MOLECULAR BASIS FOR THE IMPACT OF SEX ON BRAIN TUMORIGENESIS

性别对脑肿瘤发生影响的分子基础

• 批准号: 8839735
• 负责人: Joshua B Rubin
• 金额: $ 31.64万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8839735
• 关键词: Activities of Daily Living; Address; Affect; Age; Astrocytes; Brain; Brain Neoplasms; CXCR4 gene; Cancer Biology; Cell Aging; Cell Culture Techniques; Cell physiology; Cells; Clinical; Collaborations; Conditioned Culture Media; Data; Diagnosis; Disease; Event; Exhibits; Female; Gene Expression; Glioblastoma; Growth; Health; Human; Implant; Individual; Kinetics; Knowledge; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Modeling; Molecular; Mus; Neoplasms; Neuraxis; Neurofibromatosis Type 1 Protein; Neurosurgeon; Nude Mice; Oncogenic; Pathway interactions; Patients; Pattern; Performance; Phenotype; Positioning Attribute; Predisposition; Process; Publications; Relative (related person); Research Design; Resistance; Role; Sex Characteristics; Signal Transduction; Stem cells; Testing; Therapeutic; Tumor Biology; Tumor Suppressor Proteins; Withdrawal; X Chromosome; base; cancer therapy; follow-up; human female; human male; in vitro Model; individualized medicine; male; neoplastic cell; nerve stem cell; neuro-oncology; novel; p53-binding protein 1; pluripotency; preclinical evaluation; prevent; response; sex; sexual dimorphism; stem; stem cell niche; therapeutic target; tumor; tumorigenesis; validation studies

DESCRIPTION (provided by applicant): Primary and metastatic brain tumors occur more commonly in males than females. This is true regardless of age or region of the world. Thus, sex must affect fundamental mechanisms of neoplastic growth in the central nervous system. In preliminary studies we established conditions that result in the transformation of male but not female astrocytes. This experimental paradigm is an unprecedented opportunity to define the molecular basis for the effects of sex on tumorigenesis. We found that sex affects global gene expression, activation of the tumor suppressor p21cip1, induction of a stem cell phenotype, growth kinetics, cellular senescence and patterns of intracranial malignant growth. Moreover, we found sex differences in human GBM stem cells. In this proposal we will exploit these murine and human GBM models to define the molecular basis for the effect of sex on brain tumorigenesis. In Specific Aim 1 we build on preliminary findings that sexually dimorphic expression of the growth inhibitory molecule p202 results in differential induction of the tumor suppressor p21cip1 and thereby blocks transformation in female astrocytes. In Specific Aim 2 we will follow up on preliminary studies that indicate stem cells are more easily induced in male astrocytes and define how sex, multiple initiating oncogenic events, X chromosome reactivation and cell of origin interact to regulate transformation. In Specific Aim 3 we perform validation studies with human male and female GBM stem cell cultures and test the hypothesis that sex differences in GBM stem cells will impact on responses to therapeutic targeting of CXCR4. Together these studies will advance of fundamental knowledge of cancer biology and have the potential to impact on our approach to treating patients with malignant brain tumors.

描述（由申请人提供）：原发性和转移性脑肿瘤在男性中比女性更常见。无论年龄或世界地区如何，这都是事实。因此，性必须影响中枢神经系统肿瘤生长的基本机制。在初步研究中，我们建立了导致雄性星形胶质细胞而非雌性星形胶质细胞转化的条件。这一实验范式为定义性别对肿瘤发生影响的分子基础提供了前所未有的机会。我们发现性别影响整体基因表达、肿瘤抑制因子 p21cip1 的激活、干细胞表型的诱导、生长动力学、细胞衰老和颅内恶性生长模式。此外，我们发现人类 GBM 干细胞存在性别差异。在本提案中，我们将利用这些小鼠和人类 GBM 模型来定义性别对脑肿瘤发生影响的分子基础。在具体目标 1 中，我们基于初步发现，即生长抑制分子 p202 的性别二态性表达导致肿瘤抑制因子 p21cip1 的差异诱导，从而阻止雌性星形胶质细胞的转化。在具体目标 2 中，我们将跟进初步研究，这些研究表明干细胞在雄性星形胶质细胞中更容易被诱导，并定义性别、多重起始致癌事件、X 染色体重新激活和起源细胞如何相互作用来调节转化。在具体目标 3 中，我们对人类男性和女性 GBM 干细胞培养物进行验证研究，并测试 GBM 干细胞的性别差异将影响对 CXCR4 治疗靶向的反应的假设。这些研究将共同​​推进癌症生物学的基础知识，并有可能影响我们治疗恶性脑肿瘤患者的方法。