Growth inhibition of brain tumors by cord blood stem cells

描述(由申请人提供)：尽管对多形性胶质母细胞瘤采取了许多治疗策略，但这种侵袭性脑恶性肿瘤患者的存活率仍然很低。即使联合使用几种治疗方法，良好的预后也是极其罕见的，因为残留的癌细胞不可避免地渗透到正常脑组织并导致肿瘤复发。我们建议研究脐带血干细胞与肿瘤细胞之间的相互作用，这些细胞对胶质瘤具有特定的发病率。在目前的方案中，我们将利用来自人脐带的间充质干细胞来研究控制胶质母细胞瘤细胞在预先建立的颅内肿瘤中侵袭、迁移和血管生成的分子机制，以追逐这些肿瘤细胞并逆转肿瘤的生长。我们假设：(1)干细胞与胶质瘤细胞的相互作用将启动细胞凋亡并抑制肿瘤生长；(2)干细胞与胶质瘤细胞的相互作用将减少与细胞存活、黏附、迁移和增殖有关的几个信号分子和其他蛋白质的表达。具体目的如下：1.确定脐血干细胞对胶质母细胞瘤和异种移植瘤细胞增殖、迁移、侵袭和凋亡的分子机制的影响。具体目的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黏附和迁移的影响。具体目的1b：评价脐血干细胞对胶质母细胞瘤细胞系和异种移植细胞系增殖的分子机制的影响。具体目的1c：评价脐血干细胞对胶质瘤异种移植细胞和胶质母细胞瘤细胞系凋亡的分子机制的影响。特异性目的1D：检测脐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力的影响。具体目的2：评价脐血干细胞对已建立的颅内肿瘤生长的体内作用，以及对人脑胶质母细胞瘤细胞系和胶质瘤异种移植细胞的侵袭力和血管生成的影响。具体目的2a：检测脐血干细胞对人胶质母细胞瘤细胞系和裸鼠脑内注射的胶质瘤异种移植瘤细胞株颅内肿瘤生长的影响。具体目的2b：在体外和体内模型中，确定脐带血干细胞在脑血管生成分子机制中的作用。我们预计这些结果将大大增强我们对这些干细胞如何追逐并附着到这些肿瘤细胞的理解；因此，所获得的信息应该有助于开发治疗胶质母细胞瘤的新的治疗方法。

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.