RESUMEN
We report the rare and interesting case of a primary lung cancer detected 5 years after cancer of unknown primary (CUP) of a mediastinal lymph node (LN) was resected. A 40-year-old male was diagnosed with adenocarcinoma of unknown primary in a mediastinal lymph node after resection of the mediastinal tumor. Five years after resection of the CUP in mediastinal LN, a small, abnormal nodular shadow in left upper lobe was detected by chest CT. This pulmonary tumor was diagnosed as a lung adenocarcinoma. The pathological and immunohistological findings of the resected pulmonary tumor resembled those of the LN resected 5 years before. We speculated that the pulmonary lesion represented primary lung cancer that enlarged later than the metastatic mediastinal LN. This case illustrates the importance of careful observation and long-term follow-up in patients treated for CUP of a thoracic LN.
Asunto(s)
Adenocarcinoma/secundario , Adenocarcinoma/cirugía , Neoplasias Pulmonares/patología , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Metastasectomía/métodos , Neoplasias Primarias Desconocidas/patología , Adenocarcinoma/química , Adenocarcinoma del Pulmón , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biopsia , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/química , Neoplasias Pulmonares/cirugía , Ganglios Linfáticos/química , Metástasis Linfática , Masculino , Mediastino , Persona de Mediana Edad , Neoplasias Primarias Desconocidas/química , Neumonectomía , Reoperación , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
The prevalence of Epstein-Barr virus (EBV) and high-risk human papilloma virus (HPV) infections in patients with oral cancer in Okinawa, southwest islands of Japan, has led to the hypothesis that carcinogenesis is related to EBV and HPV co-infection. To explore the mechanisms of transformation induced by EBV and HPV co-infection, we analyzed the transformation of primary mouse embryonic fibroblasts (MEFs) expressing EBV and HPV-16 genes, alone or in combination. Expression of EBV latent membrane protein-1 (LMP-1) alone or in combination with HPV-16 E6 increased cell proliferation and decreased apoptosis, whereas single expression of EBV nuclear antigen-1 (EBNA-1), or HPV-16 E6 did not. Co-expression of LMP-1 and E6 induced anchorage-independent growth and tumor formation in nude mice, whereas expression of LMP-1 alone did not. Although the singular expression of these viral genes showed increased DNA damage and DNA damage response (DDR), co-expression of LMP-1 and E6 did not induce DDR, which is frequently seen in cancer cells. Furthermore, co-expression of LMP-1 with E6 increased NF-κB signaling, and the knockdown of LMP-1 or E6 in co-expressing cells decreased cell proliferation, anchorage independent growth, and NF-κB activation. These data suggested that expression of individual viral genes is insufficient for inducing transformation and that co-expression of LMP-1 and E6, which is associated with suppression of DDR and increased NF-κB activity, lead to transformation. Our findings demonstrate the synergistic effect by the interaction of oncogenes from different viruses on the transformation of primary MEFs.
Asunto(s)
Transformación Celular Viral , Fibroblastos/metabolismo , FN-kappa B/metabolismo , Neoplasias/metabolismo , Proteínas Oncogénicas Virales/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal , Proteínas de la Matriz Viral/metabolismo , Animales , Apoptosis , Línea Celular , Proliferación Celular , Antígenos Nucleares del Virus de Epstein-Barr/genética , Antígenos Nucleares del Virus de Epstein-Barr/metabolismo , Femenino , Fibroblastos/patología , Fibroblastos/virología , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/genética , Neoplasias/patología , Neoplasias/virología , Proteínas Oncogénicas Virales/genética , Interferencia de ARN , Proteínas Represoras/genética , Factores de Tiempo , Transfección , Proteínas de la Matriz Viral/genéticaRESUMEN
Cellular angiofibroma (CAF) is a rare soft tissue tumor characterized by random arrangement of spindle tumor cells in the stroma with short collagen bundles and thick- and hyalinized small vessels. CAFs share histological characteristics with spindle cell lipomas and mammary type myofibroblastomas. Because these tumors harbor monoallelic 13q14, common genetic and molecular mechanism for tumorigenesis is presumed. In this study, we reported a case of CAF in a 69-year-old man with monoallelic 13q14. Immunohistochemical analysis revealed that FOXO1, which is located in chromosome 13q14, was not expressed in the tumor. We also detected oxidative stress markers and found p38 MAPK activation, which is often induced by cellular stressors such as reactive oxygen species (ROS). Because FOXO1 induces the expression of genes encoding enzymes that generate antioxidants, oxidative stress induced by loss of FOXO1 expression may be common among CAFs, spindle cell lipomas, and mammary type myofibroblastomas.
Asunto(s)
Angiofibroma/metabolismo , Cromosomas Humanos Par 13/genética , Factores de Transcripción Forkhead/metabolismo , Estrés Oxidativo/fisiología , Transducción de Señal , Anciano , Angiofibroma/genética , Biomarcadores de Tumor/análisis , Carcinogénesis , Proteína Forkhead Box O1 , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Escroto/patología , Transducción de Señal/fisiologíaRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common non-skin cancer worldwide. Despite improvement in therapeutic strategies, the prognosis of advanced HNSCC remains poor. The extacellular lipid mediators known as lysophosphatidic acids (LPAs) have been implicated in tumorigenesis of HNSCC. LPAs activate G-protein-coupled receptors not only in the endothelial differentiation gene (Edg) family (LPA1, LPA2, LPA3) but also in the phylogenetically distant non-Edg family (LPA4, LPA5, LPA6). The distinct roles of these receptor isoforms in HNSCC tumorigenesis have not been clarified. In the present study, we investigated the effect of ectopic expression of LPA4 in SQ-20B, an HNSCC cell line, expressing a trivial level of endogenous LPA4. LPA (18:1) stimulated proliferation of SQ-20B cells, but did not affect proliferation of HEp-2, an SCC cell line expressing higher levels of LPA4, comparable to those of with LPA1. LPA-stimulated proliferation of SQ-20B cells was attenuated by Ki16425 and Rac1 inhibitor, but not by Y-27632. Infection with doxycycline-regulatable adenovirus vector expressing green fluorescent protein-tagged LPA4 (AdvLPA4G) abolished LPA-stimulated proliferation in SQ-20B cells with the accumulation of G2/M-phasic cells. Ectopic LPA4 induction further downregulated proliferation of Ki16425-treated SQ-20B cells, of which downregulation was partially recovered by LPA. Ectopic LPA4 induction also downregulated proliferation of Rac1 inhibitor-treated SQ-20B cells, however, LPA no longer recovered it. Finally, LPA-induced cell motility was suppressed by ectopic LPA4 expression as well as by Ki16425, Rac1 inhibitor or Y-27632. Our data suggest that LPA4 signaling potentially modulates malignant behavior of SQ-20B cells. LPA signaling, which is mediated by both Edg and non-Edg receptors, may be a determinant of malignant behavior of HNSCC and could therefore be a promising therapeutic target.