RESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is one of the most intractable and devastating malignant tumors. Epigenetic modifications such as DNA methylation and histone modification regulate tumor initiation and progression. However, the contribution of histone variants in PDAC is unknown. Here, we demonstrated that the histone variant H2A.Z is highly expressed in PDAC cell lines and PDAC patients and that its overexpression correlates with poor prognosis. Moreover, all three H2A.Z isoforms (H2A.Z.1, H2A.Z.2.1, and H2A.Z.2.2) are highly expressed in PDAC cell lines and PDAC patients. Knockdown of these H2A.Z isoforms in PDAC cell lines induces a senescent phenotype, cell cycle arrest in phase G2/M, increased expression of cyclin-dependent kinase inhibitor CDKN2A/p16, SA-ß-galactosidase activity and interleukin 8 production. Transcriptome analysis of H2A.Z-depleted PDAC cells showed altered gene expression in fatty acid biosynthesis pathways and those that regulate cell cycle and DNA damage repair. Importantly, depletion of H2A.Z isoforms reduces the tumor size in a mouse xenograft model in vivo and sensitizes PDAC cells to gemcitabine. Overexpression of H2A.Z.1 and H2A.Z.2.1 more than H2A.Z.2.2 partially restores the oncogenic phenotype. Therefore, our data suggest that overexpression of H2A.Z isoforms enables cells to overcome the oncoprotective barrier associated with senescence, favoring PDAC tumor grow and chemoresistance. These results make H2A.Z a potential candidate as a diagnostic biomarker and therapeutic target for PDAC.
Asunto(s)
Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , beta-Galactosidasa/genética , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Envejecimiento/genética , Animales , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/patología , Transformación Celular Neoplásica/genética , Daño del ADN/efectos de los fármacos , Metilación de ADN/genética , Reparación del ADN/efectos de los fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Resistencia a Antineoplásicos/genética , Epigénesis Genética/genética , Xenoinjertos , Histonas/genética , Humanos , Ratones , GemcitabinaRESUMEN
We report a small, well-demarcated stromal tumor of the gallbladder in a 69-year-old woman. The tumor and associated cholelithiasis led to chronic cholecystitis symptoms. The wall of the gallbladder contained a 2.4-cm hypocellular nodule composed of bland spindle-shaped cells that were immunoreactive for vimentin, CD34, and CD117. With the latter antibody, which stains interstitial cells of Cajal (ICC), the neoplastic cells appear fusiform with elongated bipolar projections or dendritic-like cytoplasmic projections. The gallbladder wall adjacent to the tumor contained numerous CD117-positive cells in close contact with the normal smooth muscle cells, whereas two of 10 gallbladders with minimal chronic cholecystitis showed only a few CD117-positive cells. These findings provide evidence that this stromal tumor of the gallbladder shows ICC differentiation similar to some stromal tumors of the gut. The presence of numerous ICC in the uninvolved gallbladder wall suggests that this tumor might have evolved through hyperplasia of ICC.
Asunto(s)
Neoplasias de la Vesícula Biliar/patología , Plexo Mientérico/patología , Neurilemoma/patología , Células del Estroma/patología , Anciano , Antígenos CD34/análisis , Biomarcadores de Tumor/análisis , Colecistitis/etiología , Colecistitis/patología , Colelitiasis/complicaciones , Colelitiasis/patología , Femenino , Neoplasias de la Vesícula Biliar/química , Neoplasias de la Vesícula Biliar/complicaciones , Neoplasias de la Vesícula Biliar/cirugía , Humanos , Técnicas para Inmunoenzimas , Plexo Mientérico/química , Proteínas de Neoplasias/análisis , Neurilemoma/química , Neurilemoma/complicaciones , Neurilemoma/cirugía , Proteínas Proto-Oncogénicas c-kit/análisis , Células del Estroma/química , Vimentina/análisisRESUMEN
This is the first reported case of ectopic prostatic tissue in the uterine cervix, diagnosed in a 38-year-old woman. A cluster of benign prostatic glands with cribriform and papillary patterns and focal squamous metaplasia occupied the superficial endocervical stroma. The glands were immunoreactive for prostatic specific antigen and prostatic specific acid phosphatase. This lesion, which could be confused with microglandular hyperplasia, mesonephric rests, or adenocarcinoma in situ may represent an embryonic rest.
Asunto(s)
Cuello del Útero/patología , Próstata/patología , Fosfatasa Ácida/análisis , Adulto , Cuello del Útero/química , Femenino , Humanos , Inmunohistoquímica , Masculino , Próstata/química , Antígeno Prostático Específico/análisisRESUMEN
Although gallbladder carcinoma is one of the most frequent neoplasms in Chile, there is limited information about the molecular changes involved in its pathogenesis. We investigated the incidence of ras gene mutations and loss of heterozygosity (LOH) at the following genes/loci: p53, DCC, rb, 5q 3p, 8p, and 9p. We precisely microdissected 194 relevant areas from paraffin-embedded microslides from 25 gallbladder carcinomas and their accompanying nonneoplastic lesions (which were present in 15 cases) from patients in Chile. The specimens were analyzed by PCR-based assays for LOH, and we designed a RFLP method for ras mutations and immunohistochemistry for p53 protein overexpression. We determined that LOH at p53 (91%), 9p (50%), 8p (44%) and DCC (31%) are frequent events and that LOH at p53, 9p, and DCC are early events, while ras mutations and LOH at 3p, rb, and 5q occurred occasionally. LOH at p53 occurred more frequently and earlier than protein overexpression. The mean number of mutations present in invasive carcinomas was 2.1, and in six cases, LOH at the p53 gene was the sole mutation detected. The same allele was lost in 61 (93%) of 71 nonneoplastic foci as in the corresponding invasive carcinomas for all four mutations studied. The odds of this occurring by chance are approximately 4 x 10(-15). Although clonality cannot be excluded, allelic loss appears to be highly directed, but the mechanism for allele-specific mutations remains to be determined.
Asunto(s)
Alelos , Deleción Cromosómica , Cromosomas Humanos , Neoplasias de la Vesícula Biliar/genética , Mutación , Adenocarcinoma/genética , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Secuencia de Bases , Carcinoma de Células Pequeñas/genética , Carcinoma de Células Pequeñas/patología , Carcinoma de Células Pequeñas/cirugía , Chile/epidemiología , Epitelio/patología , Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/epidemiología , Neoplasias de la Vesícula Biliar/patología , Neoplasias de la Vesícula Biliar/cirugía , Genes de Retinoblastoma , Genes p53 , Genes ras , Marcadores Genéticos , Humanos , Metaplasia , Invasividad Neoplásica , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Secuencias Repetitivas de Ácidos NucleicosRESUMEN
The clinico-pathologic features of six cases of chronic cholecystitis with focal lymphoid hyperplasia (CCLH) are described and compared with five examples of malignant lymphoma involving the gallbladder. The clinical presentation of CCLH was identical to that of conventional chronic cholecystitis with cholelithiasis. Microscopically there was chronic inflammation and fibrosis in the wall of the gallbladder as well as extensive lymphoid hyperplasia with many lymphoid follicles having germinal centers. The five patients with malignant lymphoma also had chronic cholecystitis; four had a previous diagnosis of lymphoma established by a lymph node biopsy and were also found to have liver involvement during cholecystectomy. The gallbladders with malignant lymphoma showed acute and chronic cholecystitis and a monotonous lymphoid proliferation easily distinguishable from CCLH. We conclude that CCLH displays characteristic pathologic features and should be separated from the chronic and xanthogranulomatous types of cholecystitis.
Asunto(s)
Colecistitis/patología , Neoplasias de la Vesícula Biliar/patología , Vesícula Biliar/patología , Ganglios Linfáticos/patología , Linfoma/patología , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Diagnóstico Diferencial , Femenino , Humanos , Hiperplasia/patología , Persona de Mediana EdadAsunto(s)
Tumor Carcinoide/patología , Neoplasias del Cuello Uterino/patología , Células APUD , Adulto , Anciano , Tumor Carcinoide/terapia , Tumor Carcinoide/ultraestructura , Carcinoma/diagnóstico , Carcinoma/epidemiología , Diagnóstico Diferencial , Femenino , Humanos , Histerectomía , México , Persona de Mediana Edad , Neoplasias del Cuello Uterino/terapia , Neoplasias del Cuello Uterino/ultraestructuraRESUMEN
Two cases of teratoma of the thyroid gland occurring in children are presented. Both tumors were discovered shortly after birth and were not associated with clinical hypothyroidism. One of the patients was thoroughly studied from the endocrinological point of view utilizing several techniques. There was some iodine uptake by the gland, formation of tirosine and thyroid hormones as well as their release into the blood serum. The clinical and pathological features of teratoma of the thyroid are discussed.