induces vascular endothelial growth factor (VEGF) expression [136]. Furthermore,
both PDGFR-α and PDGFR-β are related to the development of novel lymphatic
vessels [134].
4.1 PDGFR and Tumorigenesis
PDGFs and their receptors (PDGFRs) act as important mediators of tumor growth
and invasion through direct effects on tumor cells, as well as on their surrounding
microenvironment [132]. PDGFs are largely produced by different types of solid
tumors, inducing stroma formation and angiogenesis in order to ensure nutrient and
oxygen supplies [137]. Several tumors are associated with genetic alterations that
culminate in constitutive activation of PDGFRs. The overexpression of these RTKs
can be detected directly in tumor cells or in tumor-associated pericytes and stroma
cells [134]. PDGFR-β expression by pericytes mediates their recruitment and proper
integration in tumor vessels [137].
Moreover, the higher expression and activation of PDGFRs in solid tumors
contribute to an increase in the interstitial fluid pressure (IFP), causing tumor
interstitial hypertension (TIH), which reduces the permeability from the capillary
into tissue, thus decreasing the diffusion of anticancer drugs [136, 137].
Consequently, PDGFR inhibition is considered a promising therapeutic approach
for anticancer treatment, as it is supposed to control tumor growth by directly
targeting tumor cells and by decreasing angiogenesis, and is also associated with
higher chemotherapy delivery and exposure [133, 134, 136].
4.2 PDGFR Role in Several Tumor Types
Prominent expression of PDGFs and PDGFR-α in human glioma cells suggests the
relevance of this signaling pathway in gliomagenesis and disease progression
[132]. Simultaneous expression of PDGFR-α/β was detected in around 60% of
human colorectal carcinoma samples [138, 139]. High stromal expression of
PDGFR-β is also observed in breast cancer and associated with tumor aggressiveness and poor prognosis [138, 140]. Additionally, PDGFR-β is frequently
upregulated in primary and metastatic prostate cancer cells [133].
Moreover, PDGFR gain-of-function mutations and derived fusion proteins are
implicated in several tumor types. Suzuki and coworkers demonstrated that PDGFRβ carrying the gain-of-function mutation D849N in the activation loop accelerates
the establishment of B16 melanoma in a murine model of this disease [137]. These
PDGFR genetic alterations and their role in myeloid malignancies and gastrointestinal stromal tumors (GISTs) represent the most relevant examples described in
scientific literature so far.
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
183
both PDGFR-α and PDGFR-β are related to the development of novel lymphatic
vessels [134].
4.1 PDGFR and Tumorigenesis
PDGFs and their receptors (PDGFRs) act as important mediators of tumor growth
and invasion through direct effects on tumor cells, as well as on their surrounding
microenvironment [132]. PDGFs are largely produced by different types of solid
tumors, inducing stroma formation and angiogenesis in order to ensure nutrient and
oxygen supplies [137]. Several tumors are associated with genetic alterations that
culminate in constitutive activation of PDGFRs. The overexpression of these RTKs
can be detected directly in tumor cells or in tumor-associated pericytes and stroma
cells [134]. PDGFR-β expression by pericytes mediates their recruitment and proper
integration in tumor vessels [137].
Moreover, the higher expression and activation of PDGFRs in solid tumors
contribute to an increase in the interstitial fluid pressure (IFP), causing tumor
interstitial hypertension (TIH), which reduces the permeability from the capillary
into tissue, thus decreasing the diffusion of anticancer drugs [136, 137].
Consequently, PDGFR inhibition is considered a promising therapeutic approach
for anticancer treatment, as it is supposed to control tumor growth by directly
targeting tumor cells and by decreasing angiogenesis, and is also associated with
higher chemotherapy delivery and exposure [133, 134, 136].
4.2 PDGFR Role in Several Tumor Types
Prominent expression of PDGFs and PDGFR-α in human glioma cells suggests the
relevance of this signaling pathway in gliomagenesis and disease progression
[132]. Simultaneous expression of PDGFR-α/β was detected in around 60% of
human colorectal carcinoma samples [138, 139]. High stromal expression of
PDGFR-β is also observed in breast cancer and associated with tumor aggressiveness and poor prognosis [138, 140]. Additionally, PDGFR-β is frequently
upregulated in primary and metastatic prostate cancer cells [133].
Moreover, PDGFR gain-of-function mutations and derived fusion proteins are
implicated in several tumor types. Suzuki and coworkers demonstrated that PDGFRβ carrying the gain-of-function mutation D849N in the activation loop accelerates
the establishment of B16 melanoma in a murine model of this disease [137]. These
PDGFR genetic alterations and their role in myeloid malignancies and gastrointestinal stromal tumors (GISTs) represent the most relevant examples described in
scientific literature so far.
Case Study on Receptor Tyrosine Kinases EGFR, VEGFR, and PDGFR
183