Expression Profile of Genes Involved in Angiopoietin 2-induced Astrocytoma Invasion
Principal Investigator: Shiyuan Cheng, University of Pittsburgh
Funding agency: National Institute of Health
Malignant astrocytomas have the ability to diffusely invade into surrounding brain tissues making them incurable by surgical removal, even when combined with adjuvant radiation, chemotherapy and/or immunotherapy. We have previously reported that the overexpression of angiopoietin-2 (Ang2) leads to the acquisition of invasiveness in engineered U87MG intracranial astrocytomas in mice through the activation of MMP-2. However, U87MG as well as other established astrocytoma cell lines contain genetic mutations/alterations in pathways such as p53 and PTEN rendering the precise determination of the molecular mechanisms of invasion difficult. Therefore, we have utilized a minimally genetically altered human astrocyte cell line that stably expresses Ang2 and forms invasive tumors resembling human WHO grade III anaplastic astrocytomas in the murine brain. To begin to explore the mechanisms of Ang2-induced astrocytoma invasion, we employed Affymetrix GeneChip® HG-U133A to identify genes differentially expressed in both U87MG and the constructed astrocytic model systems (parental versus Ang2-expressing clones). Shared alterations and unique differences in genes and pathways involved in the induction of tumor invasion were identified in the two model systems. Ang2 promotes glioma cell invasion in the brain of animals demonstrated by two genetically distinct orthotopic models. Genome-wide analysis reveals that multiple gene pathways are involved in Ang2-stimulated glioma cell invasion. The invasion is mediated by overlapping but distinct genetic pathways in the genetically different cell lines. Such understanding of the genetic fingerprint involved in astrocytoma invasion may lead to the development of novel therapies for the treatment of these deadly brain tumors.