Platelet-derived growth factor, PDGF, was first found as a factor that comes from platelet that stimulates the growth of fibroblasts in vitro (Hannink and Donoghue 1989). Also, PDGF is characterized as a potent mitogen for mesenchymal origin cells such as smooth muscle cells, fibroblasts, and glial cells (Hannink and Donoghue 1989). Furthermore, it is known that PDGF is related to blood vessel formation and induces angiogenesis (Keck et al. 1989). Two types of PDGF polypeptides, PDGF-A and PDGF-B, were firstly reported for subtypes. In early 2000s, additional two types of PDGF were identified, which are PDGF-C and PDGF-D (Li et al. 2000; Bergsten et al. 2001). This entry examines further details of PDGF.
PDGF receptor (PDGFR) is a cell surface receptor and type of receptor tyrosine kinase (RTK). After ligand binding, PDGFR internalizes and regulates downstream signaling such as Akt and ERK (Heldin 1992). Two types of PDGFR, PDGFRα and PDGFRβ, were reported (Levitzki 2004; Demoulin and Essaghir 2014). PDGFRα regulates basically gastrulation and development of diverse organs such as the skin, kidney, lung, bones, etc. PDGFRβ has an important role as it regulates early hematopoiesis and blood vessel formation (Andrae et al. 2008).
PDGFs usually work as homodimers which are linked by disulfide. However, PDGF-A and PDGF-B can form heterodimers such as PDGF-AB which is functional (Andrae et al. 2008). PDGF-β interacts with PDGFRβ and still can bind to PDGFRα with lower binding affinity. PDGF-A can bind to a PDGFRα with higher binding affinity than PDGF-B. Also PDGF-C can bind to PDGFRα, and PDGF-D can bind to PDGFRβ each preferentially (Kim et al. 2015).
Expression of PDGFRβ is reported to be controlled by Prox1 transcription factor. Prox1 silenced human dermal LEC (lymphatic endothelial cell) had reduced PDGFRβ expression which suppressed migration of human dermal LECs toward PDGF-BB (Miyazaki et al. 2014). Lymphoma development and tumor progression in animal model of NPM-ALK-induced lymphomagenesis are reported to be triggered by JUN-mediated transcriptional upregulation of PDGFRβ (Laimer et al. 2012). There is direct evidence suggesting that EGFR inhibitor “erlotinib” only modestly inhibited growth of EGFRvIII expressing U87 glioma cells in xenografted mice model. This report revealed that PDGFRβ was upregulated and displayed increased kinase activity in EGFRvIII-silenced cells. Moreover, erlotinib-induced transcriptional upregulation of PDGFRβ was remarkable impaired in cells constitutively active AKT1. Similarly, erlotinib-induced PDGFRβ expression was also impaired in constitutively active mTOR-expressing cells (Akhavan et al. 2013).
Mechanism of PDGF
Function of PDGF
PDGFs are one of the growth factors that regulate cell growth and migration. In particular, it has significant role in blood vessel formation which is growth of blood vessel (Fig. 1). PDGF/PDGFRα signaling has important roles in animal development of the cranial and cardiac neural crest, gonads, skin, CNS, skeleton and etc. PDGF has different function along developmental stages of mammalian organogenesis. For example, PDGF is mitogenic to drive proliferation of mesenchymal cell during early developmental stage. However, PDGF signaling has been implicated in direction of migration, differentiation and tissue remodeling in later maturation stage, suggesting PDGF is no longer mitogenic in this stage. Other growth factors in this family include vascular endothelial growth factors B and C (VEGF-B, VEGF-C) which are active in angiogenesis and endothelial cell growth (Olofsson et al. 1996; Joukov et al. 1996). PDGF plays a role in embryonic development. Over-expression of PDGF has been linked to several diseases such as atherosclerosis, fibrotic disorders and malignancies (Alvarez et al. 2006). Furthermore, PDGF/PDGFRβ signaling has a significant role in and early hematopoiesis (Andrae et al. 2008).
PDGF in Disease
Studies of PDGF have been identified that PDGF/PDGFR signaling is associated with broad range of diseases. In particular, there are strong evidences that PDGF and PDGFR have causalities in many types of cancer including brain, breast, colorectal, lung, renal, thyroid, and pancreas. PDGF signaling causes proliferative clonal expansion of unstable cells and these cells become malignant (Andrae et al. 2008).
Many proteins are involved in regulating PDGF signaling, and deregulation of these proteins may upregulate the PDGF pathway. One such regulatory protein is the tumor suppressor p53, which transactivates or transrepresses a number of target genes. PDGFR is suppressed by p53 to regulate cellular proliferation suggesting PDGFR is target of p53 (Yang et al. 2008). The p53 mutation is a common occurrence in about 50% of all cancers, and this may likely be contributing to PDGF-dependent cancer progression (Heldin 2013). Interestingly, the frequently occurring gain-of-function p53R172H and p53R273H mutants even induce PDGFR-B, which may further promote the aggressive cancers (Weissmueller et al. 2014).
In colorectal cancer, PDGFRα promotes transforming growth factor (TGF)-β signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-β receptors. PDGFRα knockdown inhibited TGF-β-induced intracellular activation and nuclear accumulation of SMAD2. PDGFRα-knock-downed cells displayed marked increase in TβRII gene transcription (Liu et al. 2014). PDGF has been shown to enhance proliferation of luminal MCF-7 breast cancer cells in an estrogen-independent manner. These findings were obtained from animal model study in which mammary gland stromal cells (BJ3Z) considerably enhanced luminal breast cancer cell proliferation. It has been reported that PDGF ligands secreted by malignant stromal cell signaled through PDGF receptors present on the breast cancer cells to stimulate cellular proliferation (Pinto et al. 2014). Non-small cell lung cancer (NSCLC) patients who had overexpression of both PDGF-BB and VEGF-C displayed higher tumor growth and lymphatic invasion (Liu et al. 2014). Crenolanib has been shown to be effective against PDGFR and induced apoptosis in NSCLC A549 cells. Moreover, crenolanib significantly suppressed tumor growth in nude mice injected with A549 cells (Wang et al. 2014).
It has been also reported that PDGFRβ signaling is related to vascular diseases, whereas PDGFRα signaling has pivotal role in mesenchymal cell and fibroblast-related diseases. Both PDGFRα and PDGFRβ show common pathogenic process in various PDGF-driven diseases such as fibrotic reactions in conjunction with tumors and chronic inflammatory conditions. In addition, there are strong evidence that PDGF signaling is related to pulmonary hypertension and retinal vascular disease (Andrae et al. 2008).
Many of PDGFR kinase inhibitors, including several quinoxalines, were found to be highly potent to the PDGFR and its family members, kit and Flt3 (Heldin 2013).
Inhibition of the PDGF pathway results in loss of pericytes and a reduction in vessel density in the neovascularized cornea with reduced expression of PDGF and VEGF mRNA. PI3K is known to be involved in the regulation of VEGF and PDGF, as the PI3K inhibitors such as wortmannin and LY294002 have similar effects with inhibition of VEGF or PDGF pathway. Since PDGF is a known stimulus for PI3K activation, decrease in VEGF and PDGF mRNA levels by PDGF inhibitor is caused by the decreased activation of the PI3K signaling cascade (Heldin 2013). Various types of PDGF inhibitors are usually used to apply PDGF-related disease. However, the problem is that application of PDGF inhibitor is not completely specific to PDGF-related disease. Therefore, there are number of studies to find inhibitor targeting PDGF specifically.
PDGF in Medicine
There are many PDGF-related diseases including PDGF related to tumor stroma fibroblasts, autocrine stimulation of tumor cells, and stimulation of angiogenesis (Kristian et al. 2003). Glivec, a PDGF receptor inhibitor, is a well-known medicine for leukemia. PDGF receptor inhibitor, like Glivec, allows a meaningful evaluation of the PDGF signaling in malignancies (Buchdunger et al. 1996).
Another good example of medicine using PDGF signaling is wound healing. Recombinant human PDGF-BB protein has been suggested as a topical treatment for a chronic neuropathic diabetic ulcer (Robson et al. 1992). PDGF-BB also is applicable to recover wound healing and against pressure ulcer (Andrae et al. 2008). PDGF-BB-induced tissue repair mechanism seems to include fibroblast proliferation, collagen production, and new vessel formation (Pierce et al. 1994).
Recently, Ophthotech is developing a drug that targets aged-related macular degeneration (AMD) patients. This drug is named “Fovista,” which targets PDGF, combining with anti-VEGF drugs, disrupting the formation of abnormal new blood vessels in AMD patients (Ophthotech 2016). Ophthotech has completed phase 2b clinical trial on Fovista. This trial evaluated the safety and efficacy of Fovista administration combining an anti-VEGF agent to patients diagnosed with wet AMD. Another anti-PDGF drug targeting AMD in development is the Durasert SR (sustained release). Durasert is known to block the activation of PDGF and VEGF (Duffy 2016).
Rapamycin-mediated mTORC1 inhibition considerably enhanced PDGFRα-induced Akt phosphorylation. It has been also reported that PDGFRα overexpressing synovial sarcoma cells displayed significant response to imatinib-mediated inhibitory effects on rapamycin-induced phospho-Akt. Akt was inhibited in PDGFRα positive, recurrent, metastatic synovial sarcoma patients treated with imatinib and mTORC1 inhibitor everolimus (Ho et al. 2012).
The multicenter phase II clinical trial of pazopanib from progressive and metastatic medullary thyroid carcinoma patients revealed that pazopanib displayed promising clinical activity (Bible et al. 2014).
Olaratumab, an anti-PDGFRα monoclonal antibody, was noted to be effective when administered as evidenced by best response of 12 patients with stable disease. Recommended phase II dosages were 20 mg/kg biweekly and 16 mg/kg weekly (Chiorean et al. 2014). Data analysis from post-lapatinib-treated patient showed significant reduction of phospho-EGFR and considerably enhanced PDGFRβ expression (Akhavan et al. 2013).
Studies on PDGF signaling have revealed that PDGFs and their receptors relate to various types of human diseases. Failure of regulating PDGF signaling in the body mediates these diseases; therefore, selective PDGF inhibitors are used to cure or reverse the disease induced by PDGF signaling.
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