RESUMEN
Hybrid tumors of the kidney are not rare. Previous studies of hybrid renal tumors have been valuable for the understanding of the pathogenesis and progression pathways of renal cell neoplasm. In this paper we describe the morphologic, immunohistochemical, and genetic features of 2 oncocytomas with evolving papillary renal cell carcinoma (PRCC) in a nephrectomy specimen of a 60-year old male. The patient was referred for urologic oncology consultation after the incidental discovery of a renal tumor. Nephrectomy was performed and two separate masses were present grossly. The tumors were stained with hematoxylin and eosin, cytokeratin 7 and vimentin. Genetic studies included conventional metaphase cytogenetics and fluorescence in situ hybridization (FISH). Morphologically, both tumors were oncocytomas with numerous microscopic papillary nests and psammoma bodies. Papillary carcinoma nests were highlighted with cytokeratin 7 and vimentin positivity and were more prominent in the larger tumor. Conventional cytogenetics and FISH demonstrated loss of chromosomes Y and 1 and gains of chromosome 7. We postulate that the PRCC represents a neoplastic progression by the gain of chromosome 7 oncocytoma with -Y and -1.
Asunto(s)
Adenoma Oxifílico/genética , Carcinoma Papilar/genética , Aberraciones Cromosómicas , Deleción Cromosómica , Cromosomas Humanos Par 7 , Cromosomas Humanos Y , Neoplasias Renales/genética , Adenoma Oxifílico/patología , Carcinoma Papilar/patología , Progresión de la Enfermedad , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Neoplasias Renales/patología , Masculino , Metafase , Persona de Mediana EdadRESUMEN
PURPOSE: Loss of the methylthioadenosine phosphorylase (MTAP) gene at 9p21 is observed frequently in a variety of human cancers. We have shown previously that MTAP can act as a tumor suppressor gene and that its tumor suppressor function is related to its effect on polyamine homeostasis. Ornithine decarboxylase is a key enzyme in the regulation of polyamine metabolism. The aim of this study is to analyze MTAP and ornithine decarboxylase (ODC) expression in primary pancreatic tumor specimens. EXPERIMENTAL DESIGN: We measured MTAP and ODC activity in protein extracts derived from 30 surgically resected tumor samples and eight normal pancreas samples. In a subset of six samples, we also examined MTAP DNA using interphase fluorescence in situ hybridization. In addition, we examined the effect of the ODC inhibitor difluoromethylornithine on two pancreatic adenocarcinoma-derived cell lines. RESULT: MTAP activity was 2.8-fold reduced in adenocarcinomas and 6.3-fold reduced in neuroendocrine tumors compared with control pancreas. Conversely, ODC activity was 3.6-fold elevated in adenocarcinomas and 3.9-fold elevated in neuroendocrine tumors compared with control pancreas. Using interphase fluorescence in situ hybridization, we found in tumor samples that 43 to 75% of the nuclei had lost at least one copy of MTAP locus, indicating that loss of MTAP activity was at least partially because of deletion of the MTAP locus. We also show that inhibition of ODC by difluoromethylornithine caused decreased cell growth and increased apoptosis in two MTAP-deleted pancreatic adenocarcinoma-derived cell lines. CONCLUSIONS: MTAP activity is frequently lost, and ODC activity is frequently elevated in both pancreatic adenocarcinoma and neuroendocrine tumors. Inhibition of ODC activity caused decreased cell growth and increased apoptosis in pancreatic tumor-derived cell lines. These findings suggest that MTAP and polyamine metabolism could be potential therapeutic targets in the treatment of pancreatic cancer.
Asunto(s)
Tumores Neuroendocrinos/enzimología , Ornitina Descarboxilasa/biosíntesis , Ornitina Descarboxilasa/fisiología , Neoplasias Pancreáticas/enzimología , Purina-Nucleósido Fosforilasa/genética , Purina-Nucleósido Fosforilasa/fisiología , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Apoptosis , Western Blotting , Línea Celular Tumoral , Cromosomas Humanos Par 9 , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , ADN/metabolismo , Humanos , Hibridación Fluorescente in Situ , Modelos Biológicos , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/metabolismo , Poliaminas/químicaRESUMEN
AKT is frequently activated in various cancers, but its involvement in lung tumor development and progression is not well established. We examined AKT activity by immunohistochemistry in 110 non-small cell lung carcinomas (NSCLCs) using tissue microarrays. AKT activation was observed in 56 (51%) tumors. To further validate activation of the AKT pathway in this series, we examined the phosphorylation status of the mammalian target of rapamycin (mTOR) and forkhead (FKHR), two downstream targets of AKT. Positive staining for phospho-mTOR and phospho-FKHR were detected in 74% and 68% of tumors, respectively, and was significantly associated with activation of AKT. Tumors positive for phosphorylated (active) AKT were present with a similar frequency in low stage (I/II) and high stage (III/IV) tumors, raising the possibility that AKT activation occurs early in tumor progression. We therefore examined AKT activity in 25 bronchial epithelial lesions from 12 patients at high risk of lung cancer. Metaplastic/dysplastic areas showed AKT activity, whereas normal and hyperplastic bronchial epithelia exhibited little or no activity. Since some bronchial epithelial lesions may develop into invasive cancers, we examined the effect of AKT on invasiveness of lung cancer cells, using an in vitro cell invasion assay. Transfection of NSCLC cells with wild-type AKT increased invasiveness in response to hepatocyte growth factor, whereas transfection with dominant negative AKT abrogated this effect. Collectively, these data suggest that AKT activation is a frequent and early event in lung tumorigenesis, which may enhance risk of progression to malignancy. Thus, AKT represents a potentially important target for chemoprevention in individuals at high risk of NSCLC.
Asunto(s)
Neoplasias de los Bronquios/enzimología , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Neoplasias Pulmonares/enzimología , Lesiones Precancerosas/enzimología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Adulto , Anciano , Neoplasias de los Bronquios/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Activación Enzimática , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Fosforilación , Lesiones Precancerosas/patología , Proteínas Quinasas/metabolismo , Serina-Treonina Quinasas TORRESUMEN
Lymphangiomyomatosis (LAM) is characterized by the proliferation of abnormal smooth muscle cells and cystic degeneration of the lung. LAM affects almost exclusively young women. Although lung transplantation provides effective therapy for end-stage LAM, there are reports of LAM recurrence after lung transplantation. Whether these recurrent LAM cells arise from the patient or the lung transplant donor is an area of controversy. We used microsatellite marker fingerprinting and TSC2 gene mutational analysis to study a patient with recurrent LAM after single-lung transplantation. The DNA microsatellite marker pattern indicated the presence of patient-derived LAM cells in the allograft. A somatic one base pair deletion in exon 18 of the TSC2 gene was identified in pulmonary and lymph node LAM cells before transplantation. The same mutation was in the recurrent LAM, demonstrating that the recurrent LAM was derived from the patient. Fluorescence in situ hybridization revealed that cells immunoreactive with the monoclonal antibody HMB-45 did not contain a Y chromosome. These data indicate that histologically benign LAM cells can migrate or metastasize in vivo to the transplanted lung. In addition, the patient had no evidence of a renal angiomyolipoma at autopsy and therefore demonstrated for the first time that somatic TSC2 mutations cause LAM in patients without angiomyolipomas.
Asunto(s)
Neoplasias Pulmonares/cirugía , Trasplante de Pulmón , Linfangioleiomiomatosis/cirugía , Recurrencia Local de Neoplasia/etiología , Adulto , Alelos , Secuencia de Bases , Biomarcadores de Tumor/genética , Biopsia , Cromosomas Humanos Par 16/genética , Cromosomas Humanos Y/genética , ADN de Neoplasias/genética , Exones/genética , Femenino , Genes Supresores de Tumor , Heterocigoto , Humanos , Pérdida de Heterocigocidad/genética , Pulmón , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundario , Ganglios Linfáticos , Linfangioleiomiomatosis/genética , Linfangioleiomiomatosis/patología , Repeticiones de Microsatélite/genética , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/secundario , Complicaciones Posoperatorias/etiología , Proteínas Represoras/genética , Insuficiencia del Tratamiento , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de TumorRESUMEN
A wealth of cytogenetic data has demonstrated that numerous somatic genetic changes are involved in the pathogenesis of human lung cancer. Despite the complexity of the genomic changes observed in these neoplasms, recurrent chromosomal patterns have emerged. In this review, we summarize chromosomal alterations identified in small cell and non-small cell lung cancer, using classical and molecular cytogenetic techniques. These analyses have uncovered a set of chromosome regions implicated in lung cancer development and progression. However, many of the target genes remain unknown. Newer technology, such as array-CGH, when combined with cDNA microarrays and tissue microarrays, will facilitate the integration of genomic and gene expression data and pave the way toward a molecular classification of lung carcinomas. The molecular implications of consistent chromosome imbalances found in lung cancer to date are also discussed.