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1.  PDGFRA, PDGFRB, EGFR, and downstream signaling activation in malignant peripheral nerve sheath tumor 
Neuro-Oncology  2009;11(6):725-736.
We investigated the activation of platelet-derived growth factor (PDGF) receptor A (PDGFRA), PDGF receptor B (PDGFRB), epidermal growth factor receptor (EGFR), and their downstream pathways in malignant peripheral nerve sheath tumors (MPNSTs). PDGFRA, PDGFRB, and EGFR were immunohistochemically, biochemically, cytogenetically, and mutationally analyzed along with the detection of their cognate ligands in 16 neurofibromatosis type 1 (NF1)-related and 11 sporadic MPNSTs. The activation of the downstream receptor pathways was also studied by means of v-akt murine thymoma viral oncogene homolog (AKT), extracellular signal-regulated kinase (ERK), and mammalian target of rapamycin (mTOR) Western blotting experiments, as well as rat sarcoma viral oncogene homolog (RAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3KCA), and phosphatase and tensin homolog deleted on chromosome ten (PTEN) mutational analysis and fluorescence in situ hybridization. PDGFRA, PDGFRB, and EGFR were expressed/activated, with higher levels of EGFR expression/phosphorylation paralleling increasing EGFR gene copy numbers in the NF1-related cases (71%). Autocrine loop activation of these receptors along with their coactivation were suggested by the expression of the cognate ligands in the absence of mutations and the presence of receptor tyrosine kinase (RTK) heterodimers, respectively. Both MPNST groups showed AKT, ERK, and mTOR expression/phosphorylation. No BRAF, PI3KCA, or PTEN mutations were found in either group of MPNSTs, but 18% of the sporadic MPNSTs showed RAS mutations. PTEN monosomy segregated with the NF1-related cases (50%, p = 0.018), but PTEN protein was expressed in all but two cases. In conclusion, PDGFRA, PDGFRB, and EGFR seem to be promising molecular targets for tailored treatments in MPNST. In particular, the ligand- and heterodimerization-dependent RTK activation/expression coupled with a downstream signaling phosphorylation, mediated by the upstream receptors or RAS activation, may provide a rationale to apply combined RTK and mTOR inhibitor treatments both to sporadic and NF1-related cases.
doi:10.1215/15228517-2009-003
PMCID: PMC2802393  PMID: 19246520
EGFR; MPNST; mTOR; PDGFRA; PDG-FRB
2.  Review of current classification, molecular alterations, and tyrosine kinase inhibitor therapies in myeloproliferative disorders with hypereosinophilia 
Journal of Blood Medicine  2013;4:111-121.
Recent advances in our understanding of the molecular mechanisms underlying hypereosinophilia have led to the development of a ‘molecular’ classification of myeloproliferative disorders with eosinophilia. The revised 2008 World Health Organization classification of myeloid neoplasms included a new category called “myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1.” Despite the molecular heterogeneity of PDGFR (platelet-derived growth factor receptor) rearrangements, tyrosine kinase inhibitors at low dose induce rapid and complete hematological remission in the majority of these patients. Other kinase inhibitors are promising. Further discoveries of new molecular alterations will direct the development of new specific inhibitors. In this review, an update of the classifications of myeloproliferative disorders associated with hypereosinophilia is discussed together with open and controversial questions. Molecular mechanisms and promising results of tyrosine kinase inhibitor treatments are reviewed.
doi:10.2147/JBM.S33142
PMCID: PMC3747024  PMID: 23976869
hypereosinophilia; classification; myeloproliferative disorders; molecular alterations; tyrosine kinase inhibitor
3.  Imatinib blocks migration and invasion of medulloblastoma cells by concurrently inhibiting activation of PDGFR and transactivation of EGFR 
Molecular cancer therapeutics  2009;8(5):1137-1147.
Platelet-derived growth factor receptor (PDGFR) expression correlates with metastatic medulloblastoma. PDGF stimulation of medulloblastoma cells phosphorylates Erk and promotes migration. We sought to determine whether blocking PDGFR activity effectively inhibits signaling required for medulloblastoma cell migration and invasion. DAOY and D556 human medulloblastoma cells were treated with imatinib mesylate (Gleevec®), a PDGFR tyrosine kinase inhibitor, or transfected with siRNA to PDGFRB to test the effects of blocking PDGFR phosphorylation and expression, respectively. PDGFR cell signaling, migration, invasion, survival and proliferation following PDGF-BB stimulation, with and without PDGFR inhibition, were measured. PDGF-BB treatment of cells increased PDGFRB, Akt and Erk phosphorylation, and transactivated EGFR, which correlated with enhanced migration, survival and proliferation. Imatinib (1 uM) treatment of DAOY and D556 cells inhibited PDGF-BB- and serum-mediated migration and invasion at 24 h and 48 h, respectively, and concomitantly inhibited PDGF-BB activation of PDGFRB, Akt and Erk, but induced increased PTEN expression and activity. Imatinib treatment also induced DAOY cell apoptosis at 72 h and inhibited DAOY and D556 cell proliferation at 48 h. siRNA silencing of PDGFRB similarly inhibited signaling, migration and survival and both siRNA and imatinib treatment inhibited PDGF-BB-mediated EGFR transactivation, indicating that the effects of imatinib treatment are specific to PDGFRB target inhibition. These results indicate that PDGFRB tyrosine kinase activity is critical for migration and invasion of medulloblastoma cells, possibly by transactivating EGFR, and thus imatinib may represent an important novel therapeutic agent for the treatment of medulloblastoma.
doi:10.1158/1535-7163.MCT-08-0889
PMCID: PMC2891380  PMID: 19417143
Medulloblasotma; Imatinib mesylate; PDGFR; EGFR; PTEN
4.  Changed concepts and definitions of myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in the updated 2008 WHO classification 
Journal of Hematopathology  2009;2(4):205-210.
The purpose of this overview is to discuss the changes in the 2008 WHO classification of myeloid neoplasms, with exclusion of acute myeloid leukaemia. Specific mutations or rearrangements leading to constitutive activation of growth factor receptors or cytoplasmic tyrosine kinases are now recognised as recurrent genetic events characterising the group of myeloproliferative neoplasms (MPN). A newly introduced subgroup consists of patients with persistent eosinophilia and myeloid or lymphoid proliferations harbouring specific genetic changes involving platelet-derived growth factor receptors alpha and beta (PDGFRA and PDGFRB) or fibroblast growth factor receptor 1 (FGFR1). The clinical relevance of recognising myeloid neoplasms with aberrant tyrosine kinase activity is based in novel treatment options with tyrosine kinase inhibitors. The myelodysplastic syndromes (MDS) without increased blasts are further divided into subtypes of refractory cytopaenias with unilineage dysplasia. A new provisional entity is refractory cytopaenia of childhood. Down syndrome- and therapy-related myeloid neoplasms, including MDS, were moved to the section of acute myeloid leukaemia and related precursor neoplasms.
doi:10.1007/s12308-009-0048-6
PMCID: PMC2798935  PMID: 20309429
Review; Classification; Myelodysplastic syndrome; Myeloproliferative neoplasm; Updated WHO classification
5.  Changed concepts and definitions of myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in the updated 2008 WHO classification 
Journal of Hematopathology  2009;2(4):205-210.
The purpose of this overview is to discuss the changes in the 2008 WHO classification of myeloid neoplasms, with exclusion of acute myeloid leukaemia. Specific mutations or rearrangements leading to constitutive activation of growth factor receptors or cytoplasmic tyrosine kinases are now recognised as recurrent genetic events characterising the group of myeloproliferative neoplasms (MPN). A newly introduced subgroup consists of patients with persistent eosinophilia and myeloid or lymphoid proliferations harbouring specific genetic changes involving platelet-derived growth factor receptors alpha and beta (PDGFRA and PDGFRB) or fibroblast growth factor receptor 1 (FGFR1). The clinical relevance of recognising myeloid neoplasms with aberrant tyrosine kinase activity is based in novel treatment options with tyrosine kinase inhibitors. The myelodysplastic syndromes (MDS) without increased blasts are further divided into subtypes of refractory cytopaenias with unilineage dysplasia. A new provisional entity is refractory cytopaenia of childhood. Down syndrome- and therapy-related myeloid neoplasms, including MDS, were moved to the section of acute myeloid leukaemia and related precursor neoplasms.
doi:10.1007/s12308-009-0048-6
PMCID: PMC2798935  PMID: 20309429
Review; Classification; Myelodysplastic syndrome; Myeloproliferative neoplasm; Updated WHO classification
6.  The Roles of PDGF in Development and During Neurogenesis in the Normal and Diseased Nervous System 
The four platelet-derived growth factor (PDGF) ligands and PDGF receptors (PDGFRs), α and β (PDGFRA, PDGFRB), are essential proteins that are expressed during embryonic and mature nervous systems, i.e., in neural progenitors, neurons, astrocytes, oligodendrocytes, and vascular cells. PDGF exerts essential roles from the gastrulation period to adult neuronal maintenance by contributing to the regulation of development of preplacodal progenitors, placodal ectoderm, and neural crest cells to adult neural progenitors, in coordinating with other factors. In adulthood, PDGF plays critical roles for maintenance of many specific cell types in the nervous system together with vascular cells through controlling the blood brain barrier homeostasis. At injury or various stresses, PDGF modulates neuronal excitability through adjusting various ion channels, and affecting synaptic plasticity and function. Furthermore, PDGF stimulates survival signals, majorly PI3-K/Akt pathway but also other ways, rescuing cells from apoptosis. Studies imply an involvement of PDGF in dendrite spine morphology, being critical for memory in the developing brain. Recent studies suggest association of PDGF genes with neuropsychiatric disorders. In this review, we will describe the roles of PDGF in the nervous system, from the discovery to recent findings, in order to understand the broad spectrum of PDGF in the nervous system. Recent development of pharmacological and replacement therapies targeting the PDGF system is discussed.
doi:10.1007/s11481-013-9479-z
PMCID: PMC3955130  PMID: 23771592
PDGF; PDGFRA; PDGFRB; Nervous system
7.  The role of PDGF in radiation oncology 
Platelet-derived growth factor (PDGF) was originally identified as a constituent of blood serum and subsequently purified from human platelets. PDGF ligand is a dimeric molecule consisting of two disulfide-bonded chains from A-, B-, C- and D-polypeptide chains, which combine to homo- and heterodimers. The PDGF isoforms exert their cellular effects by binding to and activating two structurally related protein tyrosine kinase receptors. PDGF is a potent mitogen and chemoattractant for mesenchymal cells and also a chemoattractant for neutrophils and monocytes. In radiation oncology, PDGF are important for several pathologic processes, including oncogenesis, angiogenesis and fibrogenesis. Autocrine activation of PDGF was observed and interpreted as an important mechanism involved in brain and other tumors. PDGF has been shown to be fundamental for the stability of normal blood vessel formation, and may be essential for the angiogenesis in tumor tissue. PDGF also plays an important role in the proliferative disease, such as atherosclerosis and radiation-induced fibrosis, regarding its proliferative stimulation of fibroblast cells. Moreover, PDGF was also shown to stimulate production of extracellular matrix proteins, which are mainly responsible for the irreversibility of these diseases. This review introduces the structural and functional properties of PDGF and PDGF receptors and discusses the role and mechanism of PDGF signaling in normal and tumor tissues under different conditions in radiation oncology.
doi:10.1186/1748-717X-2-5
PMCID: PMC1780053  PMID: 17217530
8.  Expression, mutation and copy number analysis of platelet-derived growth factor receptor A (PDGFRA) and its ligand PDGFA in gliomas 
British Journal of Cancer  2009;101(6):973-982.
Background:
Malignant gliomas are the most prevalent type of primary brain tumours but the therapeutic armamentarium for these tumours is limited. Platelet-derived growth factor (PDGF) signalling has been shown to be a key regulator of glioma development. Clinical trials evaluating the efficacy of anti-PDGFRA therapies on gliomas are ongoing. In this study, we intended to analyse the expression of PDGFA and its receptor PDGFRA, as well as the underlying genetic (mutations and amplification) mechanisms driving their expression in a large series of human gliomas.
Methods:
PDGFA and PDGFRA expression was evaluated by immunohistochemistry in a series of 160 gliomas of distinct World Health Organization (WHO) malignancy grade. PDGFRA-activating gene mutations (exons 12, 18 and 23) were assessed in a subset of 86 cases by PCR—single-strand conformational polymorphism (PCR-SSCP), followed by direct sequencing. PDGFRA gene amplification analysis was performed in 57 cases by quantitative real-time PCR (QPCR) and further validated in a subset of cases by chromogenic in situ hybridisation (CISH) and microarray-based comparative genomic hybridisation (aCGH).
Results:
PDGFA and PDGFRA expression was found in 81.2% (130 out of 160) and 29.6% (48 out of 160) of gliomas, respectively. Its expression was significantly correlated with histological type of the tumours; however, no significant association between the expression of the ligand and its receptor was observed. The absence of PDGFA expression was significantly associated with the age of patients and with poor prognosis. Although PDGFRA gene-activating mutations were not found, PDGFRA gene amplification was observed in 21.1% (12 out of 57) of gliomas. No association was found between the presence of PDGFRA gene amplification and expression, excepting for grade II diffuse astrocytomas.
Conclusion:
The concurrent expression of PDGFA and PDGFRA in different subtypes of gliomas, reinforce the recognised significance of this signalling pathway in gliomas. PDGFRA gene amplification rather than gene mutation may be the underlying genetic mechanism driving PDGFRA overexpression in a portion of gliomas. Taken together, our results could provide in the future a molecular basis for PDGFRA-targeted therapies in gliomas.
doi:10.1038/sj.bjc.6605225
PMCID: PMC2743351  PMID: 19707201
PDGFA; PDGFRA; expression; mutations; amplification; gliomas
9.  Imatinib induces apoptosis by inhibiting PDGF- but not insulin-induced PI 3-kinase/Akt survival signaling in RGC-5 retinal ganglion cells 
Molecular Vision  2009;15:1599-1610.
Purpose
Platelet-derived growth factor (PDGF) and insulin promote the survival of neuronal cells, including retinal ganglion cells (RGCs), via activation of phosphoinositide 3-kinase (PI 3-kinase)/Akt signaling. Of importance, recent studies have shown that imatinib inhibition of PDGF receptors induces retinal toxicity in some patients. To date, the extent of activation and the functional significance of insulin-induced PI 3-kinase/Akt signaling remain unclear in the context of dysregulated PDGF receptor signaling in retinal cells. In the present study, we tested the hypothesis that the pro-survival effect of insulin-induced PI 3-kinase/Akt signaling is compromised by imatinib inhibition of PDGF receptor signaling in RGCs.
Methods
RGC-5 cells were subjected to acute and long-term treatments with imatinib, a PDGF receptor tyrosine kinase inhibitor. Afterwards, the changes in RGC phenotype and apoptotic markers were assessed by fluorescence and phase contrast microscopy and caspase-3/poly(ADP-ribose) polymerase (PARP) cleavage, respectively. In addition, imatinib regulation of PDGF- and insulin-induced PI 3-kinase/Akt survival signaling was determined by immunoblot analyses, immunoprecipitation, and in vitro PI 3-kinase assays.
Results
Treatment of RGC-5 cells with imatinib for up to 48 h resulted in apoptosis, which was not rescued by insulin supplementation. The apoptotic phenotype was associated with upregulation of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. Time dependency experiments revealed that imatinib-mediated apoptosis was preceded by early and sustained abrogation of PDGF-induced increases in PDGF receptor tyrosine phosphorylation and phosphotyrosine-associated PI 3-kinase activity. In addition, imatinib inhibited PDGF-induced downstream phosphorylation of Akt, GSK-3β, and p70S6kinase. However, imatinib exposure did not affect insulin-induced insulin receptor substrate (IRS)-associated PI 3-kinase activity and the downstream phosphorylation of Akt, GSK-3β, and p70S6kinase.
Conclusions
Together, these data indicate that disruption of PDGF receptor signaling compromises the pro-survival effect of insulin-induced IRS-dependent PI 3-kinase/Akt signaling in RGCs, and that the maintenance of PDGF-induced PI 3-kinase/Akt signaling is critical for the survival of retinal neuronal cells.
PMCID: PMC2728561  PMID: 19693287
10.  Effects of PKC412, nilotinib and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity 
Gastroenterology  2006;131(6):1734-1742.
Background & Aims
Activating mutations in platelet-derived growth factor receptor alpha (PDGFRA) have been reported in a subset of gastrointestinal stromal tumor (GIST) patients who do not express mutant stem cell factor receptor, c-KIT. The responsiveness of mutant PDGFRA-positive GIST to imatinib depends on the location of the PDGFRA mutation; for example, the V561D juxtamembrane domain mutation is more sensitive to imatinib than the D842V kinase domain mutation. In this study, we compare the effects of three tyrosine kinase inhibitors, PKC412 and nilotinib, and imatinib, on two GIST-related PDGFRA mutants, V561D and D842V, which possess differential sensitivity to imatinib.
Methods
The effects of PKC412, nilotinib, and imatinib, alone and in combination, were evaluated via in vitro proliferation studies performed with V561D- or D842V-PDGFRA mutants. The effects of nilotinib and PKC412, alone and combined, were investigated in vivo.
Results
PKC412 potently inhibited the V561D-PDGFRA mutant in vitro and the D842V-PDGFRA mutant in vitro and in vivo. Both imatinib and nilotinib displayed potent activity in vitro against the V561D-PDGFRA mutant, but were significantly less efficacious against D842V-PDGFRA. However, when combined with either imatinib or PKC412, nilotinib showed no evidence for antagonism and acted in a cooperative fashion against D842V-PDGFRA.
Conclusions
Our findings support the clinical testing of PKC412 for treatment of mutant PDGFRA-GIST. The data also support the use of nilotinib as a treatment option for V561D-PDGFRA-associated GIST, although the reduced sensitivity of D842V-PDGFRA probably limits the potential of nilotinib monotherapy for D842V-PDGFRA-associated GIST.
doi:10.1053/j.gastro.2006.09.017
PMCID: PMC2967439  PMID: 17087936
11.  Platelet-Derived Growth Factor as a Therapeutic Target for Systemic Autoimmune Diseases 
Drug Target Insights  2007;2:239-247.
Some systemic rheumatic diseases and disorders, especially fibrotic and vascular disorders, are often refractory to corticosteroid therapy. Recently, ever accumulating evidence suggests that platelet-derived growth factor (PDGF) is involved in those refractory diseases. Imatinib mesylate inhibits the activation of PDGF receptor as well as c-Abl, Bcr-Abl and c-Kit tyrosine kinases. It has therefore been widely used for the treatment of chronic myeloid leukemia and gastrointestinal stromal tumors. Imatinib effectively suppresses the activation and proliferation of fibroblasts, mesangial cells and smooth muscle cells both in vitro and in vivo. Additionally, it has recently been reported that some patients with rheumatoid arthritis or idiopathic pulmonary arterial hypertension demonstrated a good clinical response to imatinib therapy. Imatinib may therefore overcome the limitations of current therapeutic strategy with corticosteroids and immunosuppressive agents for refractory diseases, such as systemic sclerosis and interstitial lung diseases, without clinical intolerability.
PMCID: PMC3155225  PMID: 21901078
imatinib mesylate; rheumatoid arthritis; fibroblast; rheumatic diseases; interstitial lung disease
12.  Autocrine PDGF stimulation in malignancies 
Platelet-derived growth factor (PDGF) isoforms are important mitogens for different types of mesenchymal cells, which have important functions during the embryonal development and in the adult during wound healing and tissue homeostasis. In tumors, PDGF isoforms are often over-expressed and contribute to the growth of both normal and malignant cells. This review focuses on tumors expressing PDGF isoforms together with their tyrosine kinase receptors, thus resulting in autocrine stimulation of growth and survival. Patients with such tumors could benefit from treatment with inhibitors of either PDGF or PDGF receptors.
doi:10.3109/03009734.2012.658119
PMCID: PMC3339540  PMID: 22512244
Molecular biology; oncogenes; tumor biology
13.  FIP1L1/PDGFRα-Associated Systemic Mastocytosis 
Since the identification of the FIP1L1/PDGFRA fusion gene as a pathogenic cause of the hypereosinophilic syndrome (HES), the importance of the molecular classification of HES leading to the diagnosis of chronic eosinophilic leukemia (CEL) has been recognized. As a result, a new category, ‘myeloid and lymphoid neoplasm with eosinophilia and abnormalities in PDGFRA, PDGFRB or FGFR1’, has recently been added to the new WHO criteria for myeloid neoplasms. FIP1L1/PDGFRα-positive disorders are characterized by clonal hypereosinophilia, multiple organ dysfunctions due to eosinophil infiltration, systemic mastocytosis (SM) and a dramatic response to treatment with imatinib mesylate. A murine HES/CEL model by the introduction of FIP1L1/PDGFRα and IL-5 overexpression also shows SM, representing patients with FIP1L1/PDGFRα-positive HES/CEL/SM. The murine model and the in vitro development system of FIP1L1/PDGFRα-positive mast cells revealed the interaction between FIP1L1/PDGFRα, IL-5 and stem cell factor in the development of HES/CEL/SM. Current findings of FIP1L1/PDGFRα-positive HES/CEL are reviewed focusing on aberrant mast cell development leading to SM.
doi:10.1159/000312134
PMCID: PMC2917731  PMID: 20523072
Chronic eosinophilic leukemia; Eosinophils; FIP1L1/PDGFRα; Hypereosinophilic syndromes; Interleukin-5; Mast cells; Stem cell factor; Systemic mastocytosis
14.  Platelet-derived growth factor signaling in human malignancies 
Chinese journal of cancer  2011;30(9):581-584.
Platelet-derived growth factors (PDGFs) and their receptors were identified and purified decades ago. PDGFs are important during normal development and in human cancers. In particular, autocrine PDGF signaling has been implicated in various types of malignancies such as gliomas and leukemia. In contrast, paracrine signaling was found in cancers that originate from epithelial cells, where it may be involved in stromal cell recruitment, metastasis, and epithelial-mesenchymal transition. This editorial briefly discusses autocrine and paracrine PDGF signaling and their roles in human cancers, and introduces a series of review articles in this issue that address the possible roles of PDGFs in various processes involved in different types of cancers.
doi:10.5732/cjc.011.10300
PMCID: PMC3525704  PMID: 21880178
Platelet-derived growth factor; cancer; tumor progression; drug resistance
15.  Platelet-derived growth factor signaling in human malignancies 
Chinese Journal of Cancer  2011;30(9):581-584.
Platelet-derived growth factors (PDGFs) and their receptors were identified and purified decades ago. PDGFs are important during normal development and in human cancers. In particular, autocrine PDGF signaling has been implicated in various types of malignancies such as gliomas and leukemia. In contrast, paracrine signaling was found in cancers that originate from epithelial cells, where it may be involved in stromal cell recruitment, metastasis, and epithelial-mesenchymal transition. This editorial briefly discusses autocrine and paracrine PDGF signaling and their roles in human cancers, and introduces a series of review articles in this issue that address the possible roles of PDGFs in various processes involved in different types of cancers.
doi:10.5732/cjc.011.10300
PMCID: PMC3525704  PMID: 21880178
Platelet-derived growth factor; cancer; tumor progression; drug resistance
16.  Phase II testing of sunitinib: the National Cancer Institute of Canada Clinical Trials Group IND Program Trials IND.182–185 
Current Oncology  2007;14(4):154-161.
Sunitinib (SU11248) is an orally bioavailable inhibitor that affects the receptor tyrosine kinases involved in tumour proliferation and angiogenesis, including vascular endothelial growth factor (vegf) receptors 1, 2, 3, and platelet-derived growth factor receptors alpha (pdgfra) and beta (pdgfrb). Because angiogenesis is necessary for the growth and metastasis of solid tumours, and vegf is believed to have a pivotal role in that process, sunitinib treatment may have broad-spectrum clinical utility. In the present article, we discuss the biologic and clinical rationales that have recently led the Investigational New Drug Program of the National Cancer Institute of Canada Clinical Trials Group to initiate four phase ii trials testing this agent in the following four different tumour types: relapsed diffuse large cell lymphoma, malignant pleural mesothelioma, locally advanced or metastatic cervical cancer and recurrent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.
PMCID: PMC1948864  PMID: 17710208
Sunitinib; receptor tyrosine kinase inhibitor; ind; angiogenesis; ncic; phase ii
17.  Discovery of imatinib-responsive FIP1L1-PDGFRA mutation during refractory acute myeloid leukemia transformation of chronic myelomonocytic leukemia 
The FIP1L1-PDGFRA rearrangement results in constitutive activation of the tyrosine kinase PDGFRA. Neoplasms harboring this rearrangement are responsive to imatinib mesylate at doses much lower than those recommended for the treatment of chronic myelogenous leukemia. Only a single report has described the identification of FIP1L1-PDGFRA in chronic myelomonocytic leukemia (CMML). Herein, we present a case report of a patient in whom the FIP1L1-PDGFRA was discovered as he evolved from CMML to acute myeloid leukemia (AML). The presence of a dominant neoplastic clone with FIP1L1-PDGFRA rearrangement was suspected on the basis of sudden onset of peripheral and bone marrow eosinophilia and confirmed by fluorescence in situ hybridization and molecular diagnostic tests. Whereas the patient was initially refractory to chemotherapy before the rearrangement was detected, subsequent therapy with imatinib led to complete remission.
doi:10.1186/1756-8722-7-26
PMCID: PMC3994268  PMID: 24669761
FIP1L1-PDGRFA; Chronic myelomonocytic leukemia; Imatinib mesylate
18.  Differential Tumorigenic Potential and Matriptase Activation between PDGF B versus PDGF D in Prostate Cancer 
Molecular cancer research : MCR  2012;10(8):1087-1097.
The platelet-derived growth factors (PDGF A, B, C, and D) and their receptors (α-PDGFR and β-PDGFR) play an indispensible role in physiologic and pathologic conditions, including tumorigenesis. The transformative β-PDGFR is overexpressed and activated during prostate cancer progression, but the identification and functional significance of its complementary ligand have not been elucidated. This study examined potential oncogenic functions of β-PDGFR ligands PDGF B and PDGF D, using nonmalignant prostate epithelial cells engineered to overexpress these ligands. In our models, PDGF D induced cell migration and invasion more effectively than PDGF B in vitro. Importantly, PDGF D supported prostate epithelial cell tumorigenesis in vivo and showed increased tumor angiogenesis compared with PDGF B. Autocrine signaling analysis of the mitogen-activated protein kinase and phosphoinositide 3-kinase pathways found PDGF D–specific activation of the c-jun-NH2-kinase (JNK) signaling cascade. Using short hairpin RNA and pharmacologic inhibitors, we showed that PDGFD-mediated phenotypic transformation is β-PDGFR and JNK dependent. Importantly, we made a novel finding of PDGF D–specific increase in the shedding and activation of the serine protease matriptase in prostate epithelial cells. Our study, for the first time to our knowledge, showed ligand-specific β-PDGFR signaling as well as PDGF D–specific regulation of matriptase activity and its spatial distribution through shedding. Taken together with our previous finding that matriptase is a proteolytic activator of PDGF D, this study provides a molecular insight into signal amplification of the proteolytic network and PDGF signaling loop during cancer progression.
doi:10.1158/1541-7786.MCR-12-0071
PMCID: PMC3929081  PMID: 22689130
19.  The Diminished Expression of Proangiogenic Growth Factors and Their Receptors in Gastric Ulcers of Cirrhotic Patients 
PLoS ONE  2013;8(4):e61426.
Objectives
The pathogenesis of the higher occurrence of peptic ulcer disease in cirrhotic patients is complex. Platelets can stimulate angiogenesis and promote gastric ulcer healing. We compared the expressions of proangiogenic growth factors and their receptors in the gastric ulcer margin between cirrhotic patients with thrombocytopenia and those of non-cirrhotic patients to elucidate possible mechanisms.
Methods
Eligible cirrhotic patients (n = 55) and non-cirrhotic patients (n = 55) who had gastric ulcers were enrolled. Mucosa from the gastric ulcer margin and non-ulcer areas were sampled and the mRNA expressions of the proangiogenic growth factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], basic fibroblast growth factor [bFGF]) and their receptors (VEGFR1, VEGFR2, PDGFRA, PDGFRB, FGFR1, FGFR2) were measured and compared. Platelet count and the expressions of these growth factors and their receptors were correlated with each other.
Results
The two groups were comparable in terms of gender, ulcer size and infection rate of Helicobacter pylori. However, the cirrhotic group were younger in age, had a lower platelet count than those in the non-cirrhotic group (p<0.05). The cirrhotic patients had diminished mRNA expressions of PDGFB, VEGFR2, FGFR1, and FGFR2 in gastric ulcer margin when compared with those of the non-cirrhotic patients (p<0.05). Diminished expressions of PDGFB and VEGFR2, FGFR1, and FGFR2 were well correlated with the degree of thrombocytopenia in these cirrhotic patients (ρ>0.5, p<0.001).
Conclusions
Our findings implied that diminished activity of proangiogenic factors and their receptors may contribute to the pathogenesis of gastric ulcers in cirrhotic patients.
doi:10.1371/journal.pone.0061426
PMCID: PMC3631223  PMID: 23620752
20.  Down-regulation of cellular platelet-derived growth factor receptors induced by an activated neu receptor tyrosine kinase. 
Cell Regulation  1991;2(8):651-661.
The functional integration of growth factor signaling occurs at several levels in target cells. One of the most proximal mechanisms is receptor transmodulation, by which one activated receptor can regulate the expression of other receptors in the same cells. Well-established transregulatory loops involve platelet-derived growth factor (PDGF) down-regulation of epidermal growth factor (EGF) receptors and beta-type transforming growth factors modulation of PDGF receptors. We have studied the relationship between neu tyrosine kinase activation and the expression of the PDGF receptors in transfected NIH/3T3 cells. Expression of the neu oncogene, but not of the neu proto-oncogene, was associated with a decrease of PDGF alpha- and beta-receptors on the cell surface, as measured by [125-I]PDGF-AA and -BB binding. These results were corroborated by metabolic labeling and immunoprecipitation of the PDGF beta-receptors. PDGF alpha- and beta-receptor mRNAs were strongly decreased in the neu oncogene-transformed cells in comparison with control cells expressing the neu proto-oncogene. Down-regulation of the PDGF receptors and their mRNAs was also observed after EGF treatment of cells expressing a chimeric EGF receptor/neu receptor, where the neu tyrosine kinase is activated by EGF binding. These results show that the neu tyrosine kinase can down-modulate PDGF receptor expression, and the effect is mediated via decreased PDGF receptor mRNA levels.
Images
PMCID: PMC361855  PMID: 1685673
21.  Tirosin Kinase Inhibitors in Chronic Graft versus Host Disease: From Bench to Bedside 
TheScientificWorldJournal  2011;11:1908-1931.
Chronic Graft Versus Host Disease (cGVHD) is a major complication of allogeneic stem-cell transplantation (SCT). In many inflammatory fibrotic diseases, such as Systemic Scleroderma (SSc) and cGVHD with fibrotic features, an abnormal activation of transforming growth factor (TGFβ) and platelet-derived growth factor receptor (PDGF-R) pathways have been observed. Tyrosin Kinase Inhibitors (TKIs), which are currently used for treatment of patients with Chronic Myeloid Leukemia (CML), share potent antifibrotic and antiinflammatory properties, being powerful dual inhibitors of both PDGF-R and TGFβ pathways. Moreover accumulating in vitro data confirm that TKIs, interacting with the TCR and other signalling molecules, carry potent immunomodulatory effects, being involved in both T-cell and B-cell response. Translation to the clinical setting revealed that treatment with Imatinib can achieve encouraging responses in patients with autoimmune diseases and steroid-refractory cGVHD, showing a favourable toxicity profile. While the exact mechanisms leading to such efficacy are still under investigation, use of TKIs in the context of clinical trials should be promoted, aiming to evaluate the biological changes induced in vivo by TKIs and to assess the long term outcome of these patients. Second-generation TKIs, with more favourable toxicity profile are under evaluation in the same setting.
doi:10.1100/2011/924954
PMCID: PMC3217614  PMID: 22125447
cGVHD; Imatinib; TKI
22.  Ligand-dependent PDGF receptor-alpha activation sensitizes rare lung cancer and sarcoma cells to PDGF receptor kinase inhibitors 
Cancer research  2009;69(9):3937-3946.
Platelet-derived growth factor receptors (PDGFR) and their ligands play critical roles in several human malignancies. Sunitinib is a clinically-approved multi-targeted tyrosine kinase inhibitor which inhibits VEGFR, c-KIT, and PDGFR, and has demonstrated clinical activity in various solid tumors. Activation of PDGFR signaling has been described in gastrointestinal stromal tumors (GISTs) (PDGFRA mutations) as well as in chronic myeloid leukemia (BCR-PDGFRA translocation), and sunitinib can yield clinical benefit in both settings. However, the discovery of PDGFR activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti-PDGFR therapies, such as sunitinib. Using a high-throughput cancer cell line screening platform, we found that only 2 out of 637 tested human tumor-derived cell lines demonstrate significant sensitivity to single-agent sunitinib exposure. These two cell lines (a NSCLC and a rhabdomyosarcoma) demonstrated expression of highly phosphorylated PDGFRA. In the sunitinib-sensitive adeno-squamous NSCLC cell line, PDGFRA expression was associated with focal PFGRA gene amplification, which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens. Moreover, in this NSCLC cell line, focal amplification of the gene encoding the PDGFR ligand PDGFC was also detected, and silencing PDGFRA or PDGFC expression by RNA interference inhibited proliferation. A similar co-dependency on PDGFRA and PDGFC was observed in the sunitinib-sensitive rhabdomyosarcoma cell line. These findings suggest that, in addition to GISTs, rare tumors that demonstrate PDGFC-mediated PDGFRA activation may also be clinically responsive to pharmacologic PDGFRA or PDGFC inhibition.
doi:10.1158/0008-5472.CAN-08-4327
PMCID: PMC2676215  PMID: 19366796
Platelet-derived growth factor receptor; PDGF-C; NSCLC; sarcoma; sunitinib
23.  Current Concepts on the Pathogenesis of the Hypereosinophilic Syndrome/Chronic Eosinophilic Leukemia 
Chronic eosinophilic leukemia is a clonal disease characterized by hypereosinophilia and eosinophilia-related pathologic manifestations. Recently, the fusion gene FIP1L1/PDGFRA was found in the long arm of chromosome 4 and its expression has been shown to be associated with development of a clinical hypereosinophilic syndrome (HES) in a significant proportion of patients. FIP1L1/PDGFRα, the product of the gene FIP1L1/PDGFRA, is a constitutively activated tyrosine kinase and can be inhibited by imatinib mesylate. Several investigations have tried to dissect the mechanism of leukemogenesis and signaling induced by FIP1L1/PDGFRα in cell lines, primary human eosinophils and in murine myeloproliferative models. In this review, we analyzed the current knowledge on the relationship between FIP1L1/PDGFRα-induced signaling and eosinophil proliferation, survival and activation, specially focusing on its possible role in the modulation of cytokine and chemoattractant signaling pathways.
PMCID: PMC3642145  PMID: 23662039
FIP1L1/PDGFRα; chronic eosinophilic leukemia; hypereosinophilic syndrome eosinophils; mast cells
24.  Analysis of receptor tyrosine kinases (RTKs) and downstream pathways in chordomas† 
Neuro-Oncology  2010;12(8):776-789.
We have previously demonstrated that chordomas express activated platelet-derived growth factor receptor (PDGFRB) and that treatment with imatinib, which is capable of switching off the activation of various receptor tyrosine kinases (RTKs) including PDGFRB, benefits a number of patients. The aim of this study was to identify the possible presence of other activated RTKs and their downstream signaling effectors. Cryopreserved material from 22 naïve sporadic chordomas was investigated for the presence of activated RTKs and their cognate ligands and downstream signaling effectors by means of human phospho-RTK antibody arrays, Western blotting, and molecular analysis; immunohistochemistry and fluorescence in situ hybridization were used to analyze the corresponding formalin-fixed and paraffin-embedded samples. We detected activated PDGFRB, FLT3, and colony stimulating factor 1 receptor (CSF1R) of the PDGFR family and highly phosphorylated EGFR, HER2/neu, and (to a lesser extent) HER4 of the EGFR family. The detection of PDGFRB/PDGFB confirmed our previous data. The presence of activated EGFR was paralleled by the finding of high levels of epidermal growth factor (EGF) and transforming growth factor α (TGFα) and PDGFB co-expression and PDGFRB co-immunoprecipitation. Of the downstream effectors, the PI3K/AKT and RAS/MAPK pathways were both activated, thus leading to the phosphorylation of mammalian target of rapamycin (mTOR) and 4E-BP1 among the regulators involved in translational control. Taken together, our results (i) provide a rationale for tailored treatments targeting upstream activated receptors, including the PDGFR and EGFR families; (ii) support the idea that a combination of upstream antagonists and mTOR inhibitors enhances the control of tumor growth; and (iii) indicate that the 4E-BP1/eIF4E pathway is a major regulator of protein synthesis in chordoma.
doi:10.1093/neuonc/noq003
PMCID: PMC2940683  PMID: 20164240
chordomas; mTOR; receptor tyrosine kinases (RTKs); signal transduction.
25.  Platelet-derived growth factor (PDGF)-induced disulfide-linked dimerization of PDGF receptor in living cells. 
Molecular and Cellular Biology  1991;11(7):3756-3761.
It is well established that epidermal growth factor and platelet-derived growth factor (PDGF) are able to induce noncovalent dimerization of their surface receptors. It is thought that receptor dimerization plays an important role in activation of the tyrosine kinase function and in the process of receptor autophosphorylation. Here we show that the addition of either PDGF-BB or PDGF-AA to intact 3T3 cells induces formation of 400- and 430-kDa species, respectively, recognized by either anti-PDGF receptor antibodies or anti-phosphotyrosine antibodies. Interestingly, the 400- and the 430-kDa species are detected in nonreducing gels but not in reducing gels. Moreover, an alkylating agent, N-ethylmaleimide, inhibits PDGF-induced formation of high-molecular-mass species. Comparisons of V8 protease peptide maps of [35S]methionine-labeled PDGF receptors and high-molecular-mass proteins indicate that they represent dimers of PDGF receptors. It appears therefore that in addition to noncovalent dimerization, PDGF receptors undergo ligand-dependent disulfide-linked dimerization.
Images
PMCID: PMC361145  PMID: 1646395

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