Current therapies for glioblastoma are unable reach tumor cells that insinuate themselves within neural structures. However, the obstacles to effective therapy match the known biological properties of the abundant and autologous source of bone marrow derived neural stem cells (BM-NSCs). Understanding the mechanisms by which stem cells home to tumor cells and other areas of injury is important not only to understand basic stem cell biology but also to translate stem cell therapies for brain tumors and neurodegenerative disorders. Our central hypothesis is that the mechanisms that govern bone marrow derived neural stem cell (BM-NSC) tropism toward the glioma vascular niche are identical to those that mediate NSC migration to and from the homeostatic vascular niche. We will test the hypothesis that SDF-1 mediates the migration of BM-NSCs toward the pathological vascular niche of gliomas and that cancer stem cell migration is SDF-1 dependent, rendering these cells """"""""co-travelers"""""""" in the brain. We propose to:
AIM 1 : Test the hypothesis that BM-NSC migration to the tumor vascular niche is dependent on CXCR4 expression, CXCR4 interaction with SDF-1, CXCR4 receptor signaling, and downstream induction of the PI3K/Akt pathway in a transgenic spontaneous glioma model.
AIM 2 : Test the hypothesis that SDF1 will increase a6 integrin expression and EGFR expression on BM-NSCs and that this effect will increase the adhesion of BM-NSCs to the surface of tumor endothelium and increase tropism toward tumor conditioned media, respectively in vitro. In a spontaneous glioma model, we will test the hypothesis that blocking a6 integrin will separate the cells from their tumor vascular niche. We will also test the hypothesis that blocking EGFR will limit the migratory potential of BM-NSCs.
AIM 3 : Test the hypothesis that CSC invasion to the tumor vascular niche is CXCR4 dependent. Test the hypothesis that BM-NSCs and CSCs co-localize within the glioma vascular niche in a spontaneous transgenic murine model of glioma.
This grant proposes to study bone marrow derived neural stem cell (BM-NSC) migration to the tumor vascular niche by studying mechanisms mediated by the SDF-1 signal from the tumor vascular niche as it binds its receptor CXCR4 on BM-NSCs. We will investigate those mechanisms that mediate neural stem cell migration in the vascular niche which we hypothesize will parallel those that draw BM-NSCs to the pathologic tumor vascular niche. By studying the role of each of these mechanisms in BM-NSC migration to the tumor vascular niche, we may better be able to utilize these cells to deliver cytotoxic agents to glial tumor cells.
|Edwards, Lincoln A; Li, Aiguo; Berel, Dror et al. (2017) ZEB1 regulates glioma stemness through LIF repression. Sci Rep 7:69|
|Xu, Qijin; Yuan, Xiangpeng; Yu, John S (2012) Glioma stem cell research for the development of immunotherapy. Adv Exp Med Biol 746:216-25|
|Milanesi, Anna; Lee, Jang-Won; Xu, Qijin et al. (2011) Differentiation of nestin-positive cells derived from bone marrow into pancreatic endocrine and ductal cells in vitro. J Endocrinol 209:193-201|
|Irvin, Dwain K; Jouanneau, Emmanuel; Duvall, Gretchen et al. (2010) T cells enhance stem-like properties and conditional malignancy in gliomas. PLoS One 5:e10974|
|Ji, Jianfei; Black, Keith L; Yu, John S (2010) Glioma stem cell research for the development of immunotherapy. Neurosurg Clin N Am 21:159-66|
|Xu, Qijin; Yuan, Xiangpeng; Xu, Minlin et al. (2009) Chemokine CXC receptor 4--mediated glioma tumor tracking by bone marrow--derived neural progenitor/stem cells. Mol Cancer Ther 8:2746-53|
|Xu, Q; Yuan, X; Tunici, P et al. (2009) Isolation of tumour stem-like cells from benign tumours. Br J Cancer 101:303-11|
|Xu, Qijin; Liu, Gentao; Yuan, Xiangpeng et al. (2009) Antigen-specific T-cell response from dendritic cell vaccination using cancer stem-like cell-associated antigens. Stem Cells 27:1734-40|
|Xu, Qijin; Yuan, Xiangpeng; Liu, Gentao et al. (2008) Hedgehog signaling regulates brain tumor-initiating cell proliferation and portends shorter survival for patients with PTEN-coexpressing glioblastomas. Stem Cells 26:3018-26|
|Ghods, Ali Jourabchi; Irvin, Dwain; Liu, Gentao et al. (2007) Spheres isolated from 9L gliosarcoma rat cell line possess chemoresistant and aggressive cancer stem-like cells. Stem Cells 25:1645-53|
Showing the most recent 10 out of 15 publications