MOLECULAR BASIS FOR THE IMPACT OF SEX ON BRAIN TUMORIGENESIS

描述(申请人提供)：原发和转移性脑瘤男性比女性更常见。这是真实的，不分年龄和地域。因此，性别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，我们建立了导致男性星形胶质细胞转化而不是女性星形胶质细胞转化的条件。这一实验范式是一个前所未有的机会，可以确定性别对肿瘤发生的影响的分子基础。我们发现，性别影响全球基因表达、肿瘤抑制基因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，我们还发现了人类GBM干细胞的性别差异。在这项建议中，我们将利用这些小鼠和人类的GBM模型来确定性别对脑肿瘤发生的影响的分子基础。在特定的目标1中，我们建立在初步发现的基础上，生长抑制分子p202的性别二型性表达导致肿瘤抑制基因p21cip1的不同诱导，从而阻止女性星形胶质细胞的转化。在特定的目标2中，我们将跟进表明干细胞更容易在男性星形胶质细胞中诱导的初步研究，并确定性别、多个启动致癌事件、X染色体重新激活和原始细胞如何相互作用来调节转化。在具体目标3中，我们对人的男性和女性GBM干细胞培养进行了验证研究，并测试了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本知识，并有可能对我们治疗恶性脑瘤患者的方法产生影响。

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.