Monitoring of Tumor Growth and Post‐Irradiation Recurrence in a Diffuse Intrinsic Pontine Glioma Mouse Model

Abstract

Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy because of its diffuse infiltrative growth pattern. Translational research suffers from the lack of a representative DIPG animal model. Hence, human E98 glioma cells were stereotactically injected into the pons of nude mice. The E98 DIPG tumors presented a strikingly similar histhopathology to autopsy material of a DIPG patient, including diffuse and perivascular growth, brainstem- and supratentorial invasiveness and leptomeningeal growth. Magnetic resonance imaging (MRI) was effectively employed to image the E98 DIPG tumor. [(18) F] 3'-deoxy-3'-[(18) F]fluorothymidine (FLT) positron emission tomography (PET) imaging was applied to assess the subcutaneous (s.c.) E98 tumor proliferation status but no orthotopic DIPG activity could be visualized. Next, E98 cells were cultured in vitro and engineered to express firefly luciferase and mCherry (E98-Fluc-mCherry). These cultured E98-Fluc-mCherry cells developed focal pontine glioma when injected into the pons directly. However, the diffuse E98 DIPG infiltrative phenotype was restored when cells were injected into the pons immediately after an intermediate s.c. passage. The diffuse E98-Fluc-mCherry model was subsequently used to test escalating doses of irradiation, applying the bioluminescent Fluc signal to monitor tumor recurrence over time. Altogether, we here describe an accurate DIPG mouse model that can be of clinical relevance for testing experimental therapeutics in vivo.

Crizotinib Inhibits Metabolic Inactivation of Gemcitabine in c-Met–driven Pancreatic Carcinoma

“…Within 10 passages, the resulting primary cultures were transduced with two lentiviral vectors encoding firefly-luciferase-mCherry (Fluc-mCherry, FM) and Gaussia-luciferase-CFP (Gluc-CFP, GC), as described previously (17,18). Transduction efficiency was evaluated using Leica-MM-AF-NX fluorescence microscope (Leica) and by fluorescence-activated cell sorting (FACS) analysis (Becton Dickinson).…”

Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models

“…In this study, we analyzed VEGF(R) expression in adult and childhood HGG, including DIPG tumors. Furthermore, we studied bevacizumab distribution in vivo using molecular PET imaging with 89 Zirconium-labeled bevacizumab in murine DIPG models (19).…”

A new era for children with diffuse intrinsic pontine glioma: hope for cure?

“…These MRI findings suggest an intact blood-brain barrier (BBB) in DIPG. In the autopsy study the authors have been performing in The Netherlands, the BBB component glutamate was present in all postmortem samples studied so far, which also supports an intact BBB in DIPG [21]. In addition, like in most cancers, drug penetration may be further hindered by drug efflux pumps such as ATP-binding cassette (ABC) B1, ABCC1 and ABCG2, but studies in DIPG are lacking.…”

“…With the lack of DIPG cell lines, in vivo models have been developed using adult glioma cell lines, but these lack the DIPG genotype. Moreover, only few animal models show the diffuse growth typical for DIPG [21]. From the few existing DIPG cell cultures, only two groups have reported the development of xenografts thus far [17,22].…”