RESUMEN
Increased expression of CD24 is seen in a large variety of solid tumors, including up to 90% of gastrointestinal (GI) tumors. Stable derivatives of SW480 colorectal cancer (CRC) cells that overexpress CD24 proliferate faster, and increase cell motility, saturation density, plating efficiency, and growth in soft agar. They also produce larger tumors in nude mice as compared to the parental SW480 cells. Most significantly, even depletion of one copy of the CD24 allele in the APC(Min/+) mice of a transgenic mouse model led to a dramatic reduction in tumor burden in all sections of the small intestine. Homozygous deletion of both CD24 alleles resulted in complete abolishment of tumor formation. Moreover, CD24 knockout mice exhibited resistance to chemically induced inflammation-associated CRC. Finally, a new signal transduction pathway is suggested: namely, CD24 expression downstream to COX2 and PGE2 synthesis, which is directly regulated by ß-catenin. CD24 is shown in vitro and in vivo as being an important oncogene in the gut, and one that plays a critical role in the initiation and progression of carcinogenesis.
Asunto(s)
Proteína de la Poliposis Adenomatosa del Colon/genética , Antígeno CD24/genética , Carcinogénesis/genética , Neoplasias Colorrectales/inducido químicamente , Neoplasias Colorrectales/genética , Animales , Azoximetano/farmacología , Antígeno CD24/biosíntesis , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular , Colitis/inducido químicamente , Ciclooxigenasa 2/genética , Sulfato de Dextran/farmacología , Dinoprostona , Progresión de la Enfermedad , Femenino , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Células HT29 , Humanos , Intestino Delgado , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Regiones Promotoras Genéticas , Transducción de Señal/genética , Carga Tumoral/genética , beta CateninaRESUMEN
BACKGROUND: Atherosclerosis is a complex vascular inflammatory disease. In the last decade it was suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) and in particular inhibition of cyclooxygenase (COX)-2 are associated with an increase in cardiovascular morbidity and mortality. Aspirin is known to reduce the incidence and mortality from ischemic heart disease and is a mainstay in the prevention of vascular complications of atherosclerosis. OBJECTIVES: To examine the effect of meloxicam, a selective COX-2 inhibitor, or low dose aspirin on the development of experimental atherosclerosis in apoE knockout (KO) compared to wild-type (WT) mice. We aimed to test the hypothesis that meloxicam, a potential vasculitis inducer, would exacerbate atherosclerotic lesions while aspirin, which is known to reduce the incidence of thrombosis occlusive events, would increase protection in this model. METHODS: We randomly divided 36 male apoE KO and 36 WT mice, 8 weeks old. Mice were treated for 10 weeks with 0.1 mg/ml aspirin, or 0.05 mg/ml meloxicam, dissolved in their drinking water. Control groups received regular drinking water. At sacrifice, the hearts were removed for histochemical staining and plaque size and composition were examined. RESULTS: Aspirin-treated animals displayed a decreased atherosclerotic lesion area compared to the untreated control mice, while meloxicam had a null effect on the extent of atherosclerosis in Apo E KO mice. CONCLUSIONS: These results suggest that low dose aspirin reduces early atherosclerosis, while inhibition of COX-2 by meloxicam is not associated with an increase in atherosclerotic plaque size in this mouse model.
Asunto(s)
Apolipoproteínas E/genética , Aspirina/farmacología , Aterosclerosis/prevención & control , Inhibidores de la Ciclooxigenasa 2/farmacología , Tiazinas/farmacología , Tiazoles/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Aspirina/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Meloxicam , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Placa Aterosclerótica/patología , Placa Aterosclerótica/prevención & controlRESUMEN
OBJECTIVE: Chemoprevention trials have shown that celecoxib reduces adenoma recurrence but can cause cardiovascular toxicity. In this pilot study, we evaluated associations between genetic variation in several candidate pathways (e.g. prostaglandin synthesis) and adenoma recurrence and cardiovascular and gastrointestinal toxicities. METHODS: Genotyping analysis was carried out on 117 Israeli colorectal adenoma patients who participated in the Prevention of Colorectal Sporadic Adenomatous Polyps trial. Reassessment followed after 3 years on celecoxib and after 2 years from termination of treatment with celecoxib. Efficacy (absence of colorectal adenomas) was measured by colonoscopy at years 1, 3, and 5. Toxicities were assessed by investigators during celecoxib treatment and by self-report post-treatment. A linkage disequilibrium-based selection algorithm (r2≥0.90, MAF≥4%) identified 255 tagSNPs in 25 analyzed candidate genes. Genotyping was performed by using Illumina GoldenGate technology. RESULTS: Multiple genetic variants were associated with adenoma recurrence and toxicity. Genetic variability in COX1, COX2, and ALOX12/15 genes played a role in adenoma recurrence, particularly among patients on placebo. More gene variants (especially variants in PGES, CRP, SRC, and GPX3) were associated with increased risk for cardiovascular toxicity and symptoms, compared with gastrointestinal toxicity and symptoms. The increased risk for cardiovascular toxicity/symptoms associated with the SRC gene variants (rs6017996, rs6018256, rs6018257) ranged from 6.61 (95% confidence interval 1.66-26.36, P<0.01) to 10.71 (95% confidence interval 1.96-58.60, P<0.01). CONCLUSION: Genetic polymorphisms in multiple inflammation-related genes appear to interact with celecoxib on adenoma recurrence and its attendant toxicity, particularly cardiovascular toxicity/symptoms. Larger studies validating these pharmacogenetic relationships are needed.
Asunto(s)
Adenoma/tratamiento farmacológico , Enfermedades Cardiovasculares/inducido químicamente , Neoplasias Colorrectales/tratamiento farmacológico , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Enfermedades Gastrointestinales/inducido químicamente , Polimorfismo de Nucleótido Simple , Pirazoles/efectos adversos , Sulfonamidas/efectos adversos , Adenoma/genética , Pólipos Adenomatosos/tratamiento farmacológico , Pólipos Adenomatosos/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/genética , Celecoxib , Neoplasias Colorrectales/genética , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Femenino , Enfermedades Gastrointestinales/genética , Variación Genética , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/genética , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/prevención & control , Farmacogenética , Proyectos Piloto , Pirazoles/uso terapéutico , Sulfonamidas/uso terapéuticoRESUMEN
Chemopreventive strategies for colorectal cancer (CRC) have been extensively studied to prevent the recurrence of adenomas and/or delay their development in the gastrointestinal tract. The non-steroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors have been proven as promising and the most attractive candidates for CRC clinical chemoprevention. The preventive efficacy of these agents is supported by a large number of animal and epidemiological studies which have clearly demonstrated that NSAID consumption prevents adenoma formation and decreases the incidence of, and mortality from CRC. On the basis of these studies, aspirin chemoprevention may be effective in preventing CRC within the general population, while aspirin and celecoxib may be effective in preventing adenomas in patients after polypectomy. Nevertheless, the consumption of NSAID and COX-2 inhibitors is not toxic free. Well-known serious adverse events to the gastrointestinal, renal and cardiovascular systems have been reported. These reports have led to some promising studies related to the use of lower doses and in combination with other chemopreventive agents and shown efficacy. In the intriguing jigsaw puzzle of cancer prevention, we now have a definite positive answer for the basic question "if", but several other parts of the equation-proper patient selection, the ultimate drug, optimal dosage and duration are still missing.
Asunto(s)
Anticarcinógenos/uso terapéutico , Neoplasias Colorrectales/prevención & control , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Quimioprevención , HumanosRESUMEN
BACKGROUND: Functional activation of oncogenic K-Ras signaling pathway plays an important role in the early events of colorectal carcinogenesis (CRC). K-Ras proto-oncogene is involved in 35-40% of CRC cases. Mutations in the Ras gene trigger the transduction of proliferative and anti-apoptotic signals, even in the absence of extra cellular stimuli. The objective of the current study was to use a gene-targeting approach to kill human CRC cells selectively harboring mutated K-Ras. RESULTS: A recombinant adenovirus that carries a lethal gene, PUMA, under the control of a Ras responsive promoter (Ad-Py4-SV40-PUMA) was used selectively to target CRC cells (HCT116, SW480, DLD1 and RIE-Ras) that possess a hyperactive Ras pathway while using HT29 and RIE cells as a control that harbors wild type Ras and exhibit very low Ras activity. Control vector, without the Ras responsive promoter elements was used to assess the specificity of our "gene therapy" approach. Both adenoviral vectors were assed in vitro and in xenograft model in vivo. Ad-Py4-SV40-PUMA showed high potency to induce ~50% apoptosis in vitro, to abolish completely tumor formation by infecting cells with the Ad-Py4-SV40-PUMA prior xenografting them in nude mice and high ability to suppress by ~35% tumor progression in vivo in already established tumors. CONCLUSIONS: Selective targeting of CRC cells with the activated Ras pathway may be a novel and effective therapy in CRC. The high potency of this adenoviral vector may help to overcome an undetectable micro metastasis that is the major hurdle in challenging with CRC.
Asunto(s)
Adenovirus Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Genes ras , Terapia Genética , Animales , Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Vectores Genéticos , Humanos , Ratones , Regiones Promotoras Genéticas , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Ratas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: The Cox-2 inhibitor, celecoxib (Pfizer Inc., N.Y., USA), is a promising chemopreventive agent [Arber et al.: N Engl J Med 2006;355:885-895; Bertagnolli et al.: N Engl J Med 2006;355:873-884]. This study aims to explore its mechanism by defining changes in gene expression between neoplastic and normal tissue samples before and after treatment. METHODS: Patients with documented colorectal neoplasia in screening colonoscopy, destined to undergo surgical colectomy, were randomized for treatment with celecoxib (n = 11; 400 mg/day) or placebo (n = 3) for 30 days. Tissue samples were taken from the tumor and from normal adjacent mucosa during both colonoscopy and surgery. RNA was extracted and analyzed using Affymetrix Genechip®. RESULTS: 687 genes differentiated tumor samples before and after treatment, among which 310 genes did not show the same differential expression in the placebo group or normal samples. These genes were significantly related to pathways of cell cycle regulation and inflammation, and of note was the TGF-ß pathway, which held a strong association with the list of genes formerly found to be associated with the colorectal cancer expression profile in microarray analyses, as summarized in a meta-analysis by Cardoso et al. [Biochim Biophys Acta 2007;1775:103-137]. CONCLUSIONS: Celecoxib selectively affects genes and pathways involved in inflammation and malignant transformation in tumor but not normal tissues, this may assist in the development of safer and more effective chemopreventive agents.
Asunto(s)
Adenocarcinoma/genética , Transformación Celular Neoplásica/genética , Neoplasias Colorrectales/genética , Inhibidores de la Ciclooxigenasa 2/farmacología , Expresión Génica/efectos de los fármacos , Inflamación/genética , Pirazoles/farmacología , Sulfonamidas/farmacología , Celecoxib , Ciclo Celular/efectos de los fármacos , Ciclo Celular/genética , Transformación Celular Neoplásica/efectos de los fármacos , Pólipos del Colon/genética , Humanos , Mucosa Intestinal/metabolismo , Análisis por Micromatrices , ARN Neoplásico/análisis , Distribución Aleatoria , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Factor de Crecimiento Transformador beta/genéticaRESUMEN
BACKGROUND: Cancer is a leading cause of mortality worldwide. The most effective way to combat cancer is by prevention and early detection. OBJECTIVES: To evaluate the outcome of screening an asymptomatic population for the presence of benign and neoplastic lesions. METHODS: Routine screening tests for prevention and/or early detection of 11 common cancers were conducted in 300 consecutive asymptomatic apparently healthy adults aged 25-77 years. Other tests were performed as indicated. RESULTS: Malignant and benign lesions were found in 3.3% and 5% of the screenees, respectively, compared to 1.7% in the general population. The most common lesions were in the gastrointestinal tract followed by skin, urogenital tract and breast. Advanced age and a family history of a malignancy were associated with increased risk for cancer with an odds ratio of 9 and 3.5, respectively (95% confidence interval 1.1-71 and 0.9-13, respectively). Moreover, high serum C-reactive protein levels and polymorphisms in the APC and CD24 genes indicated high cancer risk. When two of the polymorphisms existed in an individual, the risk for a malignant lesion was extremely high (23.1%; OR 14, 95% CI 2.5-78). CONCLUSIONS: Screening asymptomatic subjects identifies a significant number of neoplastic lesions at an early stage. Incorporating data on genetic polymorphisms in the APC and CD24 genes can further identify individuals who are at increased risk for cancer. Cancer can be prevented and/or diagnosed at an early stage using the screening facilities of a multidisciplinary outpatient clinic.
Asunto(s)
Prestación Integrada de Atención de Salud/organización & administración , Detección Precoz del Cáncer , Tamizaje Masivo/organización & administración , Neoplasias/diagnóstico , Neoplasias/epidemiología , Adulto , Factores de Edad , Anciano , Femenino , Pruebas Genéticas , Humanos , Israel , Masculino , Persona de Mediana Edad , Neoplasias/complicaciones , Proyectos Piloto , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Ewing sarcoma (ES) is the second most common solid bone and soft tissue malignancy in children and young adults with low cure rates indicating the need to identify further prognostic markers. The importance of methylation in the inactivation of key tumor suppressor genes including RASSF1A has begun to be appreciated in context of cancer development, prognosis and therapy. However there is lack of similar broad based studies in ES. The objective of this study was to analyze RASSF1A methylation and assess its clinical significance in ES. PROCEDURE: The methylation of RASSF1A was determined 31 ES tumor samples and 4 ES cell lines. ES cell lines were also treated with demethylating agent 5-aza-2'-deoxycytidine to ascertain its effect on methylation. RASSF1A expression was studied in 12 ES tumors. The association between RASSF1A methylation, clinical parameters and outcome was also analyzed. RESULTS: Methylation of RASSF1A was observed in 21/31 (68%) tumors and in 3/4 ES cell lines. A significant correlation of methylation to reduced expression of RASSF1A was observed in 12 ES tumors analyzed (P = 0.0013) and in all cell lines. ES patients with methylated RASSF1A had worse prognosis compared to the unmethylated group (P = 0.049). Treatment with 5-aza-2'-deoxycytidine resulted in the re-expression of the unmethylated form of RASSF1A in two ES cell lines. CONCLUSION: RASSF1A is frequently methylated in ES.
Asunto(s)
Metilación de ADN , Silenciador del Gen , Sarcoma de Ewing/genética , Proteínas Supresoras de Tumor/genética , Línea Celular Tumoral , Niño , Humanos , Proteínas Supresoras de Tumor/metabolismoRESUMEN
The activation of a telomere maintenance mechanism (TMM) is crucial for the immortalization of tumor cells. Most human cancers apply telomerase-dependent TMM but some use a mechanism called alternative lengthening of telomeres (ALT). The latter was suggested to be mainly characterizing sarcomas with nonspecific complex karyotypes, whereas telomerase activation is typical of sarcomas generated by specific translocations. In this study, we investigated the TMM and its association with survival in rhabdomyosarcoma (RMS), which is characterized by two major subtypes: one that is harboring a specific translocation (alveolar) and one that has a nonspecific karyotype (embryonal). Telomerase activity (TA), using telomerase repeat amplification protocol (TRAP) assay, and telomere length (TRF), using Southern blotting, were analyzed in tumor samples from 31 patients (16 embryonal and 15 alveolar). Alveolar RMS tumors exhibited no ALT phenotype and the majority presented TA. Some embryonal tumors exhibited an ALT or "ALT-like" phenotype which lacked TA, whereas others expressed telomerase-dependent TMM, and neither TA nor ALT correlated with outcome. The average TRF length of the embryonal tumors was significantly higher than that of the alveolar tumors (10.8 vs. 7.2 kb, P = 0.003). Interestingly, some tumors of both subtypes presented no TMM. These observations suggest that alveolar RMS predominantly use telomerase-dependent TMM, whereas in embryonal tumors both telomerase and ALT may play a role. These findings have important implications for understanding the role of TMM in the development of RMS tumors, and for future designing adapted treatment strategies.
Asunto(s)
Rabdomiosarcoma Alveolar/genética , Rabdomiosarcoma Embrionario/genética , Telómero/metabolismo , Southern Blotting , Línea Celular Tumoral , Niño , Preescolar , Femenino , Humanos , Lactante , Cariotipificación , Masculino , Rabdomiosarcoma Alveolar/enzimología , Rabdomiosarcoma Alveolar/patología , Rabdomiosarcoma Embrionario/enzimología , Rabdomiosarcoma Embrionario/patología , Telomerasa/genética , Telomerasa/metabolismoRESUMEN
PURPOSE: Despite advances in therapy, >50% of patients with Ewing sarcoma will relapse. The current prognostic factors are not optimal for risk prediction. Studies have shown that telomere length could predict outcome in different malignancies. Our aim was to evaluate whether telomere length could be a better prognostic factor in Ewing sarcoma and correlate the results with clinical variables, outcome, and chromosomal instability. EXPERIMENTAL DESIGN: Telomere length was determined in the primary tumor and peripheral blood of 32 patients with Ewing sarcoma. Chromosomal instability was evaluated by combining classical cytogenetics, comparative genomic hybridization and random aneuploidy. Telomere length was correlated to clinical variables, chromosomal instability, and outcome. RESULTS: In 75% of the tumors, changes in telomere length, when compared with the corresponding peripheral blood lymphocytes, were noted. The majority of changes consisted of a reduction in telomere length. Patients harboring shorter telomeres had a significantly adverse outcome (P = 0.015). Chromosomal instability was identified in 65% of tumors, significantly correlating with short telomeres (P = 0.0094). Using multivariate analysis, telomere length remained the only significant prognostic variable (P = 0.034). Patients with short telomeres had a 5.3-fold risk of relapse as compared to those with unchanged or longer telomeres. CONCLUSION: We have shown that tumors with telomere length reduction result in genomic instability. In addition, telomere length reduction was the only significant predictor of outcome. We suggest that reduction of telomere length in tumor cells at diagnosis could serve as a prognostic marker in Ewing sarcoma.
Asunto(s)
Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Telómero/ultraestructura , Adolescente , Adulto , Niño , Preescolar , Inestabilidad Cromosómica , Cromosomas/ultraestructura , Femenino , Humanos , Lactante , Masculino , Análisis Multivariante , Hibridación de Ácido Nucleico , Pronóstico , Recurrencia , Riesgo , Factores de Riesgo , Sarcoma de Ewing/diagnóstico , Resultado del TratamientoRESUMEN
Bak is a pro-apoptotic gene, which plays an important role in the multi-step process of gastrointestinal tumorigenesis. We hypothesized that downregulation of Bak expression in normal enterocytes will result in a transformed phenotype. The nontumorigenic intestinal epithelial cell line (IEC18) was transfected with the vector pMV12-AS-bak (encoding anti-sense bak). Three clones, with Bak protein levels similar to those seen in colon cancer cell lines and significantly lower than those found in the parental cells, were further evaluated. The three clones proliferated faster, demonstrated anchorage-independent growth in soft agar and a higher saturation density and plating efficiency. Furthermore, when injected into nude mice, these cells generated tumors after approximately 2-3 weeks. The cells were more resistant to the induction of apoptosis by sulindac sulfide and sulindac sulfone but more sensitive to COX 2 inhibitors (celecoxib and nimesulide). The levels of p16, cyclin D1 and COX 2 were higher in the three transformed clones. In summary,downregulation of Bak expression in normal enterocytes contributes to abnormal growth and tumorigenesis. COX 2 inhibitors may serve as important agents in the prevention and treatment of CRC as they only inhibit the growth of malignant cells.
Asunto(s)
Apoptosis/fisiología , Transformación Celular Neoplásica/metabolismo , Enterocitos/metabolismo , Proteína Destructora del Antagonista Homólogo bcl-2/metabolismo , Adenocarcinoma/etiología , Adenocarcinoma/secundario , Animales , Ciclo Celular/fisiología , Línea Celular , Transformación Celular Neoplásica/patología , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/patología , Dinoprostona/metabolismo , Regulación hacia Abajo , Enterocitos/patología , Enterocitos/fisiología , Expresión Génica , Humanos , Neoplasias Hepáticas/secundario , Ratones , Ratones Desnudos , Ratas , Transfección , Proteína Destructora del Antagonista Homólogo bcl-2/genéticaRESUMEN
CD24 is expressed in 90% of colorectal adenomas and adenocarcinomas. Colorectal cancer (CRC) can be mostly prevented but average risk population screening by stool testing or colonoscopy faces many hurdles. Blood testing is clinically needed. We aimed to evaluate the utility of CD24 expression in peripheral blood leukocytes (PBLs). Two independent case studies were conducted in eligible individuals undergoing colonoscopy. Protein extracted from PBLs was subjected to immunoblotting using anti-CD24 monoclonal antibodies. CD24 sensitivity and specificity were determined using receiver operating characteristic (ROC) analysis. Initially, 150 subjects were examined: 63 had CRC, 19 had adenomas, and 68 had normal colonoscopies. The sensitivity and specificity of CD24 for distinguishing CRC from normal subjects were 70.5% (95% CI, 54.8-83.2%) and 83.8% (95% CI, 74.6-92.7%) and for adenomas 84.2% (95% CI, 60.4-96.4%) and 73.5% (95% CI, 61.4-83.5%), respectively. In the second trial (n = 149), a similar specificity but higher sensitivity was achieved: 80.0% (95% CI, 63.1-91.6%) for CRC and 89.2% (95% CI, 74.6-97%) for adenomas. A simple noninvasive blood test evaluating CD24 levels has high sensitivity and specificity for detecting colorectal adenomas and cancer in patients undergoing colonoscopy at an urban medical center. Larger multicenter studies are warranted to establish the potential of this promising test.
Asunto(s)
Adenocarcinoma/diagnóstico , Adenoma/diagnóstico , Antígeno CD24/sangre , Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/métodos , Adenocarcinoma/sangre , Adenocarcinoma/genética , Adenoma/sangre , Adenoma/genética , Adulto , Anciano , Antígeno CD24/genética , Estudios de Cohortes , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/genética , Femenino , Variación Genética , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Inflammatory bowel disease (IBD) results from an inappropriate inflammatory response in which genetic, immune, and environmental factors all play important roles. Recently, single nucleotide polymorphisms (SNPs) in the CD24 gene have been associated with the development of several autoimmune diseases. AIM: To evaluate whether CD24 SNPs, are associated with risk of ulcerative colitis (UC) and Crohn's disease (CD). METHODS: The CD24 polymorphisms C170T (rs8734), TG1527del (rs3838646), A1626G (rs1058881), and A1056G (rs1058818) were assessed in a case-control study of an Israeli cohort comprising 117 IBD patients and 105 age and gender-matched healthy controls. Restriction fragment length polymorphism (RFLP) analysis was performed using BstX1, Bsr1, Mfe1, and BstU1 restriction enzymes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by logistic regression models. RESULTS: Carriers of the C170T SNP were at increased risk of IBD (OR=3.022, 95% CI: 1.748-5.223, p=0.001), UC (OR=3.002, 95% CI: 1.661-5.427, p=0.001) and CD (OR=3.077, 95% CI: 1.334-7.095, p=0.008). Carrying the A1626G and A1056G SNPs was found to be a risk factor for IBD (OR=2.460, 95% CI: 1.420-4.259, p=0.001 and OR=1.856, 95% CI: 1.011-3.405, p=0.01), UC (OR=2.218, 95% CI: 1.207-4.075, p=0.01 and OR=1.944, 95% CI: 0.995-3.798, p=0.01) but not for CD (p=0.086 and p=0.299). The A1626G and TG1527del were found to be associated with younger age of IBD onset (p=0.022 and p=0.027, respectively). CONCLUSIONS: The CD24 C170T polymorphism is associated with IBD risk. The A1626G and A1056G SNPs might be associated only with UC risk. These findings suggest CD24 as a new genetic susceptibility factor, with clinical implications in the prediction of IBD prognosis and therapy.
Asunto(s)
Antígeno CD24/genética , Colitis Ulcerosa/genética , Enfermedad de Crohn/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Adulto , Anciano , Alelos , Estudios de Casos y Controles , Colitis Ulcerosa/patología , Enfermedad de Crohn/patología , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Población BlancaRESUMEN
CD24 is an extensively glycosylated membrane protein that is linked to the membrane via a glycosyl-phosphatidylinositol (GPI)-anchor. In mice, CD24 is expressed by hematopoietic and non-hematopoietic cells. CD24-/- mice do not have gross immunological defects, but detailed analysis revealed strongly reduced responses in an experimental autoimmune encephalomyelitis (EAE) model and a massive proliferation of T cells under lymphopenic conditions. It was also demonstrated that preB cells from CD24-/- mice are impaired in α4-integrin-mediated cell binding. Here we report that CD24-/- mice have strongly reduced numbers of leukocytes in the colon compared to wildtype mice. The reduction comprized all subpopulations. Leukocyte counts in spleen, mesenteric lymph nodes or small intestine were not significantly different. We find that beside leukocytes, CD24 is widely expressed in EpCAM+ epithelial and CD31+ endothelial cells of colon and small intestine. However, in CD24-/- mice the number of CD31+ endothelial cells in colons was strongly reduced and the number of epithelial cells was augmented. Leukocyte transfer experiments provided evidence that the CD24 status of recipient mice, rather than of the transferred cells, is crucial for leukocyte recruitment to the colon. We hypothesize that CD24 on colonic epithelial and endothelial cells is required for the retention and positioning of leukocytes most likely by affecting integrin function.
Asunto(s)
Antígeno CD24/genética , Colon/patología , Expresión Génica , Leucocitos/metabolismo , Animales , Recuento de Células , Quimiotaxis de Leucocito/genética , Quimiotaxis de Leucocito/inmunología , Colon/inmunología , Citocinas/metabolismo , Células Endoteliales/metabolismo , Inmunofenotipificación , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Leucocitos/inmunología , Ratones , Ratones NoqueadosRESUMEN
BACKGROUND: Cancer is a leading cause of mortality worldwide. Screening is a key strategy for reducing cancer morbidity and mortality. METHODS: We aimed to describe the experience of an integrated cancer prevention center in screening an asymptomatic population for the presence of neoplasia. One-thousand consecutive asymptomatic, apparently healthy adults, aged 20-80 years, were screened for early detection of 11 common cancers that account for 70-80% of cancer mortality. RESULTS: Malignant and benign lesions were found in 2.4% and 7.1% of the screenees, respectively. The most common malignant lesions were in the gastrointestinal tract and breast followed by gynecological and skin. The compliance rate for the different screening procedures was considerably higher than the actual screening rate in the general Israeli population - 78% compared to 60% for mammography (p<0.001) and 39% compared to 16% for colonoscopy (p<0.001). Advanced age, family history of cancer and certain lifestyle parameters were associated with increased risk. Moreover, polymorphisms in the APC and CD24 genes indicated high cancer risk. When two of the polymorphisms existed in an individual, the risk for a neoplastic lesion was extremely high (OR 2.3 [95% CI 0.94-5.9]). CONCLUSIONS: One stop shop screening for 11 common cancers in the setting of a multidisciplinary outpatient clinic is feasible and can detect cancer at an early stage.
Asunto(s)
Enfermedades Asintomáticas/epidemiología , Detección Precoz del Cáncer/métodos , Tamizaje Masivo , Neoplasias , Centros Médicos Académicos/métodos , Adulto , Factores de Edad , Anciano , Antígeno CD24/genética , Detección Precoz del Cáncer/estadística & datos numéricos , Femenino , Genes APC , Humanos , Israel/epidemiología , Estilo de Vida , Masculino , Tamizaje Masivo/métodos , Tamizaje Masivo/estadística & datos numéricos , Neoplasias/clasificación , Neoplasias/diagnóstico , Neoplasias/epidemiología , Neoplasias/genética , Polimorfismo Genético , Servicios Preventivos de Salud/métodos , Factores de RiesgoRESUMEN
BACKGROUND: Skin cancer detection is based on the macroscopic and microscopic appearance of the lesions and the experience of the surgeon. The final diagnosis is done by pathological analysis, based on established criteria. Currently, there is no serum marker that can be used for the diagnosis of skin cancer. CD24, a mucin-like glycoprotein, is overexpressed in a variety of cancers including skin malignancies. OBJECTIVE: Evaluate the potential utility of CD24 expression in peripheral blood leukocytes (PBLs) for the detection of nonmelanoma skin cancers (NMSC). METHODS: Twenty-nine consented individuals attending Tel Aviv Sourasky Medical Center for excision of suspected skin lesions, and 21 age- and gender-matched subjects were prospectively recruited. The resected lesions were examined by an expert dermatopathologist. PBLs were isolated from blood samples and protein extracts were subjected to sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. The study was double blinded. RESULTS: CD24 expression in PBLs distinguishes between NMSC and healthy subjects, with high sensitivity (81%) and specificity (67%) for basal cell carcinoma, and 100% and 71%, respectively, for squamous cell carcinoma. CONCLUSION: The CD24 test can successfully distinguish NMSC from healthy subjects. CD24 may serve as a new potential and promising diagnostic biomarker for the detection and surveillance of NMSC.
Asunto(s)
Biomarcadores de Tumor/sangre , Antígeno CD24/sangre , Carcinoma Basocelular/sangre , Carcinoma Basocelular/diagnóstico , Carcinoma de Células Escamosas/sangre , Neoplasias Cutáneas/sangre , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Antígeno CD24/biosíntesis , Antígeno CD24/genética , Carcinoma Basocelular/genética , Carcinoma Basocelular/patología , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Estudios de Casos y Controles , Método Doble Ciego , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
OBJECTIVES: Coltect is a novel dietary supplement containing curcumin, green tea and selenomethionine. Previous reports have suggested that these agents can prevent colorectal cancer (CRC). The present study examined the chemopreventive effect of Coltect alone or combined with 5-aminosalicylic acid (5-ASA) using the 1,2-dimethylhydrazine (DMH) model in rats. METHODS: The effect of Coltect was examined on HT-29 CRC cells by growth inhibition assay. Apoptosis was determined by annexin V-FITC/PI staining. Male rats were injected with DMH in vivo and treated with Coltect 150 mg/kg, 5-ASA 50 mg/kg or their combination, by oral gavage. Aberrant crypt foci (ACF) were identified by methylene blue staining. RESULTS: HT-29 cells exhibited a dose-dependent response to Coltect. Part of the growth inhibition can be explained by the induction of mild-moderate apoptosis in cancer cells (28%) compared with the untreated cells (10%). In the in vivo model, the average number of ACF was divided into small (1-3 crypts) or large (≥4 crypts). The Coltect compound reduced the number of small and large ACF similarly to 5-ASA (40% reduction). This reduction was amplified by combining the two agents (70% reduction). CONCLUSION: Coltect inhibits the growth of colon cancer cells, induces apoptosis and inhibits ACF development. Furthermore, it augments the growth inhibitory effect of 5-ASA in vivo. This may be clinically important since this safe dietary supplement-drug combination can be administered as a chemopreventive regimen for the treatment of CRC.