
including antibodies, soluble extracellular receptor domains or DNA aptamers

169



(reviewed in 35). The advantage of these types of antagonists is that they are often
highly specific, however, since they are macromolecules, they are expensive and
cumbersome to administrate.

Another type of antagonists is low molecular weight inhibitors of the PDGF
receptor kinase. These are less expensive and easier to administer, but are not
absolutely specific. For instance, imatinib (STI571, Glivec) inhibits in addition to
the �- and �-receptors for PDGF, also the kinases of stem cell factor receptor, Abl
and Arg; it is already used clinically in the treatment of chronic myeloid leukemia
which is characterized by overactivity of Abl (36; 37), and of GIST which is charac-
terized by activation of stem cell factor receptor or PDGF �-receptor (38).

Initial clinical studies in which Glivec has been used on patients with malignan-
cies characterized by activation of PDGF receptors, have shown encouraging
results. Thus, reduction of tumor mass has been reported for patients with GIST (28;
38), CMML (39), HES (26) and DFSP (40; 41). However, whereas treatment of
nude mice with intracranially growing glioblastoma has been shown to reduce
tumor growth (42), it remains to be determined whether patients with glioblastoma
benefit from treatment with PDGF antagonists.

PDGF antagonists may also potentially be useful in order to inhibit paracrine
PDGF stimulation of normal cells in the tumor. Thus, PDGF antagonists may have
an anti-angiogenic effect, or may enhance the anti-angiogenic effect of e.g. vascular
endothelial growth factor antagonists (43). 

Another interesting possibility is to lower the tumor IFP by treatment with PDGF
antagonists and thereby achieve a higher uptake and efficiently of chemotherapy.
Encouraging results have been obtained in animal models, where a significant
enhancement of chemotherapy has been observed in the presence of Glivec treat-
ment (44).

The initial clinical studies using PDGF antagonists have given encouraging
results. It will be a challenge to develop selective PDGF antagonists and explore
their usefulness for the treatment, not only of malignant diseases, but also for the
treatment of atherosclerosis and fibrotic conditions.

TRANSFORMING GROWTH FACTOR-�

Mechanism of action of TGF-�

TGF-� is a disulfide-bonded dimer, and is a prototype for a family of about 30
members in humans, including TGF-�:s, activins, bone morphogenetic proteins
(BMP:s) and growth and differentiation factors (GDF:s). TGF-� family members
regulate cell proliferation, differentiation and apoptosis, and have important func-
tions during embryonal development (reviewed in 45). They exert their cellular
effects by forming a heteromeric complex of type I and type II serine/threonine
kinase receptors. Within such complexes, the constitutively active type II receptor
phosphorylates and activates the kinase activity of the type I receptor.

Important substrates for the activated type I receptor kinase, include members of

170



the Smad family of signal transduction molecules. The Smad family consists of
three subfamilies. Receptor-activated Smad (R-Smads) are phosphorylated by type I
receptors in a C-terminal -Ser-Xaa-Ser motif (Smad2 and 3 for TGF-� and activin
receptors, and Smad1, 5 and 8 for BMP receptors). Thereafter, R-Smads form com-
plexes with the common-mediator Smad (Co-Smad; Smad4) which are translocated
into the nucleus, where they regulate transcription by direct or indirect binding to
the promoter regions of specific genes. Among the target genes for R-Smad/Co-
Smad complexes are inhibitory Smads (I-Smads; Smad6 and 7), which are induced
by TGF-� or BMP stimulation and act in a negative feed back loop to suppress
Smad signaling. I-Smads bind to the receptors and thereby prevent interaction and
phosphorylation of R-Smads; in addition, Smad7 binds the ubiquitin ligase Smurf,
which thereby is recruited to the receptors and targets them for ubiquitin-mediated
degradation in proteosomes (Fig. 2) (reviewed in 46). 

171

Fig. 2. Involvement of Smad molecules in TGF-� signaling. The picture illustrates that TGF-� induces
a heteromeric receptor complex consisting of two type I and two type II receptors. Within this com-
plex the constitutively active type II receptor (light blue) phosphorylate the type I receptor (dark blue)
in a region just upstream of the kinase domain, whereby the type I receptor kinase is activated. The
type I receptor then phosphorylates R-Smads (Smad2 and 3) which then forms complex with the Co-
Smad (Smad4); the complex is then translocated into the nucleus, where it in conjunction with other
nuclear proteins (yellow) binds to the promoter regions of specific genes. Among the target genes are
I-Smads (Smad6 and 7). The induced I-Smads act in a negative feedback mechanism by competing
with R-Smads for binding to the receptors and, in the case of Smad7, by bringing the ubiquitin ligase
Smurf to the receptor.



Smad molecules have two conserved domains, the C-terminal MH2 domain
which is present in all Smads, and the N-terminal MH1 domain which is present
in R- and Co-Smads, but not in I-Smads. The MH1 domain, in certain Smads,
regulates nuclear import and transcription by direct binding to DNA, as well as
via binding to other nuclear proteins. The MH2 domain is responsible for inter-
actions with receptors and for intermolecular interactions within Smad complex-
es. It also mediates interactions with cytoplasmic anchors, like SARA, and with
a number of nuclear transcription factors. In the linker region connecting the
MH1 and MH2 domains, there is a PY motif which binds Smurf ubiquitin ligas-
es. In addition to the activating phosphorylation of R-Smads in the C-terminal
tail by receptors, the activity of Smad molecules are also modulated by phospho-
rylation in other parts of the molecules by other kinases, including Erk MAP
kinase, protein kinase C and calmodulin-dependent kinase II. Thus, Smad mole-
cules are involved in a multitude of interactions, which regulate their activation,
subcellular localization, stability and nuclear roles as transcription factors
(reviewed in 47). 

The nuclear partners of Smad molecules include the histone acetyl-transferase
domain-containing co-activators of the p300 and P/CAF families. Certain Smads
bind directly to 5'-GAGA-3' motifs in DNA, but this binding is of low affinity, and
interactions with other DNA binding transcription factors are important for Smad
function. Smad complexes also repress the transcription of specific genes, e.g.
through interaction with co-repressors associated with histone deacetylase activity,
such as TGIF, Ski and SnoN.

Although Smad molecules have crucial importance in TGF-� signaling, also
other signaling pathways are induced after TGF-� stimulation of cells. These
include activation of the Erk, JNK and p38 MAP kinase pathways and PI3-kinase
(reviewed in 48). The importance of these signaling pathways for the effects of
TGF-� on cells, remains to be elucidated, however, evidence has been presented
that JNK and p38 activation are important for induction of apoptosis (reviewed in
49).

In vivo function of TGF-�

All TGF-� family members have roles during embryonal development. Knock-out
of their receptors or signaling Smad molecules generally leads to embryonic lethali-
ty (reviewed in 50).

In the adult, TGF-� stimulates wound healing through its ability to cause accu-
mulation of matrix molecules; TGF-� both stimulate production of extracellular
matrix molecules, and inhibit the degradation of matrix through the production of
protease inhibitors.

TGF-� in disease

Overactivity of TGF-� results in fibrotic diseases, including lung fibrosis, glomeru-
lonephritis and liver cirrhosis. Whereas PDGF promotes fibrosis by stimulation of

172



connective tissue cells to migrate and proliferate, TGF-�’s involvement in fibrosis is
through its ability to cause accumulation of extracellular matrix.

In cancer, TGF-� has a complicated role. Initially TGF-� is a tumor suppressor
because of its abilities to inhibit cell proliferation and promote apoptosis of cells. In
certain tumors loss of function mutations in components in the TGF-� pathway are
seen. Thus, mutations in the TGF-� receptor genes are seen in colorectal cancers
(51), and the Smad4 gene is mutated in 50% of pancreatic carcinoma (52). Howev-
er, at later stages of tumor progression, TGF-� has tumor promoter activity by
inducing epithelial-to-mesenchymal transdifferentiation and thereby promoting
invasiveness and metastasis of tumor cells that have retained responsiveness to
TGF-�. Moreover, the effects of TGF-� on the non-malignant cells in the tumor,
suppressing the immune response and promoting angiogenesis, also promote
tumorigenesis (reviewed in 53). The dual role of TGF-� in tumorigenesis was clear-
ly demonstrated in a keratinocyte tumorigenesis model; overexpression of TGF-� in
keratinocytes initially inhibited the formation of benign skin tumors in response to
exposure to a chemical carcinogen, but the benign tumors that eventually were
formed rapidly progressed to invasive spindle-cell carcinomas (54).

TGF-� antagonists for clinical use

TGF-� antagonists could potentially be useful in the treatment of various fibrotic
diseases, as well as in advanced forms of cancer. Inhibition of TGF-� by a soluble
extracellular domain of the type II TGF-� receptor in mouse models for breast can-
cer and melanoma led to a clear reduction in metastasis and inhibition of angiogene-
sis (55–57). Moreover, low molecular weight inhibitors of the TGF-� type I recep-
tor kinase have been developed (58–61), which offers an alternative way of inhibit-
ing TGF-� signaling.

However, the dual role of TGF-� in tumorigenesis makes use of TGF-� antag-
onists complicated. Whereas inhibition of TGF-� signaling, e.g. through seques-
tration of TGF-� or inhibition of TGF-� receptor kinases, could have beneficial
effects in fibrotic conditions or late stage cancers, such treatment would be asso-
ciated with a risk of promoting recruitment of novel tumor cells due to inhibition
of the tumor suppressive effects of TGF-�. An interesting and appealing strategy
would therefore be to develop selective TGF-� inhibitors, which inhibit only
those intracellular pathways that are involved in tumor progression, while leav-
ing those that are involved in the tumor suppressive effects unperturbed. Recent
work on the transcription factor Yin Yang-1 (YY1) has illustrated that this may
be a possible strategy. YY1 binds to Smad molecules and represses several of
their responses, however, YY1 does not affect TGF-�- or BMP-induced growth
inhibition (62). An inhibitor that mimics the effect of YY1 on TGF-� signaling,
would thus be an interesting candidate for evaluation in treatment of advanced
cancers. However, such a strategy would clearly require additional work to eluci-
date in detail which pathways are responsible for the various effects of TGF-� on
cells.

173



FUTURE PERSPECTIVES

Since many diseases involve overactivity of various growth regulatory factors,
inhibitors of signal transduction are likely to become important future drugs. The
first inhibitors of this type are currently used clinically with encouraging results.

PDGF antagonists have proven to be useful in certain rather uncommon malig-
nancies that are dependent on a constitutively active PDGF receptor. However, it is
possible that PDGF antagonists can be used in a more general manner to target nor-
mal cell types in solid tumors, in order to lower the interstitial fluid pressure and
thereby enhance the effect of chemotherapy, and to inhibit angiogenesis and thereby
starve the tumor cells. Moreover, PDGF antagonists can potentially be used also in
the treatment of atherosclerosis and fibrotic conditions. Which type of antagonist
that will be most useful, remains to be determined. The advantage with antibodies,
soluble receptor domains or aptamers is the high specificity, on the other hand, the
less specific but more convenient low molecular weight inhibitors have shown
rather modest side effects. The most noticeable side effect of Glivec treatment has
been peri-orbital edema (63), maybe reflecting that PDGF has an important role in
the control of the interstitial fluid pressure in loose connective tissue.

The first generation TGF-� antagonists, a soluble extracellular TGF-� type II
receptor and low molecular weight receptor kinase inhibitors, are now tested in ani-
mal models of advanced cancers. Initial results have shown positive treatment
effects, and have encouraged continued work to produce clinically useful TGF-�
antagonists. It remains to be seen, however, if the side effects during treatment with
TGF-� antagonists will be tolerable. Since TGF-� has an important controlling
effect of the immune system, inhibition of TGF-� may be accompanied by exces-
sive immune reactions. Moreover, TGF-� inhibits the growth of most cell types;
inhibition of TGF-� may thus promote cell growth and development of tumors. An
important future task will be to explore the side effects of TGF-� antagonists, and to
elucidate whether it is possible to develop selective TGF-� antagonists which inhib-
it only those responses that cause disease progression.

Although it is too early to say how useful antagonists for PDGF and TGF-� will
be for the treatment of human disease, the results achieved so far are clearly encour-
aging, and provide a stimulation for further work to develop and explore the clinical
utility of such antagonists. 

ACKNOWLEDGEMENTS

I thank Ingegärd Schiller for skilful secretarial work.

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About the Author
Professor Carl-Henrik Heldin is director of the Ludvig
Institute for Cancer Research in Uppsala, Sweden, and
professor of Molecular Cell Biology at Uppsala Uni-
versity. Professor Heldin received the 2003 Rudbeck
Award for his pioneering studies of the structure and
function of PDGF (Platelet Derived Growth Factor)
and its applications to various new treatments of can-
cer. He has received a number of prestigious scientific
awards and is the author of more than 480 research
articles and reviews in international journals.

Corresponding author: Professor Carl-Henrik Heldin 
Ludvig Institute for Cancer Research 
P.O. Box 595 
SE-751 24 Uppsala
Sweden

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