Characterization of CD44 in brain tumor stem cells

描述（申请人提供）：恶性脑肿瘤是毁灭性的，患者几乎没有治愈的希望。在脑肿瘤的异质性细胞群中，最近的研究，包括我们自己的研究，已经确定了一种干细胞群，称为“脑肿瘤干细胞（BTSC）”。癌症干细胞理论指出，任何治愈性治疗都需要杀死或阻止癌症干细胞的扩张，而针对癌症干细胞衍生物的治疗是无效的。然而，最近的研究表明，目前的治疗方法，包括放疗和替莫唑胺化疗，优先杀死非BTSC，而不能消除BTSC。这可能是由于代偿性致癌途径的存在，使肿瘤干细胞得以逃逸和存活。在这一探索性拨款申请中，我们假设靶向治疗策略，利用存在于异质脑肿瘤细胞群体中的分子差异，将导致特异性根除BTSC，而不会导致大脑正常细胞死亡。为了解决这一假设，我们将采取分子靶向方法来对抗细胞表面蛋白CD44。根据我们的初步数据，CD44在脑肿瘤细胞内被干细胞选择性表达，而CD133是目前唯一被用来富集BTSC的标记物。此外，CD44在BTSC的增殖中起着至关重要的作用。我们将通过体外培养和体内异种移植脑肿瘤模型来确定靶向BTSC中的CD44是否可以阻止恶性脑肿瘤的生长。公共卫生相关性：脑肿瘤干细胞的发现可以为恶性脑肿瘤患者的先进治疗提供启示。在本提案中，我们将采取针对脑肿瘤干细胞分子畸变的创新策略。这一建议的成功实现将使我们能够为脑肿瘤患者推出新的治疗方法。

DESCRIPTION (provided by applicant): Malignant brain tumors are devastating, with little hope of cure for affected patients. Among heterogeneous cell populations in brain tumors, recent investigations, including our own, have identified a stem cell population, called `brain tumor stem cells (BTSC)'. The cancer stem cell theory dictates that any curative therapy needs to kill or arrest cancer stem cells from expanding, whereas therapies targeted at derivatives of cancer stem cells are not curative. Recent studies, however, have revealed that the current treatments, including radiotherapy and chemotherapy with temozolomide, preferentially kill non-BTSC and fail to eliminate BTSC. It is likely due to the existence of compensatory oncogenic pathways that allow tumor stem cells to escape and survive. In this exploratory grant proposal, we hypothesize that targeted therapeutic strategies, which exploit molecular differences present within heterogeneous populations of brain tumor cells, will lead to the specific eradication of BTSC without causing death of normal cells in the brain. To address this hypothesis, we will take molecularly-targeted approaches against a cell surface protein, CD44. Based on our preliminary data, CD44 is selectively expressed by stem cells within brain tumor cells, in comparison to CD133, the only marker currently adopted to enrich for BTSC. In addition, CD44 plays critical roles in proliferation of BTSC. We will determine whether targeting CD44 in BTSC can arrest malignant brain tumor growth by using both in vitro cultures as well as in vivo xenograft brain tumor model. PUBLIC HEALTH RELEVANCE: The discovery of brain tumor stem cells can shed light on the advanced treatments for patients with malignant brain tumors. In this proposal, we will undertake innovative strategies targeting molecular aberrations in brain tumor stem cells. The successful achievement of this proposal will enable us to launch novel therapeutic approaches for patients with brain tumors.