RESUMEN
Primary effusion lymphoma (PEL) is an aggressive malignancy with poor prognosis even under chemotherapy. Kaposi sarcoma-associated herpesvirus (KSHV), one of the human oncogenic viruses, is the principal causative agent. Currently, there is no specific treatment for PEL; therefore, developing new therapies is of great importance. Sphingolipid metabolism plays an important role in determining the fate of tumor cells. Our previous studies have demonstrated that there is a correlation between sphingolipid metabolism and KSHV+ tumor cell survival. To further develop sphingolipid metabolism-targeted therapy, after screening a series of newly synthesized ceramide analogs, here, we have identified compounds with effective anti-PEL activity. These compounds induce significant PEL apoptosis, cell-cycle arrest, and intracellular ceramide production through regulation of ceramide synthesizing or ceramide metabolizing enzymes and dramatically suppress tumor progression without visible toxicity in vivo. These new compounds also increase viral lytic gene expression in PEL cells. Our comparative transcriptomic analysis revealed their mechanisms of action for inducing PEL cell death and identified a subset of novel cellular genes, including AURKA and CDCA3, controlled by sphingolipid metabolism, and required for PEL survival with functional validation. These data provide the framework for the development of promising sphingolipid-based therapies against this virus-associated malignancy.
Asunto(s)
Aurora Quinasa A/metabolismo , Ceramidas/farmacología , Herpesvirus Humano 8/patogenicidad , Linfoma de Efusión Primaria/tratamiento farmacológico , Sarcoma de Kaposi/complicaciones , Esfingolípidos/farmacología , Animales , Apoptosis , Aurora Quinasa A/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Supervivencia Celular , Ceramidas/química , Femenino , Perfilación de la Expresión Génica , Humanos , Linfoma de Efusión Primaria/etiología , Linfoma de Efusión Primaria/metabolismo , Linfoma de Efusión Primaria/patología , Ratones , Ratones Endogámicos NOD , Ratones SCID , Sarcoma de Kaposi/virología , Células Tumorales Cultivadas , Replicación Viral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Patterns of invasion and stromal response are understudied in vulvar squamous cell carcinoma. The aim of this study was to explore whether histologic features such as an infiltrative pattern of invasion and fibromyxoid stromal response (FMX-SR) are meaningful prognostic factors. We reviewed 143 vulvar squamous cell carcinoma resections and correlated patterns of invasion and stromal response with patient age, ethnicity, depth of invasion, tumor size, perineural invasion (S100/AE1/3 stain), lymph node involvement (LNI), extranodal extension, margin status, pathologic stage, and recurrence. Univariate analyses of continuous variables were performed using t tests, whereas Pearson χ tests were used for categorical variables. Logistic regression analyses examined the relationship between histopathologic characteristics and clinical outcomes. There was a statistically significant association between infiltrative tumors and an FMX-SR in comparison with noninfiltrative tumors (P<0.001). Tumors with FMX-SR were significantly more deeply invasive (P=0.0025) and more likely to have LNI (P=0.0364), extranodal extension (P=0.0227), and perineural invasion (P=0.0011) compared with tumors without FMX-SR. For cases with negative surgical margins, the association between tumors with FMX-SR and LNI was significantly strengthened (odds ratio=4.73, P=0.0042), even after adjustments for age, race, and depth of invasion (odds ratio=4.34, P=0.0154). The presence of both FMX-SR and an infiltrative pattern of invasion in tumors with negative margins was significantly associated with LNI (P=0.0235) and recurrence (P=0.0124). These results suggest that interactions between nerve, tumor, and stromal cells play a role in tumor progression and represent additional prognostic factors that help stratify those patients at highest risk for LNI, extranodal extension, and recurrence.
Asunto(s)
Carcinoma de Células Escamosas/secundario , Fibroma/patología , Nervios Periféricos/patología , Células del Estroma/patología , Neoplasias de la Vulva/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/etnología , Carcinoma de Células Escamosas/cirugía , Distribución de Chi-Cuadrado , Progresión de la Enfermedad , Femenino , Fibroma/química , Fibroma/etnología , Fibroma/cirugía , Humanos , Modelos Logísticos , Metástasis Linfática , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Neoplasia Residual , Oportunidad Relativa , Nervios Periféricos/química , Estudios Retrospectivos , Factores de Riesgo , Células del Estroma/química , Factores de Tiempo , Resultado del Tratamiento , Neoplasias de la Vulva/química , Neoplasias de la Vulva/etnología , Neoplasias de la Vulva/cirugía , Adulto JovenRESUMEN
OBJECTIVES: Vulvar squamous cell carcinoma (vSCC) is a gynecologic malignancy diagnosed in nearly 4500 women in the United States each year. Current criteria for treatment planning provide inadequate assessment of aggressive vSCC cases, resulting in insufficient use of adjuvant treatments and high rates of vSCC recurrence. Perineural invasion (PNI) is a pathologic feature inconsistently included in the assessment of vSCC, because its relevance to clinical outcomes in these women is not well defined. The purpose of this study was to determine the association between PNI and relevant clinical parameters such as recurrence. METHODS: A total of 103 cases of vSCC were evaluated for PNI using pathology report review and immunohistochemistry dual-chromogen staining for S100 and AE1/3. Medical records were reviewed for clinical and follow-up data. Data were analyzed using univariate and multivariate logistic regression statistical methods. RESULTS: Patients with vSCC containing PNI had a greater risk for cancer recurrence than those whose tumors did not contain PNI (odds ratio=2.8, P=0.0290). There was no significant correlation between the presence of PNI and nodal involvement, stage, or lymphovascular invasion. Tumors with PNI had greater depth of invasion (DOI) (P=0.0047); however, DOI was not associated with recurrence (P=0.2220). When analyzed using a multivariable logistic regression model, PNI was an independent predictor of recurrence in vSCC (adjusted odds ratio=2.613, P=0.045). CONCLUSIONS: PNI is an independent indicator of risk for recurrence in vSCC. The association of PNI with increased risk for recurrence, independent of DOI, nodal involvement, lymphovascular invasion, or stage, should encourage practicing pathologists to thoroughly search for and report the presence of PNI in vSCC.