RESUMEN
Glioma is a complex tumor composed of both neoplastic and non-neoplastic cells, including tumor-infiltrating leukocytes (TILs), and each cell type contributes to tumor formation and malignant progression. Among TILs, tumor-associated macrophages (TAMs) are of great importance and play a key role in the immune response to cancer. In this study, 22 types of adaptive and innate TILs were evaluated in gliomas. TAMs, which account for 38.7% of all these cells, are the most abundant immune infiltrates in the tumor microenvironment. In addition, we observed different immune cell patterns in low-grade glioma and glioblastoma. Our research indicated that there was a connection between TILs, and 13 of 22 TILs were significantly associated with patient outcomes. Finally, the prognosis and diagnostic value of TAMs were revealed using Kaplan-Meier analysis. We identified the optimal cutoff point of TAMs at an infiltrating level of 0.47 to predict patient prognosis, with a median overall survival of 448 days in patients with higher TAM infiltration levels and 2660 days in patients with lower TAM infiltration levels. These findings provide a new idea for glioma to regulate tumor-specific immunity, clarify the potential effects of TAMs on disease pathology, and provide a theoretical basis for immune intervention treatment of gliomas.
Asunto(s)
Glioblastoma , Glioma , Humanos , Pronóstico , Macrófagos Asociados a Tumores , Leucocitos , Microambiente TumoralRESUMEN
The ECM protein EFEMP1 (fibulin-3) is associated with all types of solid tumor through its cell context-dependent dual function. A variant of fibulin-3 was engineered by truncation and mutation to alleviate its oncogenic function, specifically the proinvasive role in glioblastoma multiforme (GBM) cells at stem-like state. ZR30 is an in vitro synthesized 39-kDa protein of human fibulin-3 variant. It has a therapeutic effect in intracranial xenograft models of human GBM, through suppression of epidermal growth factor receptor/AKT and NOTCH1/AKT signaling in GBM cells and extracellular MMP2 activation. Glioblastoma multiforme is highly vascular, with leaky blood vessels formed by tumor cells expressing endothelial cell markers, including CD31. Here we studied GBM intracranial xenografts, 2 weeks after intratumoral injection of ZR30 or PBS, by CD31 immunohistochemistry. We found a 70% reduction of blood vessel density in ZR30-treated xenografts compared with that of PBS-treated ones. Matrigel plug assays showed the effect of ZR30 on suppressing angiogenesis. We further studied the effect of ZR30 on genes involved in endothelial transdifferentiation (ETD), in 7 primary cultures derived from 3 GBMs under different culture conditions. Two GBM cultures formed mesh structures with upregulation of ETD genes shortly after culture in Matrigel Matrix, and ZR30 suppressed both. ZR30 also downregulated ETD genes in two GBM cultures with high expression of these genes. In conclusion, multifaceted tumor suppression effects of human fibulin-3 variant include both suppression of angiogenesis and vasculogenic mimicry in GBM.
Asunto(s)
Neoplasias Encefálicas/genética , Proteínas de la Matriz Extracelular/genética , Glioblastoma/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Regulación hacia Abajo/genética , Descubrimiento de Drogas/métodos , Células Endoteliales/metabolismo , Receptores ErbB/genética , Femenino , Expresión Génica/genética , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neovascularización Patológica/genética , Transducción de Señal/genética , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
BACKGROUND: The occurrence of medulloblastoma in the absence of hereditary syndromes is rare. Dextrocardia with situs inversus is also called mirror-image dextrocardia. A combination of mirror-image dextrocardia with medulloblastoma has not been reported previously. To the best of our knowledge, this is the first report of this rare combination in a family with medulloblastoma. METHODS: The clinical manifestation, radiographic characteristics, treatment, and outcomes of 3 medulloblastoma cases in 2 cousins and their maternal uncle was described. Tumor samples of the 2 cousins were first examined for histologic subtypes. Total RNA of their tumors was extracted from formalin-fixed and paraffin-embedded samples. Then, expression of 22 subgroup-specific genes and 3 housekeeping genes was analyzed by the NanoString nCounter Analysis System. The posttest data were normalized by NanoStringNorm package for molecular subgroup prediction. RESULTS: The proband remains tumor free and alive up to the latest follow-up. His cousin, who had combined mirror-image dextrocardia with situs inversus, died of anoxia after surgery and his uncle died of tumor 2.5 years after surgery. Medulloblastoma of the 2 cousins was classified as classic and molecular group 4 subtype. CONCLUSIONS: The same classic and molecular group 4 subtype of the 2 cousins may suggest a similar genetic predisposition. Involvement of the Otx2 gene dysfunction in both group 4 subtype medulloblastoma and mirror-image dextrocardia with situs inversus points to a possible mechanism that dysfunction of a shared signaling pathway such as Otx2 might be the underlying cause of these 2 conditions in this family.
