Cancer development and progression involve activation of multiple oncogenes and inactivation of multiple tumor suppressor genes. Many oncogenes enhance cell proliferation, inhibit apoptosis, and promote angiogenesis and invasion (the hallmarks of cancer). In contrast, tumor suppressor genes inhibit proliferation, enhance apoptosis, and inhibit cell migration and invasion. It is becoming increasingly clear that activated oncogenes do not act singly in isolation to manifest the hallmarks of cancer progression;rather, oncogene and tumor suppressor gene interaction, i.e., oncogene cooperation, comprises a critical oncogenic mechanism. Cancer development and progression also involve close interaction between tumor cells and constituents of their environment, such as the interaction with endothelial cells in the promotion of angiogenesis. These important and complex processes are difficult to elucidate through study of simple cell culture systems alone. Mouse models have thus become an instrumental tool for characterizing oncogenes and tumor suppressor genes, their interactions and cooperation, and the interactions between tumor cells and their environmental milieu. Gliomas represent the single most frequent type of primary brain malignancy. The most advanced form of glioma, and also the most invasive and refractory to therapy, is glioblastoma (GBM), which comprises 50-60% of all gliomas. The median survival for GBM patients is less than a year. Only about 20% of patients respond to therapy and live for more than 1.5 years following initial diagnosis. Primary GBMs are believed to develop de novo. Secondary GBMs are believed to arise through anaplastic progression from lower grade astrocytomas (anaplastic astrocytoma, AA;and low-grade astrocytoma, A). Intensive research over the last three decades, especially recent genomics research (The Cancer Genome Atlas on glioblastoma), has revealed a large number of putative oncogenes that are amplified and overexpressed in glioma, as well as putative glioma tumor suppressor genes that are deleted, diminished, or mutated. However, the very productive high- throughput genomic discovery process has not been matched by corresponding validation studies aimed at the functional characterization of the newly discovered putative cancer genes and their cooperative interactions. We have employed a powerful glial-specific mouse model (the RCAS/tv-a system) to characterize oncogenic events in gliomagenesis. RCAS/tv-a is a somatic gene transfer model that permits transgenic expression of multiple genes in a single experimental setting, thus allowing evaluation of oncogene cooperation. Whereas multiple genetic and molecular events are usually required for oncogenesis in humans, in mice 2 or 3 strong cooperative events are often sufficient to induce tumorigenesis;thus, animal models have been useful for identifying specific cooperative interactions critical for tumor formation and for specific tumor phenotype generation. Using genomics and informatics approaches, we have profiled gene expression in different grades of glioma and identified genes in different cellular pathways that are overexpressed in different glioma grades. We hypothesize that the signature genes in cell proliferation, cell invasion, and angiogenesis are part of key oncogene cooperation systems that are crucial for glioma progression. The novelty of the proposed studies is to test this hypothesis, and to identify key interactive and cooperative gliomagenesis genes using the RCAS/tv-a mouse model. Knowledge gained from this study will impact development of pathway-oriented therapeutics, especially for GBM, in which effective therapy is most needed.

Public Health Relevance

In order to find effective targets for glioma treatment, we have to understand the cooperative oncogenes that are underlying glioma genesis and progression. This is the key mechanism for cancer phenotypes however quite understudied in the field. The major bottleneck is lack of robust in vivo models. Our previous studies have proven that the RCAS-tva model system would allow us to systematically interrogate oncogene cooperation in a relatively low throughput fashion. Thus, this study is novel and will shift paradigm and important therapeutic strategy for glioma, especially GBM. We will characterize the pathways of gliomas generated and begin our effort to target the identified pathway for therapeutics using siRNA/shRNA, pharmacological, and allograft model strategies. Thus, this proposed study will not only study mechanism of glioma genesis and progression but will also translate the pathway understanding to pre-clinical application.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Progression and Metastasis Study Section (TPM)
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Jhappan, Chamelli
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University of Texas MD Anderson Cancer Center
Other Domestic Higher Education
United States
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