gms | German Medical Science

Despite considerable advances of research on gliomas these tumors still bear a grim prognosis. Animal models that closely reproduce the biological characteristics of gliomas might lead to a better understanding of glioma pathogenesis and could assist in the development of novel therapeutic modalities. Most available animal models of gliomas reflect the human disease only partially. In particular the hallmark of human astrocytomas, the infiltration of the surrounding brain tissue, is rarely seen in animal models.

The aim of the present study was to generate conditionally proliferating murine astrocytic tumor cells in order to establish an animal model that reproduces the relatively slow proliferation rate of human glioma cells and to investigate whether slow proliferation correlates with infiltrative behaviour.

Primary murine p53^-/- astrocytes were transduced with two oncogenes 1. constitutively active myr-Akt and 2. c-myc under control of a Tet-Off-System. The characteristics of the resulting cells were investigated in vitro and in vivo in the brain of C57BL/6 mice.

Transduced astrocytes developed a tumor cell phenotype as reported previously and in addition revealed conditional proliferation depending on c-myc expression for prolonged periods of time. Moreover, proliferation could be repeatedly switched ON and OFF in vitro. Transduced astrocytes were stereotactically implanted into the brain of congenic mice and the size of the resulting tumors could be regulated by feeding the mice tetracycline. The macroscopic and histological appearance of the tumors depended both on the number of passages in vitro and the duration of the growth in vivo. Early passage cells with slower proliferation in vitro induced only microscopically visible tumors in the brain, while cells from later passages lead to macroscopically visible tumors in the same period. Histologically, the murine tumors from early passages in vitro revealed highly polymorphic cells similar to human glioblastoma. Occasionally, infiltration of the surrounding brain was observed.

Together, we present a novel mouse model of astrocytic tumorigenesis with controllable proliferation that might be useful in the further study of gliomagenesis and glioma therapy.