Microenvironmental modulation as a result of glioma therapy

描述(申请人提供)：目前恶性胶质瘤的治疗方法，最常见的是多形性胶质母细胞瘤(GBM)，包括手术切除、放射治疗和化疗，但由于复发和治疗抵抗，仍然无效。无法充分治疗这些肿瘤，部分原因可能是肿瘤细胞的一个子集，即癌症干细胞，它们对许多传统疗法具有抵抗力。基底膜中的癌症干细胞定位于几个区域，其中包括血管周围隔室，这是已知的癌症干细胞微环境或生态位，已被证明在治疗耐药中发挥作用。了解肿瘤干细胞如何与血管周围的壁龛沟通以促进肿瘤干细胞表型和提高治疗耐药性具有直接的重要意义，并对设计更有效的胶质瘤治疗方案具有重要意义。最近，整合素α6已在人肾小球基细胞的血管周围壁龛中被发现，其高表达与肿瘤干细胞表型的细胞相关。此外，靶向整合素α6导致了生长和肿瘤的形成，表明整合素α6可能是一个有前途的治疗靶点。这一建议的假设是，整合素α6是促进肿瘤干细胞表型的统一信号，将通过以下方面进行评估：1)询问整合素α6如何与血管周围微环境相互作用以维持癌症干细胞表型；2)确定整合素α6在促进放射和化疗抵抗方面的作用。该提案还旨在开发一种活体成像模型，用于研究癌症干细胞和利基之间的体内交流。实验研究将利用人的GBM标本来评估存在于壁龛中的细胞外基质配体，并利用临床相关的放射和化疗剂量来评估通过RNA干扰或阻断抗体注射来靶向整合素α6的影响。肿瘤干细胞的表型将通过自我更新和肿瘤起始试验进行评估。这项建议的长期目标是开发具有更高疗效的GBM疗法，与传统疗法相结合，靶向癌症干细胞。这项提案中概述的这些研究将揭示癌症干细胞通过整合素16与壁龛相互作用的关键作用，并评估干扰壁龛相关沟通的GBM的潜在治疗方法。任何发现和治疗进展都可能延伸到其他含有癌症干细胞成分的肿瘤类型(如结肠、乳腺)。 公共卫生相关性：多形性胶质母细胞瘤(GBM)是最常见的恶性原发脑肿瘤，由于其复发和治疗耐药，是最致命的肿瘤之一，这些特性与肿瘤中存在的癌症干细胞成分有关。本申请中提出的研究旨在了解GBM细胞如何通过整合素16与周围微环境相互作用，促进癌症干细胞的表型。这项提议的成功完成将阐明整合素16在维持GBM细胞与微环境之间的通信方面的核心作用，并证明将这种相互作用作为更有效的人类GBM治疗的靶点是有用的。

DESCRIPTION (provided by applicant): Current treatments for malignant gliomas, the most common being Glioblastoma Multiforme (GBM), include surgical resection, radiation, and chemotherapy but remain ineffective due to recurrence and therapeutic resistance. The inability to adequately treat these tumors may be due in part to a subset of tumor cells, cancer stem cells, that are resistant to many conventional therapies. Cancer stem cells within GBMs are localized to several areas, among them the perivascular compartment, which is a known cancer stem cell microenvironment or niche and has been shown to play a role in therapeutic resistance. Understanding how the cancer stem cells communicate with the perivascular niche to promote the cancer stem cell phenotype and promote therapeutic resistance is of immediate importance and has implications in the design of more effective glioma therapies. Recently, integrin alpha 6 has been identified in the perivascular niche of human GBMs and high expression correlates to cells with a cancer stem cell phenotype. Additionally, targeting of integrin alpha 6 resulted in compromised growth and tumor formation, demonstrating integrin alpha 6 could be a promising therapeutic target. The hypothesis of this proposal is that integrin alpha 6 is a unifying signal that promotes the cancer stem cell phenotype and will be evaluated by: 1) interrogating how integrin alpha 6 interacts with the perivascular microenvironment to maintain the cancer stem cell phenotype and 2) determining the role of integrin alpha 6 in promoting resistance to radiation and chemotherapy. The proposal also aims to develop an intravital imaging model of study the in vivo communication between cancer stem cells and the niche. Experimental studies will utilize human GBM specimens to evaluate extracellular matrix ligands present in the niche and utilize clinically relevant doses of radiation and chemotherapy to assess the impact of integrin alpha 6 targeting by RNA interference or blocking antibody administration. The cancer stem cell phenotype will be evaluated by self-renewal and tumor initiation assays. The long term objective of this proposal is to develop GBM therapies with increased therapeutic efficacy that target the cancer stem cells in combination with conventional therapies. These studies outlined in this proposal will uncover the critical role of cancer stem cel interaction with the niche via integrin 16 and evaluate potential therapies to GBM which disrupt niche related communication. Any findings and therapeutic developments may extend to other tumor types with a cancer stem cell component (i.e. colon, breast). PUBLIC HEALTH RELEVANCE: Glioblastoma Multiforme (GBM) is the most common malignant primary brain tumor and among the most lethal due to their recurrence and therapeutic resistance, properties that are associated with a cancer stem cell fraction present within the tumor. The research proposed in this application aims to understand how GBM cell interaction with the surrounding microenvironment via integrin 16 is responsible for promoting the cancer stem cell phenotype. The successful completion of this proposal will elucidate the central role of integrin 16 in maintaining communication between GBM cells and the microenvironment and demonstrate the utility of targeting this interaction for more effective human GBM therapies.