No abstract available.
Colon* ; Liver* ; Platelet-Derived Growth Factor* ; Receptors, Platelet-Derived Growth Factor*

BACKGROUND: Four platelet derived growth factor (PDGF) family members have been identified; the classical PDGFs, PDGF-A and PDGF-B, and the novel PDGFs, PDGF-C and PDGF-D, which were only recently discovered. METHODS: The present study was designed to determine the changes of the platelet derived growth factor (PDGF) subtypes (C & D) and their receptors (PDGFR)-alpha & beta expression in kidneys during pre- and postnatal development. RESULTS: All the protein levels of PDGFR-alpha and -beta and the mRNA levels of PDGF-C and D were high in kidneys during the prenatal period and decreased differently during the postnatal period. PDGFR-alpha was expressed in the interstitial space at embryo day 18. PDGFR-beta protein were expressed in metanephric blastema at embryo day 18. PDGF-C mRNA was expressed in metanephric blastema, developing glomerulus at embryo 18 day and in collecting duct at postnatal day 7. PDGF-D mRNA was expressed in the parietal and vesceral epithelial cells during pre and postnatal period. CONCLUSION: These results indicate that the PDGF subtypes (C & D) and their receptors (PDGFR-alpha & -beta) are differently expressed in the kidney during the prenatal and postnatal period.
Embryonic Structures ; Epithelial Cells ; Humans ; Kidney ; Platelet-Derived Growth Factor ; Rabeprazole ; Receptors, Platelet-Derived Growth Factor* ; RNA, Messenger

BACKGROUND/AIMS: Gastrointestinal stromal tumors (GISTs) strongly express a receptor tyrosine kinase (RTK, c-KIT-CD117) harboring a KIT mutation that causes constitutive receptor activation leading to the development and growth of tumors; 35% of GISTs without KIT mutations have platelet-derived growth factor receptor alpha (PDGFRA) mutations, and the type of mutation plays an important role in the response to treatment. This study aimed to establish the frequency of stop codon mutations in the RTKs, KIT, and PDGFRA, in GISTs and correlate this molecular alteration with protein expression and treatment responsiveness. METHODS: Seventy-nine GISTs were analyzed for both KIT and PDGFRA mutations. Immunohistochemical expression was studied in tissue microarray blocks. RESULTS: We found three rare KIT mutations in exon 11 that induced a stop codon, two at position 563 and one at position 589, which have never been described before. All three tumors were CD117-, DOG1-, and CD34-positive. Two patients with a KIT stop codon mutation did not respond to imatinib therapy and died shortly after treatment. CONCLUSIONS: The association between stop codon mutations in KIT and patient survival, if confirmed in a larger population, may be useful in choosing effective therapies.
Benzamides ; Codon, Terminator ; Exons ; Gastrointestinal Stromal Tumors ; Growth and Development ; Humans ; Piperazines ; Protein-Tyrosine Kinases ; Pyrimidines ; Receptor, Platelet-Derived Growth Factor alpha ; Receptors, Platelet-Derived Growth Factor

PURPOSE: The incidence of gastrointestinal stromal tumors (GISTs) harboring platelet-derived growth factor receptor alpha (PDGFRA) mutations is low, therefore further investigation of the efficacy of imatinib in this subgroup was needed. MATERIALS AND METHODS: Patients with PDGFRA-mutant GISTs who received imatinib as primary therapy for advanced disease between January 2000 and June 2012 were identified from the GIST registry of Asan Medical Center, Seoul, Korea. RESULTS: KIT and PDGFRA genotyping in 823 patients identified 18 patients (2%) with PDGFRA mutations who were treated with first-line imatinib. Exon 18 D842V substitution, non-D842V exon 18 mutations, and exon 12 mutations were detected in nine (50%), four (22%), and five (28%) patients, respectively. Objective response rate differed significantly between patients with the D842V mutation and those with non-D842V mutations (0% [0/5] vs. 71% [5/7], p=0.03). In all patients, median progression-free survival (PFS) and overall survival (OS) was 24.8 months (95% confidence interval [CI], 0.0 to 57.2) and 51.2 months (95% CI, 37.1 to 65.3), respectively. Significantly, poorer PFS was observed for patients with D842V-mutant GISTs than those with non-D842V PDGFRA-mutant GISTs: median 3.8 months (95% CI, 1.4 to 6.3) versus 29.5 months (95% CI, 18.3 to 40.7) (p < 0.001). Patients with the D842V mutation had poorer OS than those with non-D842V PDGFRA mutations: median 25.2 months (95% CI, 12.7 to 37.8) versus 59.8 months (95% CI, 43.0 to 76.5) (p=0.02). CONCLUSION: Imatinib is active against non-D842V PDGFRA-mutant GISTs, whereas GISTs harboring the D842V mutation are primarily resistant to imatinib.
Chungcheongnam-do ; Disease-Free Survival ; Exons ; Gastrointestinal Stromal Tumors ; Humans ; Incidence ; Korea ; Platelet-Derived Growth Factor* ; Receptors, Platelet-Derived Growth Factor* ; Seoul

Platelet-derived growth factor (PDGF), a potent chemotactic and mitogenic factor, is involved in the regulation of hematopoiesis and platelet production. Our studies demonstrate the presence of functional PDGF receptors (PDGFR) on human megakaryocytes/platelets and CD34(+) cells, and their ability to mediate a mitogenic response. PDGF promotes the ex vivo expansion of human hematopoietic stem (CD34(+)) and progenitor (CD41(+)) cells. More significantly, PDGF enhances the engraftment of human CD45(+) cells and their myeloid subsets (CD33(+), CD14(+) cells) in NOD/SCID mice. PDGF also stimulates in vitro megakaryocytopoiesis via PDGFR and/or the indirect effect on bone marrow microenvironment to produce TPO and other cytokines. It also shows a direct stimulatory effect of PDGF on c-Fos, GATA-1 and NF-E2 expressions in megakaryocytes. We speculate that these transcription factors may be involved in the signal transduction of PDGF on the regulation of megakaryocytopoiesis. PDGF also enhances platelet recovery in mouse model with radiation-induced thrombocytopenia. This radioprotective effect is likely to be mediated via PDGFR with subsequent activation of the PI3K/Akt pathway. It provides a possible explanation that blockage of PDGFR may reduce thrombopoiesis and play a role in imatinib mesylate-induced thrombocytopenia.
Animals ; Hematopoietic Stem Cells ; cytology ; Humans ; Megakaryocytes ; cytology ; Mice ; Platelet-Derived Growth Factor ; metabolism ; Receptors, Platelet-Derived Growth Factor ; metabolism ; Thrombopoiesis

Benign prostatic hyperplasia (BPH) and prostatitis are very common diseases in elderly men. The recent researches demonstrate that chronic inflammation is often present in the prostatic tissue of patients with BPH and the platelet-derived growth factor (PDGF) plays an important part in stimulating prostatic cell proliferation by inducing mitogenesis. This article presents a detailed discussion on the relationship between PDGF and BPH.
Cell Proliferation ; Humans ; Male ; Platelet-Derived Growth Factor ; metabolism ; Prostatic Hyperplasia ; metabolism ; pathology ; Prostatitis ; metabolism ; pathology ; Receptors, Platelet-Derived Growth Factor ; metabolism

PURPOSE: Phyllodes tumors (PTs) of the breast have been classified as benign, borderline, or malignant based on their histopathologic features. However, predicting clinical behavior based on these features has proven to be difficult given that local recurrence occurs in both benign and malignant PTs. Recurrence has been shown to mirror the histologic pattern of the primary tumor or to show dedifferentiation. The aim of this study was to assess the value of the histopathologic parameters, expression or mutation of c-Kit and platelet derived growth factor receptor alpha (PDGFRA) in predicting tumor recurrence. METHODS: Representative areas from 39 benign, 16 borderline, and 12 malignant PTs were selected for construction of tissue microarrays. Immunohistochemical analyses for p53, Ki-67, c-Kit, and PDGFRA were performed and SSCP-PCR analysis was carried out to identify mutations in exons 9, 11, 13, and 17 of the c-Kit gene and exons 12 and 18 of the PDGFRA gene. Clinicopathologic features, including tumor recurrence and margin status, were also evaluated. RESULTS: Of the 67 PTs, 11 cases (16.4%) recurred from 3 to 92 months following initial diagnosis (4 benign, 2 borderline, and 5 malignant). One benign PT case recurred as a borderline tumor and two borderline PT cases recurred as malignancies. Three patients died of malignant PT. No mutations of the c-Kit or PDGFRA genes were found and there was no statistically significant association of either p53 or p16 immunostaining with recurrent disease (p>0.05). However, histologic grade (p=0.033), margin status (p<0.001), Ki-67 (p=0.012), c-Kit (p=0.002), and PDGFRA (p=0.007) stromal immunopositivity were significantly correlated with recurrence. CONCLUSION: Even though positive or close margins were significantly associated with tumor recurrence, stromal c-Kit, PDGFRA positivity, and the Ki-67 index were useful for predicting recurrent PTs. Despite this, no c-Kit or PDGFRA mutations were found.
Breast ; Exons ; Humans ; Phyllodes Tumor ; Proto-Oncogene Proteins c-kit ; Receptors, Platelet-Derived Growth Factor ; Recurrence

Adult ; Aged ; Fatty Liver ; metabolism ; pathology ; Female ; Humans ; Male ; Middle Aged ; Platelet-Derived Growth Factor ; metabolism ; Protein-Serine-Threonine Kinases ; metabolism ; Receptors, Platelet-Derived Growth Factor ; metabolism ; Receptors, Transforming Growth Factor beta ; metabolism ; Young Adult

Hepatocellular carcinoma (HCC) is a highly malignant tumor that has limited treatment options in its advanced state. The efficacy of current anti-cancer chemotherapy in advanced HCC has not been satisfactory, and the management of HCC remains a major challenge for physicians. However, recent advancement in our understanding of the molecular mechanisms underlying carcinogenesis has provided novel targets in key signaling pathways for tumor development. Recently, Sorafenib (Nexavar), a multi-kinase inhibitor targeting membrane receptors involved in angiogenic and mitogenic intra-cellular signaling including Raf, vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptors (PDGFR), has been approved worldwide as a new target agent for HCC, and subsequent clinical trials of newly developed molecular target agents such as Brivanib and Everolimus are being conducted globally. In the near future, continued research will lead to the identification of additional molecular targets in HCC and lead to treatments with enhanced efficacy and improved tolerability.
Alanine ; Carcinoma, Hepatocellular ; Membranes ; Molecular Targeted Therapy ; Niacinamide ; Phenylurea Compounds ; Receptors, Platelet-Derived Growth Factor ; Receptors, Vascular Endothelial Growth Factor ; Signal Transduction ; Sirolimus ; Triazines ; Everolimus

BACKGROUND: N-nitrosomorpholine (NNM) is a genotoxic hepatocarcinogenic agent. Preneoplastic and neoplastic hepatocyte lesions were induced in rats by oral exposure to NNM (200 mg/L) in a stop model experiment. Platelet-derived growth factor receptor (PDGF-R) is a tyrosine kinase receptor that works with PDGF, stimulating cellular growth and proliferation. The present study was designed to determine the role of PDGF-R alpha expression in hepatocellular neoplasms and precursors. METHODS: Seventeen rats out of a starting number of 30 died. From the fifth week until the 24th week one or two rats were evaluated. Preneoplastic single cells or foci, foci of altered hepatocytes (FAH) hepatocellular adenomas (HCA) and hepatocellular carcinomas (HCC) were studied histologically, and the expressions of GSTp and PDGF-R alpha by immunohistochemistry. RESULTS: At the fifth week, GSTp +single cells showed PDGF-R alpha expression (20.8+/-5.8%). At the sixth week, GSTp +single cells, located at periportal areas, co-expressed PDGF-R alpha (43.4+/-9.6%). Over the next several weeks periportal hepatocytes showed weaker PDGF-R alpha expression but no GSTp. GSTp+FAH, and all HCA, demonstrated no PDGF-R alpha expression. However, nine out of 10 (90%) HCC showed PDGF-R alpha expression. CONCLUSIONS: These data showed that there were two peaks of PDGF-R alpha expression, and suggest that the earlier expression is related with the response to NNM-induced hepatocyte toxicity, and that the later response is associated to malignant transformation.
Adenoma, Liver Cell ; Animals ; Carcinoma, Hepatocellular ; Hepatocytes ; Immunohistochemistry ; Models, Animal* ; Protein-Tyrosine Kinases ; Rats* ; Receptors, Platelet-Derived Growth Factor