Brain tumors, the most common type being gliomas, are among the most lethal type of cancer with current treatments consisting of a combination of surgery, radiation, and drugs offering only palliation. Hence, finding more effective treatments remains an immediate priority. New treatments for brain tumors may stem from the result from the recent identification of a subpopulation of glioma cells with a higher capacity to form tumors, called glioma tumor initiating cells (GTICs). Tumor initiating cells generally constitute less than five percent of the total tumor population, however as little as a couple hundred can cause tumors to grow in mice whereas millions of the non-tumor initiating cells do not form tumors within the same timeframe. Experimental data suggest that tumor initiating cells may be responsible for maintaining tumor growth and causing tumors to come back after therapy. We believe that targeting tumor initiating cells in brain tumors will improve patient treatment. Therefore, we are trying to understand how to better isolate tumor initiating cells from human patients and design therapies to target these cells. One such way of achieving this goal is to identify which signals are localized to the tumor initiating cell regions in gliomas. These signals can then be used for tumor initiating cell enrichment and targeting. We have identified a family of extracellular matrix receptors, integrins, as a possible target. In this application, we aim to: evaluate the utility of integrins as selection markers of GTICs and determine the therapeutic potential of targeting integrins expressed on GTICs. To achieve these aims, we will utilize human glioma surgical biopsy specimens and evaluate the ability of integrins to enrich for GTICs in comparison to currently accepted methods using flow cytometry and GTIC marker assessment at the RNA and protein levels. The tumor initiation ability of integrin enriched cell fractions will be assessed using in vivo transplantation assays. For integrin targeting purposes, we will utilize lentiviral shRNA and/or chimeric aptamers alone or in combination with other therapeutic modalities to target GTICs enriched directly from human glioma surgical biopsy specimens and will assess tumor initiation capacity with in vivo transplantation assays. These experimental approaches will allow us to evaluate the potential of integrins as a selection marker and target of GTICs in the cell population of interest and design therapies which will have direct relevance to gliomas. The long term contribution of this project will be to design more effective brain tumor therapies based on the targeting of tumor initiating cells. In addition, any findings or therapeutic developments may extend to other tumor initiating cell populations such as those described in other cancers (i.e. colon, breast, leukemia).
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| Hamerlik, Petra; Lathia, Justin D; Rasmussen, Rikke et al. (2012) Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. J Exp Med 209:507-20 |
| Lathia, Justin D; Li, Meizhang; Hall, Peter E et al. (2012) Laminin alpha 2 enables glioblastoma stem cell growth. Ann Neurol 72:766-78 |
| Lathia, J D; Hitomi, M; Gallagher, J et al. (2011) Distribution of CD133 reveals glioma stem cells self-renew through symmetric and asymmetric cell divisions. Cell Death Dis 2:e200 |
| Lathia, Justin D; Venere, Monica; Rao, Mahendra S et al. (2011) Seeing is believing: are cancer stem cells the Loch Ness monster of tumor biology? Stem Cell Rev 7:227-37 |
| Hjelmeland, A B; Wu, Q; Heddleston, J M et al. (2011) Acidic stress promotes a glioma stem cell phenotype. Cell Death Differ 18:829-40 |
| Hjelmeland, Anita B; Lathia, Justin D; Sathornsumetee, Sith et al. (2011) Twisted tango: brain tumor neurovascular interactions. Nat Neurosci 14:1375-81 |
| Lathia, Justin D; Gallagher, Joseph; Myers, Jay T et al. (2011) Direct in vivo evidence for tumor propagation by glioblastoma cancer stem cells. PLoS One 6:e24807 |
| Eyler, Christine E; Wu, Qiulian; Yan, Kenneth et al. (2011) Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2. Cell 146:53-66 |
| Lathia, Justin D; Gallagher, Joseph; Heddleston, John M et al. (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6:421-32 |
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