Detailed characterization of the mouse glioma 261 tumor model for experimental glioblastoma therapy

Abstract

Mouse glioma 261 (Gl261) cells are used frequently in experimental glioblastoma therapy; however, no detailed description of the Gl261 tumor model is available. Here we present that Gl261 cells carry point mutations in the K-ras and p53 genes. Basal major histocompatibility complex (MHC)I, but not MHCII, expression was detected in Gl261 cells. The introduction of interferon-γ γ γ γ-encoding genes increased expression of both MHCI and MHCII. A low amount of B7-1 and B7-2 RNA was detected in wild-type cells, but cytokine production did not change expression levels. Gl261 cells were transduced efficiently by adenoviral vectors; the infectivity of retroviral vectors was limited. Low numbers of transplanted Gl261 cells formed both subcutaneous and intracranial tumors in C57BL /6 mice. The cells were moderately immunogenic : prevaccination of mice with irradiated tumor cells 7 days before intracranial tumor challenge prevented tumor formation in approximately 90% of mice. When vaccination was carried out on the day or 3 days after tumor challenge, no surviving animals could be found. In vitro-growing cells were radiosensitive: less than 2 Gy was required to achieve 50% cell mortality. Local tumor irradiation with 4 Gy X-rays in brain tumor-bearing mice slowed down tumor progression, but none of the mice were cured off the tumor. In conclusion, the Gl261 brain tumor model might be efficiently used to study the antitumor effects of various therapeutic modalities, but the moderate immunogenicity of the cells should be considered. (Cancer Sci 2006; 97: 546-553) M alignant brain tumors have a poor outcome, with a median survival of 9 months and only 5-10% of patients surviving 2 years. The conventional therapies for glioblastoma multiforme are surgical removal of the bulk tumor mass, followed by radiotherapy. As complete surgical removal is almost impossible, radiotherapy continues to play a major role in the treatment of malignant gliomas, but these tumors are often radioresistant. The combination of chemotherapy with other modalities provides only modest improvements in survival rates. (1-3) The application of suitable animal models in glioma research is necessary for the development of new therapeutic approaches. An ideal animal model of human glioma should reproduce the major characteristics of this neoplasm: predictable and reproducible in vitro and in vivo growth patterns; infiltrative, but non-metastatic, tumor growth; and poor immunogenicity. A number of animal brain tumor models are being used; however, no model currently available simulates human high-grade gliomas exactly. Tumor models vary in their immunogenicity, growth patterns and invasiveness. For this reason it is important to choose an appropriate animal model depending on the endpoint examined. Most models are derived from rat and several xenograft models, based on the intracer-ebral transplantation of human brain tumors into immune-deficient nude mice, are also available. Murine models of malignant brain tumors are used much less frequently, mainly beca...

A systematic review and meta‐analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

“…Finally in animal studies gene transfection rates are evidently high enough to be therapeutic, even when vectors are delivered systemically. Indeed, GL261 tumours are transfected very efficiently by adenoviruses 60. This contrasts with human therapy where transfection rates are low; the blood–brain barrier is obstructive in glioma therapeutics, preventing the use of systemic vector delivery,43, 61 even when vectors are delivered distal to the ophthalmic artery (Dr Robin Grant, personal communication), as tumour penetration is poor and side effects high.…”

The therapeutic efficacy of the oncolytic virus Delta24-RGD in a murine glioma model depends primarily on antitumor immunity

“…8 To study this, we employed an established immunocompetent orthotopic glioma mouse model using murine GL261 tumor cells transplanted in syngeneic C57BL/6 mice. 9 In our study, we investigated the ability of Delta24-RGD oncolytic virus to infect, replicate and induce cytotoxicity in GL261 cells, allowing this model to be used to map the role of the immune response to Delta24-RGD therapy. 10 Treatment resulted in approximately 50% long-term survivors, an effect that was completely abolished when mice were co-treated with the immunosuppressive agent dexamethasone.…”

Tumor-secreted SDF-1 promotes glioma invasiveness and TAM tropism toward hypoxia in a murine astrocytoma model

“…However, unlike human GBM cell lines (such as U87MG, U-373MG, and T98G), GL261 tumors are radiosensitive. 8 Another model that could simulate human high-grade glioma with respect to their infiltrative and radioresistant nature would therefore be useful for studying the behavior of malignant brain tumors and designing new therapeutic interventions.…”