Growth inhibition of brain tumors by cord blood stem cells

描述（由申请人提供）：尽管有许多治疗多形性胶质母细胞瘤的治疗策略，但这种侵袭性脑恶性肿瘤患者的生存率仍然很低。即使联合使用几种治疗方式，由于剩余的癌细胞不可避免地渗入正常脑组织并引起肿瘤复发，预后良好的情况极为罕见。我们建议研究脐带血干细胞与胶质瘤有特定患病率的癌细胞的相互作用。在本研究中，我们将利用人脐带间充质干细胞来追赶胶质母细胞瘤细胞并抑制肿瘤生长，研究控制胶质母细胞瘤细胞侵袭、迁移和血管生成的分子机制。我们推测：(1)干细胞与胶质瘤细胞相互作用会启动细胞凋亡，抑制肿瘤生长；(2)干细胞与胶质瘤细胞的相互作用会降低一些信号分子和其他参与细胞存活、粘附、迁移和增殖的蛋白质的表达。解决这些假设的具体目的如下：确定脐带血干细胞对胶质母细胞瘤和异种移植细胞系增殖、迁移、侵袭和凋亡的分子机制的影响。特定目的1a：确定脐带血干细胞对已建立的胶质母细胞瘤细胞系和胶质瘤异种移植细胞的粘附和迁移的影响。特异性目的1b：评估脐带血干细胞对胶质母细胞瘤细胞系和异种移植物细胞系增殖的分子机制的影响。具体目的1c：评估脐带血干细胞对胶质瘤异种移植细胞和胶质瘤细胞系细胞凋亡的分子机制的影响。具体目的1：确定脐带血干细胞对胶质母细胞瘤细胞系和胶质瘤异种移植细胞侵袭性的影响。具体目标2：评估脐带血干细胞在体内对颅内肿瘤生长的影响，以及人胶质母细胞瘤细胞系和胶质瘤异种移植细胞的侵袭性和血管生成。特异性目的2a：确定脐带血干细胞对裸鼠脑内注射的人胶质瘤细胞系和胶质瘤异种移植细胞预先建立的颅内肿瘤生长的影响。特异性目的2b：在体外和体内模型中确定脐带血干细胞对脑血管生成分子机制的影响。我们预计这些结果将大大增加我们对这些干细胞如何追逐和附着在这些肿瘤细胞上的理解；因此，获得的信息应该有助于开发治疗胶质母细胞瘤的新治疗方法。

DESCRIPTION (provided by applicant): 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 1a: Determine the effect of cord blood stem cells on adhesion and migration of established glioblastoma cell lines and glioma xenograft cells. Specific aim 1b: Evaluate the effect of cord blood stem cells on the molecular mechanisms of proliferation in glioblastoma cell lines and xenograft cell lines. Specific aim 1c: Evaluate the effect of cord blood stem cells on the molecular mechanisms of apoptosis in glioma xenograft cells and glioblastoma cell lines. Specific aim 1d: 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 2a: 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 2b: 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.