RESUMEN
The phenomenon of cell fusion plays a crucial role in a plethora of physiological processes, including fertilization, wound healing, and tissue regeneration. In addition to this, cell fusion also takes place during pathophysiological processes such as virus entry into host cells and cancer. Particularly in cancer, cell fusion has been linked to a number of properties being associated with the progression of the disease including an increased proliferation rate, an enhanced metastatogenic behavior, an increased drug resistance and an increased resistance towards apoptosis. Although the process of cell fusion including the molecules to be involved-in is not completely understood in higher organisms, recent data revealed that chronic inflammation seems to be strong mediator. Since tumor tissue resembles chronically inflamed tissue, it can be concluded that cell fusion between recruited macrophages, bone marrow-derived cells (BMDCs), and tumor (stem) cells should be a common phenomenon in cancer. In the present review, we will summarize how a chronic inflamed microenvironment could originate in cancerous tissues, the role of M2-polarized tumor associated macrophages (M2-TAMs) within this process and how fusion between macrophages and BMDCs will trigger cancer progression. A particular emphasis will be drawn on recurrence cancer stem cells (rCSCs), which will play a pivotal role in "oncogenic resistance" and which might originate from fusion events between tumor (stem) cells and BMDCs.
Asunto(s)
Recurrencia Local de Neoplasia , Neoplasias/patología , Células Madre Neoplásicas/fisiología , Animales , Antineoplásicos/farmacología , Carcinogénesis/inmunología , Carcinogénesis/patología , Fusión Celular , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Humanos , Inflamación/inmunología , Inflamación/patología , Neoplasias/inmunología , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Microambiente TumoralRESUMEN
Breast cancer mortality is frequently associated with metastatic disease. Metastasis models have shown adrenoceptor (AR) stimulation induces cell migration which is inhibited by adrenoceptor antagonist drugs. We investigated adrenoceptor protein expression in clinical breast tumours and its association with disease progression and prognosis. Immunohistochemistry on tissue microarrays was used to characterise α1b, α2c and ß(2)2 adrenoceptor protein expression in operable breast tumours. Associations with tumour-relevant biological markers and clinical outcome were statistically assessed. Strong α1b expression occurred in large high grade (P < 0.0001), HER2+ (P < 0.0001) or basal-like (CK5/6, P = 0.0005; CK14, P = 0.0001; EGFR, P = 0.003) cancers, showing increased proliferation (Mib1, P = 0.002), decreased apoptosis (Bcl2, P < 0.0001) and poor NPI membership (P = 0.001). α1b expression correlated with poor cancer-specific survival (LR = 7.628, P = 0.022) and tumour recurrence (LR = 6.128, P = 0.047). Strong α2c was over-expressed in high grade (P = 0.007), HER3+ (P = 0.002) and HER4+ (P < 0.0001) cancers with borderline increase in EGFR, p53 and MIB1 proteins, and inverse association with hormonal (PgR, P = 0.002) phenotype. In contrast, strong ß(2) expression occurred in small-size, luminal-like (ER+, P < 0.001) tumours of low grade (P < 0.001) and lymph node stage (P = 0.027) that showed poor prognosis when hormonal treatment was withheld. Adrenoceptors were not found to be independent predictors of clinical outcome. Alpha1b and α2c AR is over-expressed in basal-like breast tumours of poor prognosis. Strong ß(2) adrenoceptor expression is seen in patients with a luminal (ER+) tumour phenotype and good prognosis, due to benefits derived from hormonal therapy. These findings suggest a possible role for targeted therapy using adrenoceptor antagonists.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Adulto , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/mortalidad , Carcinoma Ductal de Mama/secundario , Carcinoma Lobular/mortalidad , Carcinoma Lobular/secundario , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Receptores de Estrógenos/metabolismo , Carga TumoralRESUMEN
BACKGROUND: During the last decade, epidemiological studies uncovered the tremendous impact of metabolic syndrome/diabetes mellitus type 2 (DM T2) as risk factors of the progression of cancer. Therefore, we studied the impact of diabetogenic glucose and insulin concentrations on the activities of tumour cells, because little is known about how high glucose and insulin levels are influencing gene activities causing changes in the signal cascade activities with respect to kinases involved in the proliferation and migration of cancer cells. METHODS: To address this question we analysed the activity of more than 400 gene signatures related to (i) cell cycle, (ii) cell movement as well as (iii) signal transduction. We examined transcriptomes of kinases (PKCα, PI3K), cadherins (E-, N- VE-), integrins and cyclins by comparing physiological (5.5 mM) vs diabetogenic (11 mM) glucose concentrations (without and with insulin). RESULTS: Proliferation assays revealed that high levels of glucose (11 mM) and insulin (100 ng ml(-1)) did promote the proliferation of the tumour cell lines HT29, SW480, MCF-7, MDA MB468, PC3 and T24. Using a 3D-migration assay, we have shown that high glucose concentrations caused increased motility rates of the tumour cells. The increase in migratory activity at high glucose and insulin concentrations was mediated by an activation of PI3K, PKCα and MLCK, as figured out by the pharmacological inhibitors wortmannin, Go6976 and ML-7. CONCLUSION: We present molecular and functional data, which could help to understand how hyperglycaemia and hyperinsulinemia might trigger tumour cell proliferation and motility in patients, too.
Asunto(s)
Glucemia/metabolismo , Adhesión Celular , Movimiento Celular , Proliferación Celular , Diabetes Mellitus/metabolismo , Perfilación de la Expresión Génica , Insulina/metabolismo , Western Blotting , Línea Celular Tumoral , Citometría de Flujo , HumanosRESUMEN
Mistletoe is often used as complementary therapy in oncology. The anti-tumor effects of mistletoe (Iscador) are well documented in-vitro in respect to inhibition of cell proliferation, induction of apoptosis, segmental activation of immune competent cells and trapping of chemotherapeutic drugs within cancer cells by modulating the inhibitory potential of P-glycoprotein (P-gp)-mediated transport of cell toxifying substances (cytotoxic drugs). However, the clinical activity of mistletoe treatment remains still controversial. Implementation of mistletoe therapy as supportive care into anti-cancer programs should be based on the best evidence and must continually be evaluated to ensure safety, efficacy, collection of new data, and cost-effectiveness. Useful domains that can be evaluated include symptom control, adherence to conventional treatment protocols, quality of life, individual outcome and potential advantages of a whole-system health approach. Here we report the results of a multicenter, controlled, retrospective and observational pharmaco-epidemiological study in patients suffering from a pancreatic carcinoma. After surgery the patients were treated by adjuvant chemotherapy with gemcitabine supported by Iscador, or with gemcitabine alone, or any other best of care, but not including Iscador. Using a novel methodological pharmaco-epidemiological design and statistical approach it could be shown that Iscador offers benefits--symptom control, overall survival--as supportive care within gemcitabine protocols of patients with surgically resected pancreatic carcinoma.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Fitoterapia , Extractos Vegetales/uso terapéutico , Proteínas de Plantas/uso terapéutico , Viscum album , Adenocarcinoma/mortalidad , Adenocarcinoma/cirugía , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Protocolos Clínicos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/cirugía , Extractos Vegetales/efectos adversos , Proteínas de Plantas/efectos adversos , Estudios Retrospectivos , Análisis de Supervivencia , GemcitabinaRESUMEN
Fast growing solid tumors generally lack an inner organisation, which causes the problem of a sufficient nutrient of each part of the tumor that then happens only by diffusion. The low oxygen supply leads to the activation of hypoxia-inducible factors, which regulate a plethora of genes. The reaction of tumor cells to hypoxia can be divided into two parts: On the one hand, there are signal substances, predominantly growth factors and cytokines, which provoke the vascularisation (angiogenesis), lymph vessel development (lymphangiogenesis), and the innervation (neoneurogenesis) of tumors and thus connect the tumor to structures of the environment. On the other hand, genes for intracellular proteins and receptors are regulated, which lead to changes of the tumor cell functions. Best characterized is the metabolic shift, a high anaerobic glycolytic activity and simultaneously a reduction of respiration. Furthermore, proliferation, dedifferentiation, resistance to apoptosis, and the metastatic potential are affected. With regard to the latter, we herein show that the migratory activity and velocity of PC-3 human prostate carcinoma cells significantly increases under oxygen-deprivation, which might be an explanation for the increasing number of experimental and clinical hints, that an anti-angiogenic therapy can promote the metastasis formation.
Asunto(s)
Hipoxia/fisiopatología , Neoplasias/fisiopatología , Animales , Movimiento Celular , Expresión Génica , Humanos , Hipoxia/genética , Hipoxia/patología , Linfangiogénesis , Metástasis de la Neoplasia , Neoplasias/irrigación sanguínea , Neoplasias/genética , Neoplasias/patología , Neovascularización Patológica , Neurogénesis , Transducción de SeñalRESUMEN
The aim of the present study was to design an automated-gating hematology fluorescence flow cytometry methodology permitting the assessment of neutrophil and monocyte activation in EDTA-anticoagulated whole blood based on cell granularity, lipid membrane components, cell shape and volume, and total cell nucleic acid (NA) compounds. For particularly monitoring the proper functioning of patients' innate immune system as the first line defense against microbial invaders, the suitable test system should be rapid, simple, reliable by yielding reproducible results. It must be validated against established methods, and it must prove to work in selected clinical settings, e.g. in intensive care unit (ICU) environments. The adaptation of a routine hematology cell analyser utilizing fluorescence flow cytometry resulted in a potentially useful system for all requirements. It proved to detect in real-time and in a reliable and reproducible way the main cellular response reactions of neutrophils and monocytes during externally stimulated immune defense. Validation was successful when comparing it to established methods. The quantified activation effects were dose dependent from the applied activating agents. Cellular response kinetics could be measured and described and showed to be in line with the prevailing cell response models. Upon applying the test method to a healthy population of volunteers and a first cohort of ICU patients with and without evident immune depression, the test revealed excellent cellular responses to external activating cytotoxic stimuli (lipopolysaccharide; LPS) for the control group, slightly weaker response from ICU patients without immune depression and no response from patients with evident immune depression.We conclude that routine hematology fluorescence flow cytometry can accurately and reproducibly measure different activation steps of monocytes and polymorphonuclear neutrophilic granulocytes to defined external stimuli. This may potentially be applied as a STAT (Latin statim = immediately) and routine screening and surveillance method for inflammatory diseases.
Asunto(s)
Automatización , Citometría de Flujo/métodos , Monocitos/inmunología , Activación Neutrófila/inmunología , Neutrófilos/inmunología , Adolescente , Adulto , Anciano , Forma de la Célula/efectos de los fármacos , Niño , Femenino , Fluorescencia , Salud , Humanos , Unidades de Cuidados Intensivos , Interleucina-8/biosíntesis , Cinética , Lipopolisacáridos/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Monocitos/citología , Monocitos/efectos de los fármacos , Activación Neutrófila/efectos de los fármacos , Neutrófilos/citología , Neutrófilos/efectos de los fármacos , Reproducibilidad de los Resultados , Factores de Tiempo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
BACKGROUND AND OBJECTIVE: MDA-MB-468 breast carcinoma cells respond to non-volatile anaesthetics such as propofol with an increased migration. Here we investigated the relationship between GABA-A receptor modulators, the mode of calcium oscillation and actin reorganization with regard to breast carcinoma cell migration. METHODS: Expression of the GABA-A receptor was determined by Western blot analysis. Calcium-imaging experiments of individual MDA-MB-468 cells as well as visualization of the F-actin distribution were performed by confocal laser scanning microscopy. Cell migration was investigated in a three-dimensional collagen matrix by time-lapse video microscopy. The GABA agonist propofol was used in a final concentration of 6 microg mL(-1). GABA-A receptor antagonist bicuculline (50 micromol) and selective L-type calcium channel blocker verapamil (5 micromol) were used to modulate the propofol effects. RESULTS: A functional GABA-A receptor is expressed by MDA-MB-468 cells. Activation with propofol resulted in sustained increased intracellular calcium concentrations concomitant with actin reorganization and induction of migration in MDA-MB-468 cells. These propofol effects were completely blocked by verapamil. Spontaneous migration of MDA-MB-468 cells (64.4 +/- 7.0%) was significantly increased by propofol to 85.0 +/- 5.0%. MDA-MB-468 cells co-treated with propofol and verapamil showed a migratory activity of 63.0 +/- 2.0% indicating that verapamil blocked the propofol effect. Similar results were achieved with the GABA-A receptor inhibitor bicuculline (control: 56.3 +/- 8.5%; propofol: 80.5 +/- 7.1%; propofol + bicuculline: 52.5 +/- 8.6%). CONCLUSION: Activation of GABA-A receptor by propofol correlated with an increased migration of MDA-MB-468 breast carcinoma cells, mediated by calcium influx via L-type calcium channels and reorganization of the actin cytoskeleton.
Asunto(s)
Actinas/metabolismo , Anestésicos Intravenosos/farmacología , Neoplasias de la Mama/fisiopatología , Señalización del Calcio/efectos de los fármacos , Propofol/farmacología , Western Blotting , Neoplasias de la Mama/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Citoesqueleto/efectos de los fármacos , Femenino , Humanos , Microscopía Confocal , Receptores de GABA-A/efectos de los fármacos , Verapamilo/farmacologíaRESUMEN
Due to its pivotal role in the growth factor-mediated tumour cell migration, the adaptor protein phospholipase C-gamma1 (PLC-gamma1) is an appropriate target to block ultimately the spreading of EGFR/c-erbB-2-positive tumour cells, thereby minimising metastasis formation. Here, we present an approach to block PLC-gamma1 activity by using protein-based PLC-gamma1 inhibitors consisting of PLC-gamma1 SH2 domains, which were fused to the TAT-transduction domain to ensure a high protein transduction efficiency. Two proteins were generated containing one PLC-gamma1-SH2-domain (PS1-TAT) or two PLC-gamma1-SH2 domains (PS2-TAT). PS2-TAT treatment of the EGFR/c-erbB-2-positive cell line MDA-HER2 resulted in a reduction of the EGF-mediated PLC-gamma1 tyrosine phosphorylation of about 30%, concomitant with a complete abrogation of the EGF-driven calcium influx. In addition to this, long-term PS2-TAT treatment both reduces the EGF-mediated migration of about 75% combined with a markedly decreased time locomotion of single MDA-HER2 cells as well as decreases the proliferation of MDA-HER2 cells by about 50%. Due to its antitumoral capacity on EGFR/c-erbB-2-positive breast cancer cells, we conclude from our results that the protein-based PLC-gamma1 inhibitor PS2-TAT may be a means for novel adjuvant antitumour strategies to minimise metastasis formation because of the blockade of cell migration and proliferation.
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Adenoma/genética , Adenoma/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Productos del Gen tat , Genes erbB-1/genética , Metástasis de la Neoplasia/prevención & control , Proteínas Recombinantes de Fusión/farmacología , Fosfolipasas de Tipo C/farmacología , División Celular , Movimiento Celular , Humanos , Fosfolipasa C gamma , Células Tumorales CultivadasAsunto(s)
Investigación Biomédica/tendencias , Neoplasias , Antineoplásicos/uso terapéutico , Infecciones Bacterianas/complicaciones , Diagnóstico Precoz , Humanos , Terapia de Inmunosupresión/efectos adversos , Tamizaje Masivo/normas , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/etiología , Neoplasias/prevención & control , Virosis/complicacionesAsunto(s)
Marcación de Gen/métodos , Terapia Genética/métodos , Neoplasias/terapia , Animales , Humanos , Neoplasias/genética , ProteómicaRESUMEN
PURPOSE: In cancer the blood-borne spread of tumor cells leads to the formation of secondary tumors at distant loci whereby the extravasation of tumor cells is a prerequisite step during hematogenous metastasis. Here, we describe a novel in vitro realtime model which shows the complete sequence of the extravasation process. METHODS: We developed an in vitro system allowing us to monitor the sequence of extravasation events of tumor cell clusters across a monolayer of human umbilical cord endothelial cells (HUVEC). Fluorescence markers and laser scanning confocal microscopy were used to visualize the interactions between tumor cells and endothelium. RESULTS: Our model indicates that the extravasation of tumor cell clusters derived from the invasive human bladder carcinoma cell line T24 occurs in a relatively short time-frame up to 4 h after adhesion to the endothelium. We demonstrate that the vascular endothelium is irreversibly damaged at the site of tumor cell extravasation. CONCLUSION: Realtime laser scanning confocal microscopy leads to a better understanding of the complex and dynamic cell-to-cell and cell-to-matrix interactions during the extravasation process.
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Comunicación Celular/fisiología , Movimiento Celular/fisiología , Endotelio Vascular/metabolismo , Neoplasias de la Vejiga Urinaria/metabolismo , Endotelio Vascular/citología , Espacio Extracelular/fisiología , Humanos , Técnicas In Vitro , Microscopía Confocal , Invasividad Neoplásica , Células Neoplásicas Circulantes/patología , Células Neoplásicas Circulantes/ultraestructura , Células Tumorales Cultivadas , Venas Umbilicales/citología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: Anesthetic agents are known to influence functions of the immune system. Anesthetic drugs also support cancer progression by suppressing the activity of immune cells. In breast carcinoma an increase in expression of peripheral-type benzodiazepine receptors (PBR) and the gamma aminobutyl acid (GABA) level has been discovered. Therefore, an investigation of a direct influence of GABA-A agonist propofol, GABA-A and PBR-agonist etomidate, and the local anesthetic drug lidocaine, which can also bind to the GABA-A receptor and PBR, on migration of breast carcinoma cells was performed. METHODS: MDA-MB-468 cells were incubated with anesthetic agents using clinically relevant concentrations (propofol 3, 6, 9 mg/l, etomidate 2, 3, 4 mg/l, and lidocaine 1.25, 2.5, 5 mg/l). Locomotion was investigated in a three-dimensional collagen matrix using time-lapse video microscopy and computer-assisted cell-tracking. RESULTS: The percentage of migrating cells (57.4+/-1.9) as well as the velocity (0.22+/-0.09 microm/min) and distance migrated (89.4+/-66.8 microm/10 h) increased in the presence of propofol in a dose-dependent manner (up to 74.4+/-7.5, 0.30+/-0.09, 143.8+/-89.1, respectively) compared with the long chain triglyceride (LCT) control. In contrast, no influence of etomidate on the number of migrating cells could be observed. The velocity and distance migrated at 3 and 4 mg/l were found to be statistically significantly enhanced. Treatment with lidocaine caused an increase in the percentage of migrating cells (up to 75.0+/-5.6) in velocity dose dependently (up to 0.33+/-0.06) and in distance migrated (up to 151.5+/-92.9). CONCLUSION: These results show that different anesthetic drugs are able to modulate the migratory machinery of human breast carcinoma cells in vitro.
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Adenocarcinoma/fisiopatología , Anestésicos/farmacología , Neoplasias de la Mama/fisiopatología , Adenocarcinoma/patología , Anestésicos Intravenosos/farmacología , Anestésicos Locales/farmacología , Neoplasias de la Mama/patología , Movimiento Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Etomidato/farmacología , Femenino , Agonistas del GABA/farmacología , Agonistas de Receptores de GABA-A , Humanos , Lidocaína/farmacología , Microscopía por Video , Propofol/farmacología , Células Tumorales Cultivadas/efectos de los fármacosAsunto(s)
Neoplasias/patología , Proteína BRCA2 , Índice de Masa Corporal , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/prevención & control , Neoplasias de la Mama/terapia , Femenino , Genes BRCA1 , Marcadores Genéticos , Humanos , India/epidemiología , Proteínas de Neoplasias/genética , Neoplasias/epidemiología , Neoplasias/etiología , Neoplasias/terapia , Factores de Riesgo , Factores de Transcripción/genéticaRESUMEN
AIMS: Comparative genomic hybridisation (CGH) is a reliable tool to gain an overview of all unbalanced chromosomal alterations within a tumour. Nevertheless, the high numbers of tumour cells required and the comparatively low resolution are drawbacks of this technique. Polymerase chain reaction (PCR) based multiplex microsatellite analysis represents a semi-automated, highly reproducible method, which requires small amounts of tumour cells. This is a comparative study of CGH and microsatellite analysis. METHODS: Eighty one samples of invasive breast cancer were investigated by two sensitive multiplex PCRs containing three microsatellites each of six markers (D6S261, D11S907, D6S300, D11S927, D8S272, and D11S925), and two additional microsatellite markers located within intron 1 of the epidermal growth factor receptor gene (egfr) and p53 (p53CA). RESULTS: At least one example of loss of heterozygosity was detectable in all breast cancer tissues. However, the overall rate of accordance between the two methods tested was only 61%. An increasing rate of the number of genetic alterations in each case was mirrored by a constantly increasing fractional allelic loss index. CONCLUSIONS: PCR based multiplex microsatellite analysis using this panel of eight microsatellite markers not only enables the characterisation of cells that have malignant potential in a high frequency of patients with breast cancer, but can also give an estimate of the degree of genetic progression.
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Neoplasias de la Mama/genética , Receptores ErbB/genética , Genes p53 , Repeticiones de Microsatélite , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Humanos , Pérdida de Heterocigocidad , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa/métodos , Reproducibilidad de los ResultadosRESUMEN
The protein kinase C (PKC) is a family of serine/threonine kinases that are key regulatory enzymes involved in growth, differentiation, cytoskeletal reorganization, tumor promotion, and migration. We investigated the functional involvement of PKC isotypes and of E-cadherin in the regulation of the locomotion of six human colon-adenocarcinoma cell lines. The different levels of the PKC alpha and the E-cadherin expression have predictable implications in the spontaneous locomotory activity. With the use of PKC alpha--specific inhibitors (safingol, Go6976) as well as the PKC delta--specific inhibitor rottlerin, we showed that only PKC alpha plays a major role in the regulation of tumor cell migration. The results were verified by knocking out the translation of PKC isozymes with the use of an antisense oligonucleotide strategy. After stimulation with phorbol ester we observed a translocation and a colocalization of the activated PKC alpha at the plasma membrane to the surrounding extracellular matrix. Furthermore, we investigated the functional involvement of E-cadherin in the locomotion with the use of a blocking antibody. A high level of PKC alpha expression together with a low E-cadherin expression was strongly related to a high migratory activity of the colon carcinoma cells. This correlation was independent of the differentiation grade of the tumor cell lines.
Asunto(s)
Cadherinas/biosíntesis , Movimiento Celular/fisiología , Isoenzimas/biosíntesis , Proteína Quinasa C/biosíntesis , Esfingosina/análogos & derivados , Acetofenonas/farmacología , Benzopiranos/farmacología , Transporte Biológico , Carbazoles/farmacología , Membrana Celular/metabolismo , Neoplasias del Colon , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Humanos , Indoles/farmacología , Isoenzimas/antagonistas & inhibidores , Isoenzimas/genética , Oligonucleótidos Antisentido/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/genética , Proteína Quinasa C-alfa , Proteína Quinasa C-delta , Esfingosina/farmacología , Células Tumorales CultivadasRESUMEN
Beta-adrenoceptors are highly expressed on SW 480 colon carcinoma cells as was assessed by flow cytometry. We investigated the influence of norepinephrine on the migration of these cells using time-lapse videomicroscopy. Norepinephrine-treatment increased the locomotor activity within the population from 25% spontaneously locomoting cells to 65% locomoting cells. The beta1/2-blocker propranolol but not the beta1-blocker atenolol inhibited this increase. The intracellular signaling solely of norepinephrine-induced locomotion involved protein tyrosine kinase activity, whereas both spontaneous and norepinephrine-induced migration were reduced by inhibiting phospholipase Cgamma and protein kinase Calpha activity. In summary, norepinephrine-induced locomotion of SW 480 cells is beta2-adrenoceptor mediated and distinct from spontaneous locomotion concerning the PTK involvement.