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N-terminal ectodomains and C-terminal kinase domains. the membrane of different cell types. These single chain
TβRIII (also known as betaglycan) is a cell surface receptor proteins have fi ve Ig-like extracellular domains
proteoglycan > 300 kDa in molecular mass and does and a tyrosine kinase domain [Figure 1e]. Dimerization of
not possess an intracellular kinase domain [Figure 1c]. receptors occurs upon binding to homo/heterodimers of
TβIII binds with TGF-β ligands and presents them to PDGF (A-D) ligands, leading to conformational changes
TβRII or the ligands bind directly with TβRII depending in receptors, activating them to trans-phosphorylate and
on cell types. After binding, TβRII recruits and stimulate downstream proteins. This relays the signals into
trans-phosphorylates TβRI, which in turn activates SMAD receiving cells via mainly MAPK and PI3K pathways and
proteins. SMAD complexes translocate into the nucleus thus regulates cell proliferation, differentiation, growth,
and function as transcription factors for TGF-β responsive migration, and survival. They have roles in angiogenesis
genes and thus regulate cell proliferation, survival, and thus support tumor growth [Table 1]. Overexpression
migration and differentiation [Table 1]. TGF-βR-mediated and mutations in the PDGFR genes are associated
signals play context-dependent dual roles in cell with diverse cancers [Table 2]. Aberrant expression of
growth. Under physiological conditions, TGF-β prevents PDGFR due to amplifi cation and/or overexpression of
[1]
cell growth, stimulates apoptosis or differentiation. During PDGFRα and PDGFRβ genes were reported in human
tumorigenesis, TGF-βR-mediated signals promote cell glioblastoma multiforme. [4,20] Moreover, mutations and
growth due to genetic and epigenetic changes. Mutations genetic translocation in PDGFRα gene were observed
and dis-regulation of TGF-βR genes were observed in in gastrointestinal stromal tumors and chronic leukemia
different cancers [Table 2], for example, down-regulation respectively. [21,22] A germline point mutation (gain of
of TGF-βRII gene in breast and lung cancer [14,15] and function) in PDGFRβ gene was found in the most
different mutations in colon and pancreatic cancer. [16-18] common fi brous tumor of infancy, myofi bromatosis. [23]
Vascular endothelial growth factor receptor Fibroblast growth factor receptor
This family consists of three membrane The fi broblast growth factor receptor (FGFR) family
receptors (VEGFR1-3), predominantly expressed consists of four closely related transmembrane
on endothelial cells and few additional cell types. proteins (FGFR1-4) and their different isoforms with
VEGFRs are single pass protein with seven altered ligand specifi city due to differential splicing of
immunoglobulin (Ig)-like domains on the extracellular site FGFR mRNA. These single chain receptors contain
and two split tyrosine kinase domains in the intracellular one extracellular domain with three immunoglobulin
site [Figure 1d]. They bind with the disulfi de-linked repeats (Ig I-III) with ligand binding capacity, one
homodimer of VEGF isoform (VEGFA-D) ligands transmembrane domain and one intracellular domain with
and placenta growth factors (PIGF1 and 2) to form kinase activity at the carboxy-terminus [Figure 1f]. There
homodimers or heterodimers of VEGFR-1 and-2 and are 18 different FGF ligands that can bind to different
relay the signal inside cells. The signals transduced FGF receptors. Upon binding, dimerization of FGFR
by VEGFR are different between these receptors. For leads to auto-phosphorylation and kinase activation.
example, VEGFR2 (also known as KDR/fl k-1) induces Phosphorylated FGFRs in turn phosphorylate a number
mitogen-activated protein kinases (MAPK)-dependent of proteins and/or serve as molecular docking sites for
cell proliferation whereas VEGFR1 (fl t-1) does not induce many effectors, thus orchestrating context-dependent
cell growth. However, activation of VEGFR1 by VEGF cellular functions including cell proliferation, growth,
stimulates cell migration, a response that is also triggered differentiation, migration, vascular repair, wound healing,
by VEGFR2 activation. These VEGF-VEGFR interactions and cell survival. FGF-FGFR interactions have pivotal
are well-known for their key roles in vasculogenesis roles in tumorigenesis [Table 1] as the downstream
and angiogenesis. VEGFR3 (fl t-4) that is expressed on mitogenic growth signals ( MAPK) and anti-apoptotic
lymphatic vessels interacts with VEGF-C and VEGF-D PI3K/AKT signals lead to uncontrolled growth and
and is thought to promote lymphangiogensis. VEGFRs inhibition of cell death, respectively. The PLC/PKC
are thought to be responsible for blood and lymph vessel pathway downstream of FGFRs also converges to the
formation in tumor microenvironment and thus promote MAPK pathway to support cell growth. [24-26] These
tumor growth and progression [Table 1]. High expression receptors have been shown to exert profound roles in
of VEGFR gene is observed in many different types of angiogenesis both in paracrine and autocrine fashions.
malignancies [Table 2]. Moreover, somatic mutations in FGFR expression causes tumor cells to acquire resistance
VEGFR2 and VEGFR3 genes were identifi ed in the most to several drugs, especially inhibitors targeting other
common infants’ malignancy, juvenile hemangioma. [19] growth factor receptors (EGFR, PDGFR and VEGFR)
because of their extensive cross-talks. Amplifi cation
Platelet derived growth factor receptor
and mutations in FGFR genes that lead to constitutive
The platelet-derived growth factor receptor (PDGFR) activation/up-regulation of receptors are found in
family contains two receptors (PDGFR-α and-β) that different types of malignancies, including breast, ovarian,
are encoded by two different genes and are expressed on gastric and lung cancers [Table 2].

Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 193