Signaling in Solid Tumors: A Clinical Perspective
growth factor (PDGF) is an essential mitogen for mesenchymal cells such as fibroblasts,
pericytes, and vascular smooth muscle cells. It has key regulatory functions in
organogenesis and wound healing. Despite its known physiologic functions, PDGF overactivity
is also linked to malignant transformation. Genetic and epigenetic aberrations
in PDGF ligands or receptors can drive tumor proliferation and survival. Likewise,
the role of PDGF within the tumor microenvironment has been described. PDGF
stimulates the tumor stroma, supports angiogenesis, and promotes development of
cancer associated fibroblasts. 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 the emerging
prognostic biomarkers in this field. We will also briefly look into anti-PDGF
treatment and discuss the potential challenges and future directions.
of the PDGF System
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 in mesenchymal cells such as 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.