Glioma oncogenesis and animal models of glioma formation.

Recent advances in animal models have improved our understanding of the pathway abnormalities driving glioma growth. This article reviews key molecular abnormalities that have been modeled in mice, and describes major tumor modeling techniques along with examples of astrocytoma and oligodendroglioma models. Animal models are important not only for the testing of novel therapeutics but also as a means to understand the molecular explanations for treatment success and failure in humans.

The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats.

Chronic platelet-derived growth factor (PDGF) signaling in glial progenitors leads to the formation of oligodendrogliomas in mice, whereas chronic combined Ras and Akt signaling leads to astrocytomas. Different histologies of these tumors imply that the pathways activated by these two oncogenic stimulations are different, and that the apparent lineage of the tumor cells may result from specific signaling activity. Therefore, we have investigated the signaling effects of PDGF in culture and in gliomas in vivo. In culture, PDGF transiently activates ERK1/2 and Akt, and subsequently elevates p21 and PCNA expression similar to chronic PDGF autocrine signaling in cultured astrocytes and PDGF-induced oligodendrogliomas in vivo. Culture experiments show that autocrine PDGF stimulation, and combined active Ras and Akt generate signaling patterns that are in some ways mutually exclusive. Furthermore, forced Akt activity in the context of chronic PDGF stimulation results in cells with an astrocytic differentiation pattern both in culture and in vivo. These data imply that these two interconvertible signaling motifs are distinct in mice and lead to gliomas resembling the two major glioma histologies found in humans. The ability of signaling activity to convert tumor cells from one lineage to another presents a mechanism for the development of tumors apparently comprised of cells from multiple lineages.

Constitutive activation of Raf-1 induces glioma formation in mice.

In human glioblastoma multiforme (GBM), RAS activity is upregulated in the majority of the tumors. Furthermore, the levels of phospho-mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK), a downstream effector of RAS, are also increased. In mice, activated KRas cooperates with the loss of INK4a-ARF locus or with activated Akt to induce gliomas, confirming an important role for this pathway in glioma biology. However, to correctly target therapies against the RAS signaling pathway, it is necessary to identify the effectors that contribute to RAS-mediated gliomagenesis. In this study, we investigated the contribution of RAF signaling in glioma oncogenesis. We find that the levels of RAF-1 and BRAF proteins and RAF kinase activity are increased in human GBM samples. We confirm the importance of this finding by demonstrating a causal role for a constitutively active Raf-1 mutant in glioma formation in mice. Specifically, we find that activated Raf-1 cooperates with Arf loss or Akt activation to generate gliomas similar to activated KRas under the same conditions. Our study suggests that the oncogenic effect of KRas in glioma formation may be transduced at least in part through Raf signaling and that therapeutic targeting of this pathway may be beneficial in glioma treatment.

An update on mouse brain tumor models in cancer drug discovery.

Gliomas and medulloblastomas are the most common primary brain tumors in adults and children, respectively. Although the standard of care for gliomas may have evolved slightly over the last 50 years, the clinical outcome of this disease remains unchanged. Therefore, further research to improve the treatment modalities is urgently needed. An important step forward is the use of genetically and histologically accurate mouse glioma models that mimic the human tumors in their native microenvironment in order to fully understand the biology and mechanistic causes of this disease. Such strategy will help us to identify novel targets for therapies and use these models for preclinical testing.