Microenvironmental regulation of the cancer stem cell phenotype by integrin a6

项目概述恶性胶质瘤的当前治疗方法，最常见的是胶质母细胞瘤 多种形式(GBM)，包括手术切除、放射治疗和化疗，但由于以下原因仍无效 复发和治疗耐药。无法充分治疗这些肿瘤可能部分是由于 肿瘤细胞的子集，癌症干细胞，对许多传统疗法具有抵抗力。肿瘤干细胞 在GBM内定位于几个区域，其中包括血管周围间隔，这是一种已知的 肿瘤干细胞微环境或利基，已被证明在治疗耐药中发挥作用。 了解癌症干细胞如何与血管周围的壁龛沟通以促进癌症干细胞 细胞表型和促进治疗耐药具有直接重要意义，并在 设计更有效的胶质瘤治疗方法。最近，整合素α6已在血管周围被发现。 人GBM的生态位和高表达与具有癌症干细胞表型的细胞相关。另外， 靶向整合素α6导致抑制生长和肿瘤形成，显示整合素α 6可能是一个很有前途的治疗靶点。这个提议的假设是整合素α6是一种统一的 促进肿瘤干细胞表型的信号，将通过以下方式进行评估：1)询问整合素 阿尔法6与血管周围微环境相互作用以维持肿瘤干细胞表型和2) 确定整合素α6在促进放化疗抵抗中的作用。这项建议 还旨在开发一种活体成像模型，用于研究癌症干细胞之间的体内通讯 以及利基市场。实验研究将利用人的GBM标本来评估细胞外基质配体 并利用临床相关剂量的放射和化疗来评估 通过RNA干扰或阻断抗体注射来靶向整合素α6。癌症干细胞 表型将通过自我更新和肿瘤起始试验进行评估。这样做的长期目标是 建议开发具有更高疗效的以癌症干细胞为靶点的GBM疗法 与传统疗法相结合。本提案中概述的这些研究将揭示 癌症干细胞通过整合素与利基细胞相互作用，并评估治疗基底膜的潜在疗法 中断与利基市场相关的沟通。任何发现和治疗进展都可能延伸到其他肿瘤。 具有癌症干细胞成分的类型(即结肠癌、乳房)。

PROJECT SUMMARY 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 cell interaction with the niche via integrin ¿6 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).