Platelet-derived (1). These chains make up five functional

growth factor (PDGF) is an essential mitogen for mesenchymal cells such as
fibroblasts, pericytes, and vascular smooth muscle cells. It has key
physiologic functions in organogenesis and wound healing. However, PDGF
overactivity has been linked to malignant transformation. Genetic and
epigenetic aberrations in PDGF ligands or receptors drive tumor proliferation
and survival. Likewise, there is growing recognition as to the role of PDGF
within the tumor microenvironment. Understanding the complex molecular
mechanisms involved is pivotal to identify new diagnostic and therapeutic
targets in the clinics. This review aims to summarize the clinical relevance of
PDGF signaling in the pathogenesis of solid tumors. Additionally, we will
tackle anti-PDGF treatment and the emerging prognostic biomarkers in the field.

Lastly, the potential challenges and future directions will be discussed.

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PDGF ligands and receptors. PDGF isoforms
are derived from endothelial cells, macrophages, epithelial cells, and platelet
degranulation. They come in the form of polypeptide chains PDGF-A, -B, -C, and
-D (1). These chains make up five functional growth factors denoted as PDGF-AA,
-BB, -AB, -CC, and -DD, which activate the PDGF signaling system (1,2). These
PDGF ligands act on target cells by binding to tyrosine kinase receptors PDGFR?
and PDGFR? expressed by mesenchymal cells (i.e. fibroblasts, pericytes, and
vascular smooth muscle cells). Specific PDGF ligand-receptor affinity has been
described: PDGF-A, -B, and -C bind PDGFR?, whereas PDGF-B and -D bind PDGFR?
(reviewed in (3,4)) (Figure 1).

These interactions are important as distinct signaling events can be triggered
from such specificity.


PDGFR activation and downstream signaling

Binding of the dimeric PDGF isoforms results in dimerization of the receptors. Ligand-induced
dimerization draws the intracellular kinase domains close together, triggers
asymmetric dimer arrangement, and subsequently leads to transphosphorylation of
PDGFR tyrosine residues (5). The initial phosphorylation event causes
conformational change in the intracellular domain and exposes the catalytic
sites, thereby activating the kinases. Likewise, distinct autophosphorylated
tyrosine sites selectively recruit signal transduction proteins containing SH2
domains (Figure 1). These include
phospholipase C, tyrosine phosphatase SHP2, as well as kinases Src and
PI3-kinase (6). Transcription factor Stat5 as well as adapter proteins Grb2,
Gab2, Nck can also bind and lead to further activation of downstream signaling
molecules MAP kinase, PI3-kinase-Akt, and PLC? (7). The resulting signaling
cascades promote cell migration, proliferation, differentiation, and survival.


Gliomas. Self-sufficiency in
tumoral growth occurs through PDGF/PDGFR autocrine stimulatory loops in certain
neoplasms such as gliomas. These tumors represent the most common type of brain
cancer, with an incidence of 5 to 10 cases per 100,000 annually (8). The role
for PDGFR signaling in gliomas has been established in various experimental and
clinical studies (reviewed in (9)). Specifically, PDGFRA gene amplification has been observed in 10–15% of
glioblastoma multiforme (GBM) (8). In addition, an activating deletion mutation
in PDGFRA?8,9 has been
described (10). Despite the vast number of studies implicating PDGF
overactivity, targeted treatment has failed to improve overall survival among
GBM patients (11). Nevertheless, the enthusiasm in this approach has not waned.

Currently, tyrosine kinase inhibitor (TKI) Nilotinib (Tasigna®) is under phase
II clinical trial on patients with malignant glioma and are positive for PDGFR
amplification (NCT01140568).


Dermatofibrosarcoma protruberans (DFSP). DFSP is a
rare mesenchymal neoplasm which accounts for ~2–6% of soft tissue sarcomas
worldwide. Pathognomonic to DFSP is chro­mosomal translocation t(17;22), which
leads to the fusion of collagen gene COL1A1 and PDGFB gene (12). The resulting fusion protein is processed into
mature PDGF-BB. Overproduction of the PDGF-BB ligand subsequently leads to
proliferation and survival of fibroblasts via self-stimulatory growth
signaling. The TKI imatinib is the standard of care for advanced DFSP (i.e.

unresectable or metastatic) (13). As second-line treatment, sunitinib and
sorafenib are being used for imatinib-resistant cases (6). There have been
attempts to evaluate broad-spectrum kinase inhibitor pazopanib but these have
failed in phase II clinical trials.


Gastrointestinal stromal tumors (GIST). GISTs
account for less than 1% of gastrointestinal malignancies but considered as the
most common mesenchymal neoplasm that affects the stomach or the small
intestines. It often presents with non-specific symptoms related to bowel
obstruction, hemorrhage, or perforation. Activating point mutations drive
majority of cases: KIT (85%) and
PDGFRA (10%) (14). The first systemic
drug utilized against GIST was imatinib, a TKI that targets both KIT and
PDGFR?/?. This revolutionized the treatment of inoperable or metastatic GIST.

However, the most common PDGFR mutations in GIST (eg. D842V) do not respond
well to imatinib (15). As such, these mutations are now considered as
predictive marker of non-response to TKI treatment. For these patients,
dasatinib or crenolanib are considered as second line regimen (4).


Sarcomas. Rhabdomyosarcoma and
Ewing sarcoma are soft tissue malignancies often diagnosed in children or young
adults. In both cases, upregulation of PDGF or PDGFR is related to gene
translocations that eventually lead to formation of abnormal transcription
factors: PAX3/FOXO1 in alveolar rhabdomyosarcoma (16) and EWS/FLI1 in Ewing
sarcoma (17). Subsequently, upregulated PDGFR? has been linked to progression
of rhabdomyosarcoma while overexpression of PDGF-C acts as transforming growth
factor in Ewing sarcoma (18). Studies show that inhibition of PDGFR? by RNA
interference or antibody had a considerable effect on tumor growth in
rhabdomyosarcoma (19). Likewise, treatment of Ewing
sarcoma cell line with PDGFR kinase inhibitor inhibited its growth (6). Recently, the
monoclonal antibody olaratumab received its first global approval for the
treatment of soft tissue sarcoma (see further discussions below) (20).


Dermal malignancies. PDGF is also highly
expressed in malignant melanoma, particularly playing a role in the recruitment
of stromal fibroblasts (7, 21). The crosstalk between tumor cells and stromal
cells support angiogenesis. In a recent study, PDGF-C is able to activate
Neuropilin-1, a co-receptor for vascular endothelial growth factor A (22). This
resulted in more aggressive melanoma phenotype in vitro (22). In the more benign basal cell carcinoma, the
activation of hedgehog pathway induces Gli1 transcription factor, which in turn
activates PDGFR? (23).