Defining mechanisms of extracellular communication for cancer therapy

描述（由申请人提供）：癌症是世界范围内的一个主要健康问题，迫切需要新的治疗方法，特别是针对胶质母细胞瘤（最致命的脑肿瘤）。我们实验室未发表的研究揭示了肿瘤抑制因子p53的一种新的旁观者效应。在通过化学或放射疗法激活时，p53诱导邻近肿瘤细胞的死亡，同时保留正常细胞。我们发现效应机制依赖于半乳糖凝集素-3的分泌，半乳糖凝集素-3是一种半乳糖识别凝集素，它诱导细胞凋亡。我们还发现分泌的半乳糖凝集素-3减少体内肿瘤形成。在本提案中，我们将通过剖析潜在机制来扩展这些初步发现，并确定Gal 3是否具有临床潜力。我们将确定细胞外半乳糖凝集素-3在肿瘤细胞中激活的凋亡信号传导途径的类型（Aim 1），分泌的半乳糖凝集素-3是否选择性地结合到具有肿瘤特异性特征的特定细胞表面受体（Aim 2），以及Gal-3递送是否可以使用体内小鼠神经胶质瘤模型作为癌症的可行治疗剂（Aim 3）。我们的工作假设是，p53通过刺激Gal 3的外泌体分泌而发挥肿瘤抑制性旁观者效应，Gal 3又由于癌症中独特的N-聚糖化而以肿瘤选择性方式结合至β 1-整联蛋白复合物，并通过激活细胞凋亡诱导治疗效果。这些研究是重要的，因为我们确定了一个新的p53诱导的肿瘤抑制机制介导的可溶性Gal 3，这具有治疗意义。检测细胞外Gal 3在体内胶质瘤细胞凋亡和肿瘤生长中的作用是新颖的。这些研究将为用Gal 3（或激动剂如肽模拟物或小分子）靶向癌症提供原理验证数据。该项目的成功结果将支持Gal 3用于治疗恶性胶质瘤和可能的其他癌症的临床转化，这与公共卫生高度相关。

DESCRIPTION (provided by applicant): Cancer is a major health problem worldwide and new therapies are critically needed, especially for glioblastoma the most fatal brain tumor. Unpublished studies in our lab have revealed a new bystander effect for tumor suppressor p53. Upon activation by chemo- or radiation therapies p53 induces the death of adjacent tumor cells, while sparing normal cells. We discovered that the effecter mechanism relies upon the secretion of galectin-3, a ¿-galactose-recognizing lectin, which induces apoptosis. We also found that secreted galectin-3 reduced tumor formation in vivo. In this proposal we will extend these initial findings by dissecting the underlying mechanisms and determine whether Gal3 has clinical potential. We will determine the type of apoptotic signaling pathways activated in tumor cells by extracellular galectin-3 (Aim 1), whether secreted galectin-3 selectively binds to a specific cell surface receptor, with tumor-specific characteristics (Aim 2), and whether Gal-3 delivery can be used as a viable therapeutic for cancer using an in vivo mouse glioma model (Aim 3). Our working hypothesis is that p53 exerts a tumor suppressive bystander effect by stimulating exosomal secretion of Gal3, which in turn binds in a tumor-selective fashion to ¿ 1-integrin complexes due to unique N-glycanation in cancer, and induces a therapeutic effect by activating apoptosis. These studies are important because we identified a new p53-induced tumor suppressive mechanism mediated by soluble Gal3, which has therapeutic implications. Examining the role of extracellular Gal3 in glioma apoptosis and tumor growth in vivo is novel. These studies will provide proof-of-principle data for targeting cancer with Gal3 (or agonists such as peptidomimetics or small molecules). Successful outcome of this project will support the clinical translation of Gal3 for the treatment of malignant glioma and possibly other cancers, which is highly relevant to public health.