A reproducible brain tumour model established from human glioblastoma biopsies

Abstract

BackgroundEstablishing clinically relevant animal models of glioblastoma multiforme (GBM) remains a challenge, and many commonly used cell line-based models do not recapitulate the invasive growth patterns of patient GBMs. Previously, we have reported the formation of highly invasive tumour xenografts in nude rats from human GBMs. However, implementing tumour models based on primary tissue requires that these models can be sufficiently standardised with consistently high take rates.MethodsIn this work, we collected data on growth kinetics from a material of 29 biopsies xenografted in nude rats, and characterised this model with an emphasis on neuropathological and radiological features.ResultsThe tumour take rate for xenografted GBM biopsies were 96% and remained close to 100% at subsequent passages in vivo, whereas only one of four lower grade tumours engrafted. Average time from transplantation to the onset of symptoms was 125 days ± 11.5 SEM. Histologically, the primary xenografts recapitulated the invasive features of the parent tumours while endothelial cell proliferations and necrosis were mostly absent. After 4-5 in vivo passages, the tumours became more vascular with necrotic areas, but also appeared more circumscribed. MRI typically revealed changes related to tumour growth, several months prior to the onset of symptoms.ConclusionsIn vivo passaging of patient GBM biopsies produced tumours representative of the patient tumours, with high take rates and a reproducible disease course. The model provides combinations of angiogenic and invasive phenotypes and represents a good alternative to in vitro propagated cell lines for dissecting mechanisms of brain tumour progression.

Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma

“…We have developed a clinically highly relevant human GBM model in rats that fully reflects the growth pattern of human tumors in situ, including extensive infiltration into the brain parenchyma (major pattern of invasion along fiber tracts and blood vessels), prominent angiogenesis, and necrosis (13)(14)(15). Comparative genomic hybridization studies have confirmed the genetic similarity between xenografted tumors and the corresponding human tumors (Fig.…”

“…Patient GBM-derived spheroids (from patient P3) were expanded through serial transplantation in nude rats, thus generating a standardized pool of spheroids (300-400 μm) and giving rise to phenotypically identical (highly invasive and highly angiogenic) GBMs in all xenografts (14). The same genetic aberrations were present in the primary biopsy and in resulting xenografts as determined by array comparative genomic hybridization (Fig.…”

“…Ten GBM spheroids were stereotactically implanted into the brain (posterior to the bregma and 3 mm to the right of the midline suture at a depth of 2.5 mm) of 30 athymic nude rats (rnu−/rnu−) as described (14). Surgical procedures were in accordance with the Norwegian Animal Act and the local ethical committee.…”

MR Imaging Features of High-Grade Gliomas in Murine Models: How They Compare with Human Disease, Reflect Tumor Biology, and Play a Role in Preclinical Trials

“…4,5 Engraftment of primary glioblastoma biopsies has shown high take rates but a long average latency. 6 The use of primary tissue prevents the genetic drift and phenotypic changes secondary to prolonged passages in vitro, reproduces the phenotypic traits of the native tumor, and displays more cellular heterogeneity than established cell lines. 6 The use of spheroids (3D cultures), as opposed to cell suspensions (2D cultures), avoids the disruption of the stromal compartment preserving the original tumor environment.…”

“…6 The use of primary tissue prevents the genetic drift and phenotypic changes secondary to prolonged passages in vitro, reproduces the phenotypic traits of the native tumor, and displays more cellular heterogeneity than established cell lines. 6 The use of spheroids (3D cultures), as opposed to cell suspensions (2D cultures), avoids the disruption of the stromal compartment preserving the original tumor environment. 6 Many HGG cell lines of human and murine origin are currently available and accurately reproduce the histologic and cytologic features of human neoplasms.…”