RESUMEN
The zinc finger protein glioma-associated oncogene homologue 1 (Gli-1) is a critical component of the Hedgehog (Hh) signalling pathway, which is essential for morphogenesis and stem-cell renewal, and is dysregulated in many cancer types. As data were not available on the role of Gli-1 expression in oesophageal cancer progression, we analysed whether it could be used to predict disease progression and prognosis in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Among 69 patients with histologically confirmed oesophageal squamous cell carcinomas (ESCCs), 25 showed a pathological complete response after preoperative CRT. Overall survival (OS) was significantly associated with lymph-node metastasis, distant metastasis, and CRT, and was further correlated with the absence of both Gli-1 nuclear expression and residual tumour. All patients with Gli-1 nuclear expression (10.1%) had distant or lymph-node metastasis, and six out of seven died within 13 months. Furthermore, patients with Gli-1 nuclear-positive cancers showed significantly poorer prognoses than those without (disease-free survival: mean DFS time 250 vs 1738 months, 2-year DFS 0 vs 54.9%, P=0.009; OS: mean OS time 386 vs 1742 months, 2-year OS 16.7 vs 54.9%, P=0.001). Our study provides the first evidence that Gli-1 nuclear expression is a strong and independent predictor of early relapse and poor prognosis in ESCC after CRT. These findings suggest that Hh signal activation might promote cancer regrowth and progression after CRT.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/terapia , Proteínas Hedgehog/metabolismo , Terapia Neoadyuvante/métodos , Transducción de Señal , Factores de Transcripción/metabolismo , Adulto , Anciano , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/cirugía , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/radioterapia , Neoplasias Esofágicas/cirugía , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Valor Predictivo de las Pruebas , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Análisis de Supervivencia , Proteína con Dedos de Zinc GLI1RESUMEN
Four members of collapsin response mediator proteins (CRMPs) are thought to be involved in the semaphorin-induced growth cone collapse during neural development. Here we report the identification of a novel CRMP3-associated protein, designated CRAM for CRMP3-associated molecule, that belongs to the unc-33 gene family. The deduced amino acid sequence reveals that the CRAM gene encodes a protein of 563 amino acids, shows 57% identity with dihydropyrimidinase, and shows 50-51% identity with CRMPs. CRAM appears to form a large complex composed of CRMP3 and other unidentified proteins in vivo. Indeed, CRAM physically associates with CRMP3 when co-expressed in COS-7 cells. The expression of CRAM is brain-specific, is high in fetal and neonatal rat brain, and decreases to very low levels in adult brain. Moreover, CRAM expression is up-regulated during neuronal differentiation of embryonal carcinoma P19 and PC12 cells. Finally, immunoprecipitation analysis of rat brain extracts shows that CRAM is co-immunoprecipitated with proteins that contain protein-tyrosine kinase activity. Taken together, our results suggest that CRAM, which interacts with CRMP3 and protein-tyrosine kinase(s), is a new member of an emerging family of molecules that potentially mediate signals involved in the guidance and outgrowth of axons.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales , Encéfalo/metabolismo , Proteínas Portadoras/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Encéfalo/enzimología , Encéfalo/crecimiento & desarrollo , Proteínas Portadoras/química , Proteínas Portadoras/genética , Clonación Molecular , Reacciones Cruzadas , ADN Complementario , Datos de Secuencia Molecular , Familia de Multigenes , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/genética , Filogenia , Proteínas Tirosina Quinasas/inmunología , Ratas , Homología de Secuencia de Aminoácido , Especificidad por Sustrato , Células Tumorales Cultivadas , Proteína Tirosina Quinasa ZAP-70RESUMEN
A 56-year-old woman with symptoms of chronic bowel disease presented a peculiar calcification of the mesenteric vein of the ascending to transverse colon on barium enema study. The resected colon was hard and black. Histo-pathologic examinations demonstrated fibrous change of the colon with a calcified and hyaline-deposited mesenteric vein. No cell infiltration was observed. These findings were compatible with phlebosclerosis and also with systemic sclerosis. Positive anti-centromere antibody and Raynaud's phenomenon, hallmarks of a variant systemic sclerosis, the CREST syndrome were observed. We therefore speculated that the pathogenesis of the phlebosclerosis of the colon is related to the CREST syndrome.
Asunto(s)
Autoanticuerpos/análisis , Calcinosis/patología , Centrómero/inmunología , Colon/irrigación sanguínea , Venas Mesentéricas/patología , Enfermedades Vasculares/patología , Síndrome CREST/diagnóstico por imagen , Síndrome CREST/inmunología , Síndrome CREST/patología , Calcinosis/diagnóstico por imagen , Calcinosis/inmunología , Colon/diagnóstico por imagen , Colon/patología , Femenino , Fibrosis , Humanos , Venas Mesentéricas/diagnóstico por imagen , Persona de Mediana Edad , Radiografía , Esclerosis , Enfermedades Vasculares/diagnóstico por imagen , Enfermedades Vasculares/inmunologíaRESUMEN
BACKGROUND: The radiological appearance of peritoneal serous papillary carcinoma (PSPC) is described. METHODS: Three cases of PSPC were analyzed retrospectively with regard to the radiological appearance and histopathological features. RESULTS: All three patients were women, aged 44-71 years. Massive ascites and a greater omentum tumor were observed on computed tomography in all patients. Double-contrast enema performed in one patient showed irregularity on the upper aspect of the transverse colon. Radiological examinations excluded primary tumors in both gastrointestinal and genital organs in all patients. Histological diagnosis was made from the surgical specimen in two patients and from an autopsy specimen in one patient. All patients had a large omental tumor involving the transverse colon, but the ovaries were not involved or only minimally involved on the surface. Serum CA125 was markedly elevated, and immunohistochemical staining for CA125 was positive within the tumor cell cytoplasm in all three patients. CONCLUSION: PSPC cannot be diagnosed from radiological findings alone because of its similarity to metastatic peritoneal carcinomatosis and peritoneal mesothelioma. Marked elevation of serum CA125 may help with PSPC diagnosis. Response to treatment is promising, and exploratory laparotomy is thus justified when a patient shows characteristic radiological findings and high CA125 level.
Asunto(s)
Cistadenocarcinoma Papilar/diagnóstico por imagen , Epiplón , Neoplasias Peritoneales/diagnóstico por imagen , Adulto , Anciano , Biomarcadores de Tumor/sangre , Antígeno Ca-125/sangre , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana Edad , Tomografía Computarizada por Rayos XAsunto(s)
Adenocarcinoma Papilar/secundario , Carcinoma Hepatocelular/patología , Aceite Yodado/farmacocinética , Neoplasias Hepáticas/secundario , Neoplasias Gástricas/patología , Adenocarcinoma Papilar/metabolismo , Adenocarcinoma Papilar/terapia , Anciano , Quimioembolización Terapéutica , Diagnóstico Diferencial , Humanos , Aceite Yodado/administración & dosificación , Neoplasias Hepáticas/metabolismo , Masculino , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/terapiaRESUMEN
The c-kit protooncogene encodes a receptor tyrosine kinase that mediates signals required for differentiation, proliferation and survival of mast cells. We have already shown the constitutive activation of c-kit receptor tyrosine kinase (KIT) in a human mast cell leukemia line (HMC-1) and a murine mastocytoma cell line (P-815). We here examined whether such constitutive activation of KIT occurred in the rat tumor mast cell line RBL-2H3 as well, which is frequently used as a tool for studying functions of mast cells. In RBL-2H3 cells, KIT was constitutively phosphorylated on tyrosine and activated in the absence of autocrine production of its ligand, stem cell factor (SCF). Sequencing analysis revealed that one of c-kit genes of RBL-2H3 cells had a point mutation, resulting in amino acid substitution of Tyr for Asp in codon 817. When rat wild-type c-kit cDNA and mutant-type c-kit cDNA encoding KITTyr817 were transfected into cells of a human embryonic kidney cell line (293T), only mutant form KITTyr817 was constitutively phosphorylated on tyrosine and activated in the absence of SCF. Since mutations at the same Asp codon constitutively activated KIT in all the human HMC-1, murine P-815, and rat RBL-2H3 cell lines, and since the incorporation of antisense oligonucleotides of c-kit messenger RNA significantly suppressed the proliferation of RBL-2H3 cells, the activating mutations in the Asp codon of the c-kit gene appeared to be involved in neoplastic growth of mast cells.
Asunto(s)
Ácido Aspártico/farmacología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores del Factor Estimulante de Colonias/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , ADN Complementario/genética , Humanos , Ratones , Datos de Secuencia Molecular , Mutación , Oligonucleótidos Antisentido/antagonistas & inhibidores , Oligonucleótidos Antisentido/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-kit , Ratas , Proteínas Tirosina Quinasas Receptoras/genética , Receptores del Factor Estimulante de Colonias/genética , Transfección , Células Tumorales Cultivadas , Tirosina/metabolismoRESUMEN
The c-kit proto-oncogene encodes a receptor tyrosine kinase that is known to play a crucial role in hematopoiesis, especially in mast cell growth and differentiation. Although a number of dominant loss-of-function mutations of c-kit gene have been well characterized in mice, rats, and humans, little is known about the c-kit mutations contributing to ligand-independent activation of the c-kit receptor tyrosine kinase (KIT). In a murine mastocytoma cell line, P-815, KIT has been found to be constitutively phosphorylated on tyrosine and activated in a ligand-independent manner. Sequencing of the whole coding region of c-kit cDNA showed that c-kit cDNA of P-815 cells carries a point mutation in codon 814, resulting in amino acid substitution of Tyr for Asp. Murine wild-type c-kit cDNA and mutant-type c-kit cDNA encoding Tyr in codon 814 were expressed in cells of a human embryonic kidney cell line, 293T. In the transfected cells, mutant-form KITTyr814 was strikingly phosphorylated on tyrosine and activated in immune complex kinase reaction regardless of stimulation with a ligand for KIT (stem cell factor), whereas tyrosine phosphorylation and activation was barely detectable in wild-form KIT. The data presented here provide evidence for a novel activating mutation of c-kit gene that might be involved in neoplastic growth or oncogenesis of some cell types, including mast cells.
Asunto(s)
Sarcoma de Mastocitos/genética , Mutación Puntual , Proteínas Tirosina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores del Factor Estimulante de Colonias/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Southern Blotting , ADN Complementario/química , Activación Enzimática , Ratones , Datos de Secuencia Molecular , Fosforilación , Fosfotirosina , Proteínas Tirosina Quinasas/química , Proteínas Tirosina Quinasas/genética , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-kit , Proteínas Tirosina Quinasas Receptoras/genética , Receptores del Factor Estimulante de Colonias/genética , Transfección , Células Tumorales Cultivadas , Tirosina/análogos & derivados , Tirosina/metabolismoRESUMEN
Human tumor cell strains having different activities of O6-alkylguanine-DNA alkyltransferase (ATR) were transplanted into nude mice and chemotherapeutic responses of tumor xenografts were compared after intraperitoneal injection of the anti-tumor drug 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU). The tumor strains used were four Mer+ strains possessing high ATR activity and three Mer- strains lacking this activity. Included in these Mer+ strains was a clone 5'dD which expresses the Escherichia coli ATR in Mer- HeLa cells and thus shows the Mer+ phenotype. All the Mer- tumor xenografts were much more sensitive than tumors of Mer+ strains, including the clone 5'dD; after the highest ACNU dose (three injections of 50 mg/kg), some Mer- tumors disappeared completely and the growth of other tumors was severely retarded, whereas all Mer+ tumors continued to grow. These results demonstrate that ATR activity in tumor cells is a major determinant of tumor response to ACNU, and further suggest that measurement of ATR activity in biopsy specimens may provide a useful guide to predict the response to chemotherapy.
Asunto(s)
Metiltransferasas/metabolismo , Neoplasias/tratamiento farmacológico , Nimustina/uso terapéutico , Animales , Línea Celular , Evaluación Preclínica de Medicamentos/métodos , Humanos , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias/enzimología , O(6)-Metilguanina-ADN Metiltransferasa , Células Tumorales CultivadasRESUMEN
A case of primary signet ring cell carcinoma of the urinary bladder is reported. A 52-year-old man was admitted with the complaint of gross hematuria. Cystoscopy showed non-papillary tumor on the right lateral wall. Abdominal CT, Ga scintigraphy, upper gastrointestinal series and barium enema, revealed no signs of a tumor other than the bladder carcinoma. The routine hematologic and chemistry profiles showed no abnormalities except for the serum level of carcinoembryonic antigen elevated to 210 ng/ml. Total cystectomy and right nephroureterectomy with left cutaneous ureterostomy was performed and the surgical specimen showed adenocarcinoma of the bladder. The patient died 5 months after the operation, and autopsy was performed. No tumors were found on the mucosa of the whole digestive tracts or pancreas. This case might be of primary adenocarcinoma originated from the bladder. The literature on the differential diagnosis of the cases reported as bladder adenocarcinoma are reviewed briefly.