Growth inhibition of brain tumors by cord blood stem cells

脐带血干细胞抑制脑肿瘤的生长

• 批准号: 7935184
• 负责人: JASTI S. RAO
• 金额: $ 25.44万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7935184
• 关键词: Address; Adhesions; Adhesives; Apoptosis; Behavior; Bone Marrow; Brain Neoplasms; Cell Line; Cell Survival; Cell Transplantation; Cells; Cerebrum; Glioblastoma; Glioma; Growth; Growth Factor; Human; In Vitro; Intracranial Neoplasms; Laboratories; Malignant Neoplasms; Mesenchymal Stem Cells; Modality; Molecular; Morbidity - disease rate; Nude Mice; Patients; Peptide Hydrolases; Prevalence; Primary Neoplasm; Proteins; Recurrence; Research; Risk; Role; Signal Pathway; Signaling Molecule; Stem cells; Stress; Survival Rate; Therapeutic; Tropism; Umbilical Cord Blood; Umbilical cord structure; Xenograft procedure; angiogenesis; brain tissue; cancer cell; glioma cell line; graft vs host disease; high risk; human stem cells; in vivo; in vivo Model; migration; mortality; neoplastic cell; novel therapeutic intervention; outcome forecast; tumor; tumor growth

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.

描述（由申请人提供）：尽管采取了许多用于治疗多形胶质母细胞瘤的治疗策略，但患有这种侵略性脑恶性肿瘤的患者的存活率仍然很低。即使使用了几种治疗方式，良好的预后也极为罕见，因为剩下的癌细胞不可避免地渗入正常的脑组织并引起肿瘤的复发。我们建议研究脐带血干细胞与具有特异性胶质瘤患病率的癌细胞的相互作用。在本提案中，我们将研究使用人脐带中充质干细胞的胶质母细胞瘤细胞的颅内肿瘤中控制侵袭，迁移和血管生成的分子机制，以追逐这些肿瘤细胞并回归肿瘤的生长。我们假设：（1）干细胞与神经胶质瘤细胞的相互作用将启动凋亡并抑制肿瘤生长； （2）干细胞与神经胶质瘤细胞的相互作用将降低几种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：特定目标1。确定脐带血细胞对胶质母细胞瘤和异种移植细胞系中增殖，迁移，侵袭和凋亡的分子机制的影响。特定目标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。特定目标1B：评估胶带血干细胞对胶质母细胞瘤细胞系和异种移植细胞系中增殖的分子机制的影响。特定目标1C：评估脐带血干细胞对神经胶质瘤细胞和胶质母细胞瘤细胞系中凋亡分子机制的影响。特定目标1D：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的侵入性的影响。具体目标2：评估脐带血干细胞对预先建立的颅内肿瘤生长的体内影响，以及人胶质母细胞瘤细胞系和神经胶质瘤异种移植细胞的侵袭性和血管生成。特定目标2a：确定脐带血干细胞对人胶质母细胞瘤细胞系的颅内肿瘤生长和胶质瘤异种移植细胞的影响，并在裸鼠中注射了脑内。具体目标2B：确定脐带血干细胞对体外和体内模型中脑血管生成的分子机制的影响。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和附着这些肿瘤细胞的理解。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。

项目成果

Upregulation of PTEN in glioma cells by cord blood mesenchymal stem cells inhibits migration via downregulation of the PI3K/Akt pathway.

• DOI: 10.1371/journal.pone.0010350
• 发表时间: 2010-04-26
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dasari VR;Kaur K;Velpula KK;Gujrati M;Fassett D;Klopfenstein JD;Dinh DH;Rao JS
• 通讯作者: Rao JS

Cord blood stem cell-mediated induction of apoptosis in glioma downregulates X-linked inhibitor of apoptosis protein (XIAP).

• DOI: 10.1371/journal.pone.0011813
• 发表时间: 2010-07-28
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Dasari VR;Velpula KK;Kaur K;Fassett D;Klopfenstein JD;Dinh DH;Gujrati M;Rao JS
• 通讯作者: Rao JS

Transcriptional repression of Mad-Max complex by human umbilical cord blood stem cells downregulates extracellular signal-regulated kinase in glioblastoma.

• DOI: 10.1089/scd.2011.0424
• 发表时间: 2012-07
• 期刊: Stem cells and development
• 影响因子: 4
• 作者: K. Velpula;V. R. Dasari;A. Tsung;D. Dinh;J. S. Rao

Regulation of glioblastoma progression by cord blood stem cells is mediated by downregulation of cyclin D1.

• DOI: 10.1371/journal.pone.0018017
• 发表时间: 2011-03-24
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Velpula KK;Dasari VR;Tsung AJ;Gondi CS;Klopfenstein JD;Mohanam S;Rao JS
• 通讯作者: Rao JS

Downregulation of Focal Adhesion Kinase (FAK) by cord blood stem cells inhibits angiogenesis in glioblastoma.

• DOI: 10.18632/aging.100217
• 发表时间: 2010-11
• 期刊: Aging
• 作者: Dasari VR;Kaur K;Velpula KK;Dinh DH;Tsung AJ;Mohanam S;Rao JS
• 通讯作者: Rao JS