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.
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