RESUMO
Oncolytic herpes simplex viruses (HSVs) represent a novel frontier against tumors resistant to standard therapies, like glioblastoma (GBM). The oncolytic HSVs that entered clinical trials so far showed encouraging results; however, they are marred by the fact that they are highly attenuated. We engineered HSVs that maintain unimpaired lytic efficacy and specifically target cells that express tumor-specific receptors, thus limiting the cytotoxicity only to cancer cells, and leaving unharmed the neighboring tissues. We report on the safety and efficacy in a high-grade glioma (HGG) model of R-LM113, an HSV recombinant retargeted to human epidermal growth factor receptor 2 (HER2), frequently expressed in GBMs. We demonstrated that R-LM113 is safe in vivo as it does not cause encephalitis when intracranially injected in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, extremely sensitive to wild-type HSV. The efficacy of R-LM113 was assessed in a platelet-derived growth factor (PDGF)-induced infiltrative glioma model engineered to express HER2 and transplanted intracranially in adult NOD/SCID mice. Mice injected with HER2-engineered glioma cells infected with R-LM113 showed a doubled survival time compared with mice injected with uninfected cells. A doubling in survival time from the beginning of treatment was obtained also when R-LM113 was administered into already established tumors. These data demonstrate the efficacy of R-LM113 in thwarting tumor growth.
Assuntos
Neoplasias Encefálicas/terapia , Vetores Genéticos , Glioma/terapia , Terapia Viral Oncolítica/métodos , Receptor ErbB-2/genética , Simplexvirus/genética , Adulto , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Encefalite/prevenção & controle , Engenharia Genética , Glioma/genética , Glioma/mortalidade , Humanos , Injeções Intraventriculares , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Gradação de Tumores , Transplante de Neoplasias , Fator de Crescimento Derivado de Plaquetas/genética , Taxa de Sobrevida , Replicação ViralRESUMO
Tumor progression is a key aspect in oncology. Not even the overexpression of a powerful oncogenic stimulus such as platelet derived growth factor-B (PDGF-B) is sufficient per se to confer full malignancy to cells. In previous studies we showed that neural progenitors overexpressing PDGF-B need to undergo progression to acquire the capability to give rise to secondary tumor following transplant. By comparing the expression profile of PDGF-expressing cells before and after progression, we found that progressed tumors consistently downregulate the expression of the antiproliferative gene Btg2. We therefore tested whether the downregulation of Btg2 is sufficient and necessary for glioma progression with loss and gain of function experiments. Our results show that downregulation of Btg2 is not sufficient but is necessary for tumor progression since the re-introduction of Btg2 in fully progressed tumors dramatically impairs their gliomagenic potential. These results suggest an important role of Btg2 in glioma progression. Accordingly with this view, the analysis of public datasets of human gliomas showed that reduced level of Btg2 expression correlates with a significantly worse prognosis.
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteínas Imediatamente Precoces/genética , Oligodendroglioma/genética , Oligodendroglioma/patologia , Proteínas Proto-Oncogênicas c-sis/genética , Proteínas Supressoras de Tumor/genética , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Linhagem Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Imediatamente Precoces/metabolismo , Camundongos , Gradação de Tumores , Oligodendroglioma/metabolismo , Oligodendroglioma/mortalidade , Ligação Proteica , Proteínas Proto-Oncogênicas c-sis/metabolismo , Interferência de RNA , Transdução Genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismoRESUMO
The mutual reshape of tumor and immune system cells during tumor progression is a widely accepted notion in different cancers including gliomas. The importance of this phenomenon in shaping glioma progression and the mechanisms governing it, however, are not fully elucidated. Taking advantage of a well-characterized in vivo glioma model we performed an analysis of glioma cells transcriptomes at different stages of progression and unveiled the reorganization of glioma-immune system interactions. Specifically, we show that the inability of low-grade glioma cells to orthotopically graft in syngeneic immunocompetent mice, positively correlates with the abundance of infiltrating lymphocytes in donor tumors and with a highly immunostimulatory transcriptional profile. Notably, during tumor progression glioma cells downregulate these genes and the immune infiltrate shifts towards a pro-tumorigenic phenotype. Challenging low-grade gliomas by grafting into immunodeficient hosts revealed the crucial role of the adaptive immune system in constraining glioma progression. Finally, we observed that although progression still takes place in immunodeficient mice, it is slower, likely due to a milder selection thus reinforcing the view of a pivotal role for the immune system in regulating glioma progression.
Assuntos
Imunidade Adaptativa , Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Linfócitos do Interstício Tumoral/imunologia , Evasão Tumoral , Imunidade Adaptativa/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Proliferação de Células , Sobrevivência Celular , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Glioblastoma/patologia , Imunocompetência , Hospedeiro Imunocomprometido , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Gradação de Tumores , Transplante de Neoplasias , Fatores de Tempo , Transcriptoma , Evasão Tumoral/genéticaRESUMO
The stem cell-determining transcription factor Sox2 is required for the maintenance of normal neural stem cells. In this study, we investigated the requirement for Sox2 in neural cancer stem-like cells using a conditional genetic deletion mutant in a mouse model of platelet-derived growth factor-induced malignant oligodendroglioma. Transplanting wild-type oligodendroglioma cells into the brain generated lethal tumors, but mice transplanted with Sox2-deleted cells remained free of tumors. Loss of the tumor-initiating ability of Sox2-deleted cells was reversed by lentiviral-mediated expression of Sox2. In cell culture, Sox2-deleted tumor cells were highly sensitive to differentiation stimuli, displaying impaired proliferation, increased cell death, and aberrant differentiation. Gene expression analysis revealed an early transcriptional response to Sox2 loss. The observed requirement of oligodendroglioma stem cells for Sox2 suggested its relevance as a target for therapy. In support of this possibility, an immunotherapeutic approach based on immunization of mice with SOX2 peptides delayed tumor development and prolonged survival. Taken together, our results showed that Sox2 is essential for tumor initiation by mouse oligodendroglioma cells, and they illustrated a Sox2-directed strategy of immunotherapy to eradicate tumor-initiating cells.