RESUMEN
Organophosphorus chlorpyrifos (CPF) is currently considered an endocrine disruptor (ED), as it can imitate hormone actions both in vitro and in vivo. We recently reported that CPF induces migration and invasion in 2D cultures and changes the expression of key molecular markers involved in epithelial mesenchymal transition in MCF-7 and MDA-MB-231 cell lines. In this study, we investigated whether CPF could behave as a predisposing factor for tumors to become more metastatic and aggressive using 3D culture models. In MCF-7 cells, 0.05 µM CPF induced an increase in the number and size of mammospheres via estrogen receptor alpha (ERα) and c-SRC. Furthermore, 0.05 µM CPF increased the area of spheroids generated from MCF-7 cells, induced invasion using both Matrigel® and type 1 collagen matrices, and increased cell migration capacity via ERα in this 3D model. In turn, 50 µM CPF increased cell migration capacity and invasion using type 1 collagen matrix. In monolayers, CPF increased the phosphorylation and membrane translocation of c-SRC at both concentrations assayed. CPF at 0.05 µM boosted p-AKT, p-GSK-3ß and p-P38. While p-AKT rose in a ERα-dependent way, p-GSK-3ß was dependent on ERα- and c-SRC, and p-P38 was only dependent on c-SRC. On the other hand, the increase in p-AKT and p-P38 induced by 50 µM CPF was dependent on the c-SRC pathway. We also observed that 0.05 µM CPF increased IGF-1R and IRS-1 expression and that 50 µM CPF induced IGF-1Rß phosphorylation. In the MDA-MB-231 cell line, 0.05 and 50 µM CPF increased p-c-SRC. Finally, p-AKT and p-GSK-3ß were also induced by CPF at 0.05 and 50 µM, and an increase in p-P38 was observed at 50 µM. Taken together, these data provide support for the notion that CPF may represent a risk factor for breast cancer development and progression.
Asunto(s)
Neoplasias de la Mama , Cloropirifos , Disruptores Endocrinos , Línea Celular Tumoral , Proliferación Celular , Cloropirifos/toxicidad , Disruptores Endocrinos/toxicidad , Femenino , Glucógeno Sintasa Quinasa 3 beta , Humanos , Fenotipo , FosforilaciónRESUMEN
Chlorpyrifos (CPF) is one of the most frequently used pesticide in extensive agriculture around the world and can be incorporated by humans and animals with possible consequences on health. The effects of this pesticide on carcinogenesis are not clear and there is no consensus concerning the risks of this compound. In previous work, we demonstrated that CPF induces proliferation of breast cancer cells both in vivo and in vitro. In this work we investigate whether CPF promotes the epithelial-mesenchymal transition (EMT) in breast cancer cells. Herein, we demonstrate that 50 µM CFP induces invasion in MCF-7 and MDA-MB-231 cells. In addition, 0.05 and 50 µM CPF increases migration in both cell lines. In MCF-7 cells, 0.05 and 50 µM CPF increase the metalloprotease MMP2 expression and decrease E-Cadherin and ß-Catenin expression diminishing their membrane location. Furthermore, 50 µM CPF induces Vimentin expression and Slug nuclear translocation in MCF-7 cells. 0.05 and 50 µM CPF increase MMP2 gelatinolytic activity and expression, decrease ß-Catenin expression and increase Vimentin expression in MDA-MB-231 cells. Inhibition of the oncoprotein c-Src reverses all the effects induced by CPF in MDA-MB-231 but not in MCF-7 indicating that c-Src is a kinase with a crucial role in the cells which grow in an estrogen-independent way. In MCF-7 cells both c-Src and estrogen receptor alpha must be blocked to completly inhibit the CPF-mediated effects. Our results show for the first time that the exposure to subthreshold concentrations of CPF promotes the modulation of EMT-molecular markers and pathways. These results, together with the ubiquitous distribution of the pesticide CPF, make it of utmost importance to take measures to minimize the risk of exposure to this compound.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Cloropirifos/toxicidad , Disruptores Endocrinos/toxicidad , Transición Epitelial-Mesenquimal/efectos de los fármacos , Plaguicidas/toxicidad , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proteína Tirosina Quinasa CSK/genética , Línea Celular Tumoral , Movimiento Celular/genética , Relación Dosis-Respuesta a Droga , Transición Epitelial-Mesenquimal/genética , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Células MCF-7 , Metaloproteinasa 2 de la Matriz/genética , Transducción de SeñalRESUMEN
Neonatal antiphospholipid syndrome (neonatal APS) seems to be exceedingly rare, as the antiphospholipid antibodies (aPL) related thrombosis in the neonatal period. The pathogenesis of perinatal aPL related thrombosis may be explained both by the transplacental passage of the maternal antibodies and by the production of de novo antibodies by the neonate. However, few cases of neonatal APS are reported in the literature, especially regarding arterial thrombotic events. In particular, only two cases of neonatal aPL related isolated cerebral sinovenous thrombosis (CSVT) are described in the literature. Despite its frequency, CSVT results in significant mortality and morbidity, probably also due to the difficulty in early diagnosis and then in correct managing in the neonatal period. A diagnosis of neonatal APS should be considered in the evaluation of neonates with CSVT, as well as in any case of neonatal thrombosis, to correctly manage the affected neonates and counsel the mother for future pregnancies.
Asunto(s)
Síndrome Antifosfolípido/complicaciones , Trombosis Intracraneal/inmunología , Humanos , Recién Nacido , MasculinoRESUMEN
OBJECTIVE: To describe the clinical features and outcome of functional thyroid tumours in dogs. MATERIALS AND METHODS: Retrospective multi-institutional study of 70 dogs diagnosed with thyroid mass and concurrent hyperthyroidism. Clinical data regarding presentation, treatment, outcome and functional thyroid status were retrieved. RESULTS: Overall median survival of dogs with functional thyroid tumours was 35.1 months and 1- and 3-year survival rates were 83 and 49%, respectively. Median survival time was 72.6 months for dogs treated with surgical excision and 15.7 months for dogs that did not receive surgery. Of the 50 dogs treated by surgery and for which thyroid status was known following treatment, 64% developed hypothyroidism after surgery. Histopathologically confirmed metastasis was identified in 3% of dogs. CLINICAL SIGNIFICANCE: Dogs with functional thyroid tumours may survive a long time after surgical excision, although post-operative hypothyroidism is common.
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Enfermedades de los Perros , Hipotiroidismo/veterinaria , Neoplasias de la Tiroides/veterinaria , Animales , Perros , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The objective of this study was to evaluate the effect of sweet lupin (Lupinusalbus L. var. Multitalia) as a substitute for soybean (Glicinemax [L] Merr.) in feed on the productive performance and meat quality of Podolian young bulls. The steers were divided into 2 homogeneous groups and were fed durum wheat (Triticumdurum L.), straw and a complete pellet feed containing 20% sweet lupin seeds or 16.5% soybean. Productive performances were similar for both groups. The values of pH, measured on Longissimuslumborum and Semitendinosus muscles 24h after slaughter, were similar. No differences were shown between groups regarding the colour characteristics of both muscles or the tenderness of the cooked meat. No statistical differences were found between diets regarding the fatty acid profile of meats, except for a significantly higher incidence of linoleic acid in the meat obtained from animals on soybean feed. In conclusion, comparable results were obtained when soybean was replaced with sweet lupin seeds in complete pellet feed for Podolian steers.
RESUMEN
Chlorpyrifos (CPF) is an organophosphorus pesticide used for agricultural pest control all over the world. We have previously demonstrated that environmental concentrations of this pesticide alter mammary gland histological structure and hormonal balance in rats chronically exposed. In this work, we analyzed the effects of CPF on mammary tumors development. Our results demonstrated that CPF increases tumor incidence and reduces latency of NMU-induced mammary tumors. Although no changes were observed in tumor growth rate, we found a reduced steroid hormone receptor expression in the tumors of animals exposed to the pesticide. Moreover, we analyzed the role of epigenetic mechanisms in CPF effects. Our results indicated that CPF alters HDAC1 mRNA expression in mammary gland, although no changes were observed in DNA methylation. In summary, we demonstrate that the exposure to CPF promotes mammary tumors development with a reduced steroid receptors expression. It has also been found that CPF affects HDAC1 mRNA levels in mammary tissue pointing that CPF may act as a breast cancer risk factor.
Asunto(s)
Neoplasias de la Mama/inducido químicamente , Neoplasias de la Mama/genética , Cloropirifos/efectos adversos , Epigénesis Genética/efectos de los fármacos , Metilnitrosourea , Plaguicidas/efectos adversos , Animales , Neoplasias de la Mama/patología , Metilación de ADN/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Histona Desacetilasa 1/genética , Humanos , Ratas , Ratas Sprague-DawleyRESUMEN
Hexachlorobenzene (HCB) is an organochlorine pollutant widely distributed in the environment around the entire world. Previous reports from our group and others have demonstrated that this compound is as an endocrine disruptor. We have also reported that HCB presents a co-carcinogenic effect in N-Nitroso-N-methyl-urea-induced mammary tumours in rats. In this work, we studied the effects of HCB on cell cycle progression and cell cycle regulating protein expression in the estrogen-sensitive breast cancer cell line, MCF-7. Here, we show that HCB alters cell cycle in a concentration-dependent way. The lowest assessed concentration (0.005µM) promotes the cell cycle progression, enhances cyclin D1 expression, and reduces the nuclear localization of p27 accompanied by an increased interaction between p27 and c-Src kinase. On the other hand, 5µM HCB delays the cell cycle progression and promotes the formation of the cyclin E-CDK2-p27 protein complex. Our results show that HCB stimulates cell proliferation through cell cycle modulation and c-Src involvement in MCF-7 cells. Here, we report for the first time that differential mechanisms of action of HCB on mammary cell cycle progression are triggered at different concentrations of this pollutant.
Asunto(s)
Ciclo Celular/efectos de los fármacos , Ciclina E/metabolismo , Quinasa 2 Dependiente de la Ciclina/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Hexaclorobenceno/toxicidad , Proteínas Oncogénicas/metabolismo , Familia-src Quinasas/metabolismo , Proteína Tirosina Quinasa CSK , División Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclina D1/genética , Ciclina D1/metabolismo , Ciclina E/genética , Quinasa 2 Dependiente de la Ciclina/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Humanos , Células MCF-7 , Proteínas Oncogénicas/genética , Fosforilación , Familia-src Quinasas/genéticaRESUMEN
BACKGROUND: Infants born at 34 to 36 weeks of gestation (late preterm) are at greater risk for adverse outcomes than those born at 37 weeks of gestation or later. Aim of this paper is to examine risk factors for late preterm births and to investigate the complications of the transition period in late preterm infants (LPIs). METHODS: All consecutive late preterm deliveries, excluded stillbirths, were included. Maternal and neonatal data, need for delivery room resuscitative procedures, temperature at birth (T1) and two hours after the admission (T2) were analyzed in all LPIs stratified by Gestational Age (GA) and divided into three groups (34, 35 and 36 weeks). RESULTS: Two hundred seventy-six LPIs were analyzed. Pregnancy complications were present in 72 mothers (26.1 %), more frequently at 34 weeks of gestation respect to 35 and 36 weeks (p = 0.008, p = 0.006 respectively). Forty seven LPIs (17.1 %) needed for any resuscitation and 37 (13.4 %) were ventilated at birth. LPIs at 34 weeks were significantly more likely to receive ventilation respect to those at 35 and 36. At T1 the mean temperature resulted lower at 34 weeks respect to 36 weeks (p = 0.03). At T2 respect to T1, the rate of normothermic neonates increased at 35 and 36 weeks (p = 0.003, p = 0.005, respectively). Hypoglicemia rate was similar among the groups; 66.7 % of hypoglicemic neonates were hypothermic at T1. The rate of respiratory diseases and NICU admission decreased with increasing GA. Higher number of neonates ventilated at birth developed respiratory disorders respect to those unventilated (40.5 % vs 8.4 %; p < 0.001). CONCLUSIONS: Transition period in LPIs may become critical, as resuscitation strategies can be required and heat loss can occur. LPIs, especially at 34 gestational weeks, are higher-risk group needing adequate and targeted management at birth.
RESUMEN
The aim of this study was to develop an experimental model for the study of cancer associated with diabetes. For diabetes induction, Sprague-Dawley rats were given streptozotocin (STZ, 90 mg/kg body weight (BW), by intraperitoneal injection on the second day of life. For mammary tumour induction, rats were injected with 50 mg/kg BW of N-nitroso-N-methylurea (NMU) at 50, 80 and 110 days old. The neoplastic process and the effect of tamoxifen treatment was examined in non-diabetic and diabetic rats. The latency period, NMU-induced tumour incidence and the number of tumours per rat in diabetic rats versus controls were 117 +/- 7 days versus 79 +/- 9 days (P < 0.001); 93% versus 95% (NS); and 5.2 +/- 1.6 versus 2.7 +/- 0.5 (P < 0.02). A more benign histological pattern for tumours in diabetic animals was observed. Mammary tumours in diabetic rats grew more slowly than in controls. Tamoxifen (1 mg/kg/day) treated diabetic rats showed tumour regression in 67% of NMU-induced mammary tumours versus 53% in controls (NS). Our results show that tumour progression seems to be affected by diabetes in this experimental model. We suggest this is the result of changes to insulin-like growth factors and their receptors, which occur in diabetics, and our future research will examine this hypothesis.
Asunto(s)
Anticarcinógenos/uso terapéutico , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Neoplasias Mamarias Experimentales/etiología , Tamoxifeno/uso terapéutico , Animales , Antibacterianos , Carcinógenos/toxicidad , División Celular , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/patología , Femenino , Insulina/sangre , Neoplasias Mamarias Experimentales/sangre , Neoplasias Mamarias Experimentales/patología , Metilnitrosourea/toxicidad , Ratas , EstreptozocinaRESUMEN
Mammary adenocarcinomas induces in female Sprague-Dawley rats by three intraperitoneal injections of N-nitroso-N-methylurea were studied in order to characterize their estrogen (ER), progesterone (PgR), prolactin (PRLR) and epidermal growth factor (EGFR) receptors. All samples evaluated showed the presence of ER and PgR in the cytosol fraction and PRLR amd EGFR in the membrane fraction. Q (fmol/mg) and K(d) (nM) values were as follows: ER, 56 +/- 11 and 0.5 +/- 0.1; PgR, 109 +/- 25 and 2.2 +/- 0.5 and PRLR, 335 +/- 75 and 0.5 +/- 0.2, respectively. In all tumors studied, two specific sites were found for EGFR, one with Q(1) = 22 +/- 9 and K(d1) = 0.6 +/- 0.3, and the other with Q(2) = 125 +/- 33 and K(d2) = 2.1 +/- 0.5. Receptor content was found to be independent of tumor histopathological variety. Displacement index (DI) with estradiol and tamoxifen of [I(3)H]E2-ER binding showed great heterogeneity, with values ranging from 0.01 to1.54. No correlation between ER content and DI values was found. Antiestrogenic binding sites were not found in the microsomal fraction of ten mammary tumors examined. Proliferation of this experimental mammary tumor may be regulated by a complex interaction of steroid and polypeptide hormones, as well as growth factors.
Asunto(s)
Carcinoma Ductal de Mama/química , Receptores ErbB/análisis , Neoplasias Mamarias Experimentales/química , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Receptores de Prolactina/análisis , Animales , Carcinógenos , Carcinoma Ductal de Mama/inducido químicamente , Femenino , Neoplasias Mamarias Experimentales/inducido químicamente , Metilnitrosourea , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVE: The relative contribution of fasting and post-prandial glucose to glycated hemoglobin (HbA1c) is controversial. In the present study, we assessed the relationship with HbA1c of fasting and post-prandial glucose measured in a more naturalistic setting, through home glucose self-monitoring or with a continuous glucose monitoring system (CGM). MATERIALS AND METHODS: A consecutive series of 300 patients with Type 2 diabetes were enrolled in the study, provided that they performed blood glucose self-monitoring. HbA1c and fasting plasma glucose (FPG) were measured at enrolment. RESULTS: Both fasting plasma and capillary glucose showed a significant correlation with HbA1c (r=0.66 and 0.61, respectively; p<0.001). When home glucose monitoring was considered, both mean fasting and post-prandial glucose showed a significant correlation with HbA1c (r=0.71 and 0.73, respectively). In patients in the lower tertile of body mass index (BMI), HbA1c showed a significant correlation at multivariate analysis with post-prandial glucose, but not with fasting glucose. In patients with HbA1c >7%, both fasting and post-prandial glucose showed a significant correlation, after adjustment for age and BMI, with HbA1c (both p<0.01); conversely, in those with HbA1c < or =7%, such a correlation could be observed for fasting (p<0.01), but not for post-prandial glucose. CONCLUSION: In conclusion, both fasting and post-prandial glucose contribute to the determination of HbA1c . Home glucose self-monitoring appears to provide a more accurate assessment of metabolic control than a single plasma glucose measurement in experimental conditions. Fasting glucose could provide a greater contribution to HbA1c in patients with lower HbA1c, while post-prandial glucose seems to play a major role in leaner Type 2 diabetic subjects.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/sangre , Ayuno/sangre , Hemoglobina Glucada/análisis , Periodo Posprandial , Anciano , Automonitorización de la Glucosa Sanguínea/estadística & datos numéricos , Presión Sanguínea , Índice de Masa Corporal , Colesterol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadística como AsuntoRESUMEN
In this work we analyze the hypothesis that tumors induced by i.p. N-nitroso-N-methylurea injection express EGF-like peptides and EGF receptors which could be involved in the response to hormone manipulation. EGF receptors (EGFR) were determined in the purified membrane fraction of tumors from control and ovariectomized (OVX) animals and no significant differences were found in either maximal binding capacities (Q) or dissociation constants (Kd) between them. Neither did we observe differences between tumors that regressed (HR) or continued growing (HU) after ovariectomy. In order to test the ability of EGFR to trigger a biological response we measured the production of second messengers inositol triphosphates (IP3) and cAMP levels; we found that EGF increases IP3 production in a dose-dependent way, while cAMP levels were not affected. In addition, EGF was able to induce in vitro cell proliferation in a concentration-dependent manner when tested in primary cultures of tumor cells by the clonogenic soft agar technique. EGF/TGF-alpha activity was determined by a radioreceptor assay in tumor cytosols from control and OVX rats. Results showed a trend to lower values in tumors from OVX rats, but no differences between HR and HU tumors. A positive correlation was found between EGF/TGF-alpha activity and progesterone receptor maximal binding capacity. When we tested the action of estradiol and EGF added together to primary cultures of tumor cells we found an additive effect on cell proliferation. The study of steady state mRNA levels showed that E2 increases PgR and c-myc mRNA levels in HR but not in HU tumors. In conclusion, the autocrine loop EGFR-EGF/TGF-alpha present in all tumors is hormonally regulated, possibly by Pg, but is not related to the tumor response to ovariectomy.
Asunto(s)
Factor de Crecimiento Epidérmico/análisis , Receptores ErbB/análisis , Neoplasias Mamarias Animales/metabolismo , Animales , Carcinógenos , AMP Cíclico/análisis , Factor de Crecimiento Epidérmico/farmacología , Femenino , Neoplasias Mamarias Animales/inducido químicamente , Neoplasias Mamarias Animales/patología , Metilnitrosourea , Ovariectomía , Fosfatidilinositoles/metabolismo , Proteínas Proto-Oncogénicas c-myc/análisis , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Factor de Crecimiento Transformador alfa/análisisRESUMEN
OBJECTIVE: The aim of this work was to analyze the effect of estradiol (E(2)), medroxyprogesterone and the two selective estrogen receptor modulators (SERMs) (tamoxifen (Tam) and raloxifene (Ral)) on the estrogen receptor (ER) conformers profile performed by size exclusion HPLC in relation to hormone dependence of mammary tumors. MATERIALS AND METHODS: Two types of mammary tumors were studied: tumors transplanted in BALB/c mice that are medroxyprogesterone acetate (MPA)-dependent for growth, and tumors induced in Sprague-Dawley rats by intraperitoneal injection of N-nitroso-N-methylurea (NMU). Tumors from mice treated with MPA, E(2), Tam or Ral and NMU-treated rats were analyzed and compared to that of control. RESULTS: The tumor conformer profiles were as follows: control and MPA-treated mice showed only one peak (oligomeric form); E(2)-treated mice also showed only one peak (dimer); Tam-treated mice showed one peak corresponding to a possible proteolytic fragment, and Ral-treated mice showed two peaks (oligomeric and a possible proteolytic fragment). On the other hand, NMU-induced mammary tumors from rats showed three peaks (oligomeric, monomeric and proteolytic). CONCLUSION: Our findings may indicate that SERMs affect the aggregation state of ER and thereby its ability to modulate genomic transcription mechanisms related to growth rate.
Asunto(s)
Neoplasias Mamarias Experimentales/metabolismo , Clorhidrato de Raloxifeno/farmacología , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Tamoxifeno/farmacología , Animales , Cromatografía Líquida de Alta Presión , Femenino , Neoplasias Mamarias Experimentales/inducido químicamente , Neoplasias Mamarias Experimentales/patología , Metilnitrosourea , Ratones , Ratones Endogámicos BALB C , Neoplasias Hormono-Dependientes/metabolismo , Conformación Proteica , Ratas , Ratas Sprague-Dawley , Receptores de Estrógenos/químicaRESUMEN
Treatment with exogenous spermidine enhanced acute malathion toxicity during larval development of the toad Bufo arenarum Hensel. The polyamine was rapidly incorporated in the larvae with a subsequent metabolization to putrescine and spermine, which were excreted to the media. Endogenous polyamine levels were not changed by either spermidine or malathion treatments. However, 0.5-mM spermidine modified malathion uptake and bioavailability increasing the concentration of the xenobiotic in the larvae. The amount of reduced thiols was decreased by both compounds, but the depletion was insufficient to induce cytotoxicity. The oxidative degradation of polyamines competes for the pool of reduced glutathione used in the conjugation of malathion in the larvae, thus leading to the reported potentiation of toxicity. Our results suggest that exposure to thiols-depleting agents may induce alteration of organophosphate degradation in amphibian larvae.
Asunto(s)
Bufo arenarum/crecimiento & desarrollo , Malatión/toxicidad , Sinergistas de Plaguicidas/farmacología , Espermidina/farmacología , Compuestos de Sulfhidrilo/metabolismo , Animales , Disponibilidad Biológica , Biotransformación/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Disulfuro de Glutatión/efectos de los fármacos , Larva/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Malatión/farmacocinética , Oxidación-Reducción , Sinergistas de Plaguicidas/farmacocinética , Espermidina/farmacocinéticaAsunto(s)
Histamina/metabolismo , Mucosa Intestinal/patología , Mucosa Intestinal/efectos de la radiación , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de la radiación , Humanos , Inmunohistoquímica , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/patología , Intestino Delgado/efectos de la radiación , Ratones , Radiación IonizanteAsunto(s)
Adenocarcinoma/patología , Histamina/fisiología , Neoplasias Pancreáticas/patología , División Celular/efectos de los fármacos , Histamina/farmacología , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Humanos , Receptores Histamínicos H1/análisis , Receptores Histamínicos H1/fisiología , Receptores Histamínicos H2/análisis , Receptores Histamínicos H2/fisiología , Células Tumorales CultivadasAsunto(s)
División Celular/efectos de los fármacos , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Histamina/farmacología , Receptores Histamínicos H2/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Humanos , Fosfatidilinositoles/metabolismo , Fosfolipasas de Tipo C/antagonistas & inhibidores , Fosfolipasas de Tipo C/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
Las terapias oncológicas conllevan generalmente efectos secundarios indeseados por lo que el mejor conocimiento de los mecanismos regulatorios del desarrollo y crecimiento tumoral puede abrir el camino a enfoques terapeúticos más adecuados. El objetivo de éste trabajo fue profundizar el estudio de la implicancia de factores que regulan el crecimiento del cáncer mamario empleando un modelo experimental químicamente inducido en rata, el que presenta similitudes con el cáncer mamario humano principalmente en lo que respecta a la regulación hormonal de su crecimiento. El tumor mamario fue inducido químicamente en ratas normales y diabéticas. Se analizó la expresión de receptores a factor de crecimiento insulínico tipo I (RIGF-I), el que forma parte de un sistema formado por factores de crecimiento, sus receptores y proteínas transportadas; éste sistema se encuentra alterado en pacientes con diabetes mellitus no dependiente de insulina. También se analizó la expresión de las proteínas c-FOS y PCNA (antígeno nuclear de proliferación celular), ambas relacionadas con la proliferación celular. Los resultados experimentales mostraron significativas diferencias en los tumores mamarios desarrollados: los de las ratas diabéticas presentaron mayor período de latencia (p<0,001), menor número de tumores desarrollados por rata (p<0,02) y una velocidad de crecimiento menor (p<0,05) con respecto a los tumores desarrollados en ratas normales. Asimismo, mostraron un patrón histológico de marcada benignidad, en contraste con los adenocarcinomas malignos ductales desarrollados en los animales normales. La expresión de las proteínas c-FOS y PCNA detectada por métodos inmunohistoquímicos fue significativamente menor en los tumores de las ratas diabéticas que en ratas normales. En cuanto a la expresión de RIGF-I, los resultados indicaron que la misma estaría regulada por las hormonas esteroides en animales diabéticos y normales. El trabajo permitió analizar experimentalmente la interrelación entre factores de crecimiento insulínicos y hormonas esteroides en el desarrollo y crecimiento tumoral mamario, particularmente cuando están presentes la patología mamaria y la diabetes
Asunto(s)
Animales , Ratas , Antígeno Nuclear de Célula en Proliferación , Neoplasias Mamarias Experimentales , Receptor IGF Tipo 1 , Antagonistas de Estrógenos , Diabetes Mellitus , Diabetes Mellitus Experimental , Genes fos , Inmunohistoquímica , Neoplasias Mamarias Experimentales , Compuestos de Metilurea , Receptor IGF Tipo 1 , TamoxifenoRESUMEN
La insulina, miembro de la familia de factores de crecimiento que incluyen al factor de crecimiento tipo insulina I (IGF-I) y II (IGF-II), presenta efectos mitogénicos sobre células epiteliales mamarias normales y malignas (Goodwin y col., 2002). Se postula que altos niveles de insulina permiten identificar mujeres con una mala evolución de su cáncer de mama, en quienes deberán aplicarse estrategias terapéuticas más efectivas. Se estudiaron 32 pacientes con cáncer de mama, de las cuales 18 presentaron carcinoma ductal invasor, incluidos 3 multifocales (56 por ciento), 6 carcinoma lobulillar infiltrante (19 por ciento), 3 carcinoma papilar (10 por ciento) y el resto otros tipos (15 por ciento). Dos pacientes (7 por ciento) presentan diabetes mellitus no-insulino dependiente. Los niveles de insulina plasmática en ayunas determinados por RIA (Insulin-CT kit) resultaron en: 18 pacientes (56 por ciento) con niveles normales (5,5 a 19,9 µUI/ml), el resto (44 por ciento) con insulinemias superiores al normal. La insulinemia plasmática en ayunas en voluntarias sanas resultó ser de 13,9ñ4,3 µUI/ml (n=10)...