Among the billions of neurons and glia in the vertebrate central nervous system (CNS) is a rich milieu of extracellular matrix (ECM) proteins. Most CNS cells interact with ECM components via members of the integrin family of cell surface adhesion receptors. Precise regulation of integrin-ECM communication is necessary for normal CNS development and homeostasis, and abnormal regulation of these events can contribute to the pathogenesis of various CNS diseases, including cancer. In this project we will determine how av?8 integrin contributes to the pathogenesis of the deadly brain cancer, glioblastoma multiforme (GBM). GBMs and other high-grade gliomas develop severe blood vessel pathologies, including abnormal angiogenesis and associated edema and hemorrhage. Our working hypothesis is that reduced av?8 integrin expression and function in tumor-initiating cells contributes to vascular pathologies in high-grade gliomas. The rationale for pursuing these studies is based on the following experimental data: (i) av?8 integrin is expressed in neural stem cells and astroglia, which are presumptive cells of origin for glioma;(ii) genetic ablation of the murine av or ?8 integrin genes in mouse neural stem cells and astroglia results in brain-specific vascular phenotypes that are similar to pathologies observed in high-grade gliomas;(iii) transformed astroglia that lack av?8 integrin generate intracranial tumors with vascular abnormalities similar to those found in high-grade gliomas;and (iv) tumor stem cells primarily contribute to vascular pathologies in gliomas, and av?8 integrin expression defines sub-populations of human glioma stem cells, with nearly 50% of GBM stem cells lacking av?8 integrin expression. In this project we propose experiments to study functions for av?8 integrin in brain tumor-initiating cells during gliomagenesis. To accomplish these goals we will use a unique set of molecular genetic tools, consisting of av and ?8 integrin mutant mice, as well as cells purified from mutant animals. Additionally, we will study the expression and function of av?8 integrin in resected human glioma tissues and human glioma stem cells. We propose the following Specific Aims: (1) We will determine the functional roles for av?8 integrin in tumor-induced angiogenesis using orthotopic and genetically engineered mouse models of glioma, and (2) We will determine the functional roles for av?8 integrin in vascular pathologies that typify human malignant gliomas. Collectively, these experiments will elucidate the functional role for av?8 integrin during gliomagenesis, particularly related to tumor-induced vascular pathologies. This work may eventually lead to new therapeutic strategies for treating or preventing the progression of high-grade gliomas in humans.
Gliomas afflict approximately 20,000 people within the United States each year. They represent the most common type of primary brain tumors, and, in their advanced stages, they are one of the deadliest forms of cancer. Understanding the basic cellular and molecular events that contribute to glioma growth, angiogenesis, and invasiveness may lead to new therapeutic strategies to treat or prevent the pathogenesis of this insidious disease. In this project we will study how cell adhesion molecules, known as integrins, regulate the onset and progression of gliomas in mice and humans. These results may identify new therapeutic targets to treat or prevent the development of gliomas in humans.
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|McCarty, Joseph H (2013) Glioblastoma resistance to anti-VEGF therapy: has the challenge been MET? Clin Cancer Res 19:1631-3|
|Mobley, Aaron K; McCarty, Joseph H (2012) Use of Cre-lox technology to analyze integrin functions in astrocytes. Methods Mol Biol 814:555-70|
|Hirota, Shinya; Liu, Qian; Lee, Hye Shin et al. (2011) The astrocyte-expressed integrin ýývýý8 governs blood vessel sprouting in the developing retina. Development 138:5157-66|
|Mobley, Aaron K; McCarty, Joseph H (2011) ýý8 integrin is essential for neuroblast migration in the rostral migratory stream. Glia 59:1579-87|
|Tchaicha, Jeremy H; Reyes, Steve B; Shin, Jaekyung et al. (2011) Glioblastoma angiogenesis and tumor cell invasiveness are differentially regulated by ýý8 integrin. Cancer Res 71:6371-81|
|Nguyen, Ha-Long; Lee, Young Jae; Shin, Jaekyung et al. (2011) TGF-ýý signaling in endothelial cells, but not neuroepithelial cells, is essential for cerebral vascular development. Lab Invest 91:1554-63|
|Tchaicha, J H; Mobley, A K; Hossain, M G et al. (2010) A mosaic mouse model of astrocytoma identifies alphavbeta8 integrin as a negative regulator of tumor angiogenesis. Oncogene 29:4460-72|
|McCarty, Joseph H (2009) Cell adhesion and signaling networks in brain neurovascular units. Curr Opin Hematol 16:209-14|
|Mobley, Aaron K; Tchaicha, Jeremy H; Shin, Jaekyung et al. (2009) Beta8 integrin regulates neurogenesis and neurovascular homeostasis in the adult brain. J Cell Sci 122:1842-51|
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