Despite the many therapeutic strategies undertaken for treatment of glioblastoma multiforme, the survival rate for patients afflicted with this aggressive cerebral malignancy remains low. Even with the combined use of several therapeutic modalities, a good prognosis is extremely rare as the remaining cancer cells inevitably infiltrate the normal brain tissue and cause tumor recurrence. We propose to study the interaction of umbilical cord blood stem cells with cancer cells that have a specific prevalence to gliomas. In the present proposal, we will study the molecular mechanisms that control invasion, migration, and angiogenesis in pre-established intracranial tumors of glioblastoma cells using mesenchymal stem cells from the human umbilical cord to chase these tumor cells and regress tumor growth. We hypothesize that: (1) the interaction of stem cells with glioma cells will initiate apoptosis and inhibit tumor growth; and (2) the interaction of stem cells with glioma cells will decrease expression of several signaling molecules and other proteins involved in cell survival, adhesion, migration and proliferation.
The specific aims to address these hypotheses are as follows:
Specific aim 1. Determine the effect of cord blood stem cells on the molecular mechanisms of proliferation, migration, invasion and apoptosis in glioblastoma and xenograft cell lines.
Specific aim 1 a: Determine the effect of cord blood stem cells on adhesion and migration of established glioblastoma cell lines and glioma xenograft cells.
Specific aim 1 b: Evaluate the effect of cord blood stem cells on the molecular mechanisms of proliferation in glioblastoma cell lines and xenograft cell lines.
Specific aim 1 c: Evaluate the effect of cord blood stem cells on the molecular mechanisms of apoptosis in glioma xenograft cells and glioblastoma cell lines.
Specific aim 1 d: Determine the effect of cord blood stem cells on the invasiveness of glioblastoma cell lines and glioma xenograft cells.
Specific aim 2 : Evaluate the in vivo effects of cord blood stem cells on pre-established intracranial tumor growth, and invasiveness and angiogenesis of human glioblastoma cell lines and glioma xenograft cells.
Specific aim 2 a: Determine the effect of the cord blood stem cells on pre-established intracranial tumor growth of human glioblastoma cell lines and glioma xenograft cells injected intracerebrally in nude mice.
Specific aim 2 b: Determine the effect of cord blood stem cells on the molecular mechanisms of cerebral angiogenesis in both in vitro and in vivo models. We anticipate that these results will substantially augment our understanding of how these stem cells chase and attach to these tumor cells; thus, the information gained should be of help in developing new therapeutic approaches to treating glioblastomas. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS057529-03
Application #
7446166
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Fountain, Jane W
Project Start
2006-08-15
Project End
2011-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
3
Fiscal Year
2008
Total Cost
$390,181
Indirect Cost
Name
University of Illinois at Chicago
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Velpula, Kiran Kumar; Dasari, Venkata Ramesh; Rao, Jasti S (2012) The homing of human cord blood stem cells to sites of inflammation: unfolding mysteries of a novel therapeutic paradigm for glioblastoma multiforme. Cell Cycle 11:2303-13
Velpula, Kiran Kumar; Dasari, Venkata Ramesh; Tsung, Andrew J et al. (2012) Transcriptional repression of Mad-Max complex by human umbilical cord blood stem cells downregulates extracellular signal-regulated kinase in glioblastoma. Stem Cells Dev 21:1779-93
Velpula, Kiran Kumar; Dasari, Venkata Ramesh; Tsung, Andrew J et al. (2011) Regulation of glioblastoma progression by cord blood stem cells is mediated by downregulation of cyclin D1. PLoS One 6:e18017
Dasari, Venkata Ramesh; Velpula, Kiran Kumar; Kaur, Kiranpreet et al. (2010) Cord blood stem cell-mediated induction of apoptosis in glioma downregulates X-linked inhibitor of apoptosis protein (XIAP). PLoS One 5:e11813
Dasari, Venkata Ramesh; Kaur, Kiranpreet; Velpula, Kiran Kumar et al. (2010) Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway. PLoS One 5:e10350
Gondi, Christopher S; Gogineni, Venkateswara R; Chetty, Chandramu et al. (2010) Induction of apoptosis in glioma cells requires cell-to-cell contact with human umbilical cord blood stem cells. Int J Oncol 36:1165-73
Gondi, Christopher S; Veeravalli, Krishna Kumar; Gorantla, Bharathi et al. (2010) Human umbilical cord blood stem cells show PDGF-D-dependent glioma cell tropism in vitro and in vivo. Neuro Oncol 12:453-65
Dasari, Venkata Ramesh; Kaur, Kiranpreet; Velpula, Kiran Kumar et al. (2010) Downregulation of Focal Adhesion Kinase (FAK) by cord blood stem cells inhibits angiogenesis in glioblastoma. Aging (Albany NY) 2:791-803
Gondi, Christopher S; Rao, Jasti S (2009) Therapeutic potential of siRNA-mediated targeting of urokinase plasminogen activator, its receptor, and matrix metalloproteinases. Methods Mol Biol 487:267-81
Gogineni, Venkateswara Rao; Kargiotis, Odysseas; Klopfenstein, Jeffrey D et al. (2009) RNAi-mediated downregulation of radiation-induced MMP-9 leads to apoptosis via activation of ERK and Akt in IOMM-Lee cells. Int J Oncol 34:209-18

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