Analysis of tissue chimerism in nude mouse brain and abdominal xenograft models of human glioblastoma multiforme: What does it tell us about the models and about glioblastoma biology and therapy?

In situ hybridization coupled to immunohistochemistry for antigens of inter est allows unequivocal identification of tumor cells from reactive stroma c ells and normal adjacent structures in human glioblastoma multiforme grafts transplanted into nude mice. With this methodology, we have explored the d evelopment of glioblastoma multiforme solid grafts transplanted into nude m ouse brains or flanks. The brain transplants closely resembled the human si tuation, particularly in relation to differentiation and growth patterns. T he morphological features of peritumoral reactive gliosis were similar to t hose observed in humans. A mouse glial stroma within the main tumor masses was also demonstrated. Kinetic studies showed that the compartment of isola ted tumor cells that infiltrated host brains and the reactive gliosis const ituted two cycling cell populations. Despite VEGF protein expression by tum or cells and some reactive astrocytes, the abnormally permeable microvascul ar beds were not hyperplastic. The observation of a non-infiltrative patter n of growth when grafts were established in host flanks demonstrated that t he organ-specific environment plays a determining role in the growth and in vasive properties of glioblastoma. The phylogenetic distance between man an d mouse and the recipient immunoincompetence should not impose serious limi tations on the use of this model for studying malignant glioma biology and therapy in vivo.