Abstract
Diffuse intrinsic pontine glioma (DIPG) is a devastating brain tumor, with a median survival of less than one year. Due to enormous difficulties in the acquisition of DIPG specimens and the sophisticated technique required to perform brainstem orthotopic injection, only a handful of DIPG pre-clinical models are available. In this study, we successfully established eight patient-derived DIPG cell lines, mostly derived from treatment-naïve surgery or biopsy specimens. These patient-derived cell lines can be stably passaged in serum-free neural stem cell media and displayed distinct morphologies, growth rates and chromosome abnormalities. In addition, these cells retained genomic hallmarks identical to original human DIPG tumors. Notably, expression of several neural stem cell lineage markers was observed in DIPG cell lines. Moreover, three out of eight cell lines can form orthotopic tumors in mouse brainstem by stereotactic injection and these tumors faithfully represented the characteristics of human DIPG by magnetic resonance imaging (MRI) and histopathological staining. Taken together, we established DIPG pre-clinical models resembling human DIPG and they provided a valuable resource for future biological and therapeutic studies.
Highlights
Diffuse intrinsic pontine glioma (DIPG) affects approximately 200-300 children in the U.S each year
Tumor tissues were obtained from eight DIPG patients
An optimal DIPG pre-clinical model should incorporate the following features: (1) a patient-derived www.impactjournals.com/oncotarget origin retaining the characteristic of human DIPG; (2) a specific brainstem microenvironment created by precise orthotopic injection; (3) a cohort of resource which can be explicitly stratified in order to test novel therapeutic strategies; and (4) a stability and reproducibility which enables the model to be repeated according to a standard protocol
Summary
Diffuse intrinsic pontine glioma (DIPG) affects approximately 200-300 children in the U.S each year. The majority of patients are diagnosed between five and ten years old, with a median survival of less than one year [1]. The standard care for newly diagnosed DIPG patients is fractionated focal intensity modulated radiation therapy (IMRT) which only provides temporary relief of neurological symptoms and has little improvement on overall survival. Hyper-fractionated RT and hypofractionated RT have been used by several groups, but neither provides survival advantage. Numerous other treatment methods have failed to show survival improvement, including chemotherapy [2], www.impactjournals.com/oncotarget concurrent chemoradiotherapy using temozolomide [3, 4], and several targeted therapies employed in clinical trials [5, 6]. The scarcity of DIPG pre-clinical models is perhaps the main reason for this lack of therapeutic progress
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