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1.
Oncology ; 98(4): 252-258, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32053815

RESUMEN

BACKGROUND: Very little is known about receptor tyrosine kinase (RTK) expression on peripheral blood mononuclear cells (PBMC) in humans including renal cell carcinoma (RCC) patients. OBJECTIVES: The primary objective of this study was to evaluate expression levels of major RTKs on PBMC and tumor-infiltrating lymphocytes (TIL) isolated from RCC patients. The secondary aim was to compare levels of RTK expression in RCC patients before surgery and on the 180th day after surgery (lymphocyte lifetime) and to compare them with the expression in healthy donors. In addition, we compared RTK and PD-L1 expression in TIL. METHODS: Tumor and blood samples were obtained from 20 patients with primary RCC immediately after surgical resection. Blood samples were collected from 20 healthy donors. Tumors were harvested into RPMI 1640 medium (Gibco) and processed within 4 h. TIL isolation was performed using a modified protocol [Baldan et al. Br J Cancer. 2015;112:1510-18]. Expression of RTKs was evaluated with NovoExpress Software. Twenty tumors from the same patients were stained with PD-L1 IHC assay (clone SP142; Ventana). RESULTS: PBMC and TIL express RTKs in humans. The RTK expression level was significantly lower on peripheral blood cells in patients with RCC (mean 41%, range 27.1-62.6%) as compared with healthy donor PBMC (mean 77.1%, range 72.1-80.1%, all p < 0.05). Furthermore, RTK expression was significantly downregulated on intratumoral cells (mean 40%, range 23.2-52.3%) in comparison with healthy donor PBMC. There was no significant recovery of RTK expression on the 180th day except for VEGFR2. Five of 20 (25%) patients were PD-L1 positive. PD-L1 expression on TIL was strongly associated with downregulated expression of PDGFRα (p = 0.017) and PDGFRß (p = 0.024). CONCLUSIONS: PBMC and TIL had similar low RTK expression levels in RCC patients. PBMC of healthy humans had a significantly higher expression of RTK. PD-L1 and PDGFRα-ß expression could correlate. Comprehensive basic and clinical studies will be needed to define a biological role of RTKs on different lymphocyte subsets and correlations between clinical outcomes and expression levels.


Asunto(s)
Donantes de Sangre , Carcinoma de Células Renales/enzimología , Neoplasias Renales/enzimología , Leucocitos Mononucleares/enzimología , Linfocitos Infiltrantes de Tumor/enzimología , Proteínas Tirosina Quinasas Receptoras/sangre , Adulto , Anciano , Antígeno B7-H1/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangre
2.
Pediatr Res ; 80(5): 759-765, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27603563

RESUMEN

BACKGROUND: Growth factors (GFs) are milk bioactive components contributing to the regulation of neonatal small intestinal maturation, and their receptors on the small intestinal epithelium play essential roles in mediating the functions of GFs. There is limited data correlating milk GFs and their receptors in the neonatal small intestine during the perinatal period. METHODS: Small intestines of C57BL/6N mouse pups were collected at regular intervals during fetal life and up to postnatal day (PD) 60. Gene expression of GF receptors was determined by real-time qPCR. Milk GF concentrations up to PD21 were analyzed by enzyme-linked immunosorbent assay. RESULTS: The majority of GF receptors showed significantly greater expression in the fetus than in postnatal life, and a sharp decrease occurred from PD14 extending to PD60; solid food restriction (PD14 and PD18) did not affect this decrease. Concentrations of five detected milk GFs demonstrated that GFs and the corresponding small intestinal receptors exhibited different correlations, with only milk transforming growth factor ß1 (TGF-ß1) having a significant positive correlation with TGF-ß receptor 1 mRNA. CONCLUSION: Gene expression of small intestinal GF receptors is likely a process of neonatal intestinal maturation that is affected concurrently by milk GFs and additional endogenous factors.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/metabolismo , Intestino Delgado/metabolismo , Leche/química , Animales , Animales Recién Nacidos , Receptores ErbB/sangre , Femenino , Regulación del Desarrollo de la Expresión Génica , Intestino Delgado/embriología , Intestino Delgado/crecimiento & desarrollo , Lactancia , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-met/sangre , Receptor IGF Tipo 1/sangre , Receptor de Insulina/sangre , Receptor de Factor de Crecimiento Nervioso/sangre , Receptores de Factores de Crecimiento de Fibroblastos/sangre , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangre , Receptores de Factores de Crecimiento Transformadores beta/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre
3.
Blood ; 122(25): 4111-8, 2013 Dec 12.
Artículo en Inglés | MEDLINE | ID: mdl-24152907

RESUMEN

Forty adults aged 28 to 73 years were entered into a prospective trial of imatinib for the treatment of steroid-refractory chronic graft-versus-host disease (SR-cGVHD). After 6 months, intention-to-treat (ITT) analysis of 39 patients who received the drug, regardless of the duration of treatment, revealed 14 partial responses (PR), 4 minor responses (MR) with relevant steroid sparing (46%) according to Couriel criteria, and 20 ≥ PR (51.3%), as per the National Institutes of Health (NIH) criteria and NIH severity score changes. The best responses were seen in the lungs, gut, and skin (35%, 50%, and 32%, respectively). After a median follow-up of 40 months, 28 patients were alive, with a 3-year overall survival (OS) and event-free survival of 72% and 46%, respectively. The 3-year OS was 94% for patients responding at 6 months and 58% for nonresponders according to NIH response, suggesting that these criteria represent a reliable tool for predicting OS after second-line treatment. Monitoring of anti-platelet-derived growth factor receptor (PDGF-R) antibodies showed a significant decrease in PDGF-R stimulatory activity in 7 responders, whereas it remained high in 4 nonresponders. This study confirms the efficacy of imatinib against SR-cGVHD and suggests that the response at 6 months significantly predicts long-term survival.


Asunto(s)
Benzamidas/administración & dosificación , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/mortalidad , Piperazinas/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Adulto , Anciano , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/efectos adversos , Autoanticuerpos/sangre , Benzamidas/efectos adversos , Enfermedad Crónica , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/sangre , Trasplante de Células Madre Hematopoyéticas , Humanos , Mesilato de Imatinib , Trastornos Linfoproliferativos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Trastornos Mieloproliferativos/mortalidad , Trastornos Mieloproliferativos/terapia , Piperazinas/efectos adversos , Prednisolona/administración & dosificación , Prednisolona/efectos adversos , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangre , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Factores de Tiempo
4.
Blood ; 116(16): 2984-93, 2010 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-20606160

RESUMEN

Malignant cells are capable of influencing the microenvironment in a manner that facilitates tumor cell survival. Bidirectional crosstalk between chronic lymphocytic leukemic (CLL) cells and marrow-derived mesenchymal stromal cells (MSCs) activates both cell types. In this study, we observed that the conditioned medium (CM) obtained from CLL cells was able to induce Akt activation in MSC. Subsequent studies investigated the mechanism of MSC activation mediated by CLL-CM. Platelet-derived growth factor receptors (PDGFRs) were selectively activated in MSCs by CLL-CM and found to be critical receptors for CLL-CM-driven MSC proliferation and MSC Akt activation. The known ligands of PDGFR, platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF), were detected in CLL-CM, but PDGF was the predominant ligand involved in the CM-mediated PDGFR activation. Both PDGF and VEGF were found to be elevated in the plasma of CLL patients with a positive association for high-risk factors and more advanced stage. Finally, we demonstrated that PDGF induced MSC VEGF production through a phosphatidylinositol 3-kinase (PI3K)-dependent mechanism. These results show that PDGF-PDGFR signaling influences at least the MSC in the microenvironment of CLL and may play a role in the induction of an angiogenic switch known to be permissive for disease progression.


Asunto(s)
Células de la Médula Ósea/citología , Leucemia Linfocítica Crónica de Células B/metabolismo , Células Madre Mesenquimatosas/citología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Células de la Médula Ósea/metabolismo , Movimiento Celular , Proliferación Celular , Medios de Cultivo Condicionados , Humanos , Células Madre Mesenquimatosas/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangre , Células del Estroma/citología , Células del Estroma/metabolismo , Factor A de Crecimiento Endotelial Vascular/sangre , Factor A de Crecimiento Endotelial Vascular/metabolismo
5.
Anal Chem ; 81(18): 7795-800, 2009 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-19691297

RESUMEN

Tunable aptamer capillary electrophoresis (CE) techniques were developed to enable the separation and detection of platelet derived growth factor (PDGF) isomers and their receptors. Using an aptamer that formed a stable complex with the B chain but not with the A chain of PDGF, we were able to tweak the electrophoretic mobilities of the PDGF isomers for their separation. PDGF-AB bound to a single aptamer molecule was well resolved from PDGF-BB bound to two aptamer molecules. Simultaneous determination of 50 pM of two isomers was accomplished in a single analysis. Furthermore, PDGF-AB was used as a connector to bring receptor alpha and fluorescent aptamer into a single complex molecule. As a result, the formation of a (receptor alpha)-(PDGF-AB)-(fluorescent aptamer) ternary complex enabled the detection of the receptor alpha by tunable aptamer CE. A competitive assay was developed to determine receptor beta, making use of the competition between the receptor beta and fluorescent aptamer in binding to PDGF-BB. Detection limits were 0.5 nM for PDGF receptor alpha and 3 nM for receptor beta. Determination of PDGF isomers and their receptors in diluted serum samples showed no interference from the sample matrix.


Asunto(s)
Aptámeros de Nucleótidos/metabolismo , Electroforesis Capilar/métodos , Factor de Crecimiento Derivado de Plaquetas/análisis , Receptores del Factor de Crecimiento Derivado de Plaquetas/análisis , Aptámeros de Nucleótidos/química , Colorantes Fluorescentes/química , Factor de Crecimiento Derivado de Plaquetas/química , Isoformas de Proteínas/análisis , Isoformas de Proteínas/química , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangre , Receptores del Factor de Crecimiento Derivado de Plaquetas/química , Proteínas Recombinantes/análisis , Proteínas Recombinantes/química
6.
Curr Opin Immunol ; 19(6): 640-5, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18083509

RESUMEN

Systemic sclerosis, scleroderma, is a disease characterized by widespread vascular injury and fibrosis of the skin and visceral organs. Circulating autoantibodies against several intracellular antigens are common in scleroderma patients. The specificities of such autoantibodies correlate with distinct clinical manifestations. However, till date there is no evidence that these autoantibodies, though helpful in diagnosis and prognosis, are linked to the pathogenesis of scleroderma nor that they may cause any feature of the disease. Recently, the discovery of novel agonistic autoantibodies targeting the PDGF receptor has provided important insight into the molecular pathogenesis of scleroderma and the intracellular mechanisms leading to fibrosis. Although their pathogenic role awaits validation in in vivo models, these antibodies represent the molecular link between the immune system and fibrosis.


Asunto(s)
Autoanticuerpos/sangre , Autoinmunidad , Proteínas Cromosómicas no Histona/inmunología , ADN-Topoisomerasas de Tipo I/inmunología , Receptores del Factor de Crecimiento Derivado de Plaquetas/inmunología , Esclerodermia Sistémica/inmunología , Animales , Autoanticuerpos/inmunología , Proteínas Cromosómicas no Histona/sangre , ADN-Topoisomerasas de Tipo I/sangre , Células Endoteliales/inmunología , Fibroblastos/inmunología , Humanos , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangre , Esclerodermia Sistémica/sangre , Esclerodermia Sistémica/terapia
7.
Am J Hematol ; 81(2): 121-3, 2006 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-16432874

RESUMEN

Chronic graft-versus-host disease (cGVHD) is a frequent complication of allogenic bone marrow transplantation. Even with aggressive treatment, cGVHD is associated with a significant degree of morbidity and mortality. cGVHD resembles autoimmune disorder, particularly systemic sclerosis (SSc). Sarpogrelate hydrochloride (SH) is an antagonist of the 5-hydroxytryptamine2A (5HT2A) receptor and has been reported to be effective in the treatment of systemic sclerosis (SSc) patients with Raynaud phenomenon. We used SH to treat a cGVHD patient, and we measured plasma PDGF and total TGF-beta levels. After SH treatment, his plasma PDGF and total TGF-beta levels decreased, and he noticed improvement in his skin pigmentation. In the present case, SH may have improved the skin lesion by inhibiting the synthesis of PDGF and TGF-beta.


Asunto(s)
Enfermedad Injerto contra Huésped/tratamiento farmacológico , Antagonistas de la Serotonina/uso terapéutico , Succinatos/farmacología , Adulto , Trasplante de Médula Ósea/efectos adversos , Enfermedad Crónica , Humanos , Masculino , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangre , Receptores del Factor de Crecimiento Derivado de Plaquetas/efectos de los fármacos , Succinatos/uso terapéutico , Factor de Crecimiento Transformador beta/sangre , Factor de Crecimiento Transformador beta/efectos de los fármacos
8.
Dev Biol ; 212(1): 124-36, 1999 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-10419690

RESUMEN

PDGFB is a growth factor which is vital for the completion of normal prenatal development. In this study, we report the phenotypic analysis of placentas from mouse conceptuses that lack a functional PDGFB or PDGFRbeta gene. Placentas of both types of mutant exhibit changes in the labyrinthine layer, including dilated embryonic blood vessels and reduced numbers of both pericytes and trophoblasts. These changes are seen from embryonic day (E) 13.5, which coincides with the upregulation of PDGFB mRNA levels in normal placentas. By E17, modifications in shape, size, and number of the fetal blood vessels in the mutant placentas cause an abnormal ratio of the surface areas between the fetal and the maternal blood vessels in the labyrinthine layer. Our data suggest that PDGFB acts locally to contribute to the development of the labyrinthine layer of the fetal placenta and the formation of a proper nutrient-waste exchange system during fetal development. We point out that the roles of PDGFB/Rbeta signaling in the placenta may be analogous to those in the developing kidney, by controlling pericytes in the labyrinthine layer and mesangial cells in the kidney.


Asunto(s)
Placenta/anatomía & histología , Factor de Crecimiento Derivado de Plaquetas/fisiología , Proteínas Proto-Oncogénicas/fisiología , Animales , Capilares/anatomía & histología , Femenino , Riñón/embriología , Intercambio Materno-Fetal , Ratones , Ratones Noqueados , Modelos Biológicos , Pericitos/metabolismo , Placenta/irrigación sanguínea , Placenta/ultraestructura , Factor de Crecimiento Derivado de Plaquetas/análisis , Embarazo , Proteínas Proto-Oncogénicas/análisis , Proteínas Proto-Oncogénicas c-sis , Receptores del Factor de Crecimiento Derivado de Plaquetas/análisis , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangre , Receptores del Factor de Crecimiento Derivado de Plaquetas/fisiología , Factores de Tiempo , Trofoblastos/metabolismo
9.
Gen Pharmacol ; 31(5): 765-73, 1998 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-9809476

RESUMEN

1. Our original compound, Ki6896 ((4-t-butylphenyl)(4-[(6,7-dimethoxy-4-quinolyl) oxy]phenyl) methanone) strongly inhibited the autophosphorylation of platelet-derived growth factor (PDGF) beta-receptor (IC50=0.31 microM) and that of basic fibroblast growth factor receptor (IC50=3.1 microM), whereas it did not inhibit some other kinases. 2. The [3H]thymidine incorporation and the growth of mesangial cells under the stimulation of PDGF were inhibited by Ki6896 in a dose-dependent manner. 3. In the mesangial proliferative glomerulonephritis rats induced by anti-Thy-1 monoclonal antibody, glomerulosclerosis was ameliorated and the number of glomerular proliferating cells was decreased by the daily administration of Ki6896. However, the accumulation of type I collagen and fibronectin in the glomeruli was not suppressed by Ki6896.


Asunto(s)
Mesangio Glomerular/efectos de los fármacos , Glomerulonefritis Membranoproliferativa/metabolismo , Quinolinas/farmacología , Receptores del Factor de Crecimiento Derivado de Plaquetas/antagonistas & inhibidores , Células 3T3 , Animales , Anticuerpos Monoclonales/inmunología , División Celular/efectos de los fármacos , Células Cultivadas , Colágeno/metabolismo , Fibronectinas/metabolismo , Mesangio Glomerular/metabolismo , Mesangio Glomerular/patología , Glomerulonefritis Membranoproliferativa/inmunología , Glomerulonefritis Membranoproliferativa/patología , Isoanticuerpos/inmunología , Masculino , Ratones , Fosforilación , Fosfotransferasas/metabolismo , Ratas , Ratas Endogámicas WKY , Receptor beta de Factor de Crecimiento Derivado de Plaquetas , Receptores del Factor de Crecimiento Derivado de Plaquetas/sangre , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Esclerosis , Linfocitos T/inmunología , Timidina/metabolismo
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