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主要健康问题，迫切需要新的治疗方法，特别是对于最致命的脑肿瘤胶质母细胞瘤。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。在化疗或放疗激活后，p53诱导邻近肿瘤细胞死亡，而保留正常细胞。我们发现效应机制依赖于半乳糖凝集素-3的分泌，这是一种半乳糖识别凝集素，可诱导细胞凋亡。我们还发现体内分泌的半乳糖凝集素-3可以减少肿瘤的形成。在本提案中，我们将通过剖析潜在的机制来扩展这些初步发现，并确定Gal3是否具有临床潜力。我们将确定细胞外半乳糖凝集素-3 （Aim 1）在肿瘤细胞中激活的凋亡信号通路的类型，分泌的半乳糖凝集素-3是否选择性地结合特定的细胞表面受体，具有肿瘤特异性（Aim 2），以及在体内小鼠胶质瘤模型中，Gal-3递送是否可以作为一种可行的癌症治疗方法（Aim 3）。我们的工作假设是，p53通过刺激外泌体分泌Gal3来发挥肿瘤抑制旁观者效应，而Gal3反过来由于癌症中独特的n -糖基化而以肿瘤选择性的方式与1-整合素复合物结合，并通过激活细胞凋亡诱导治疗效果。这些研究很重要，因为我们发现了一种新的p53诱导的由可溶性Gal3介导的肿瘤抑制机制，这具有治疗意义。在体内研究细胞外Gal3在胶质瘤凋亡和肿瘤生长中的作用是新的。这些研究将为用Gal3（或激动剂，如拟肽剂或小分子）靶向癌症提供原理证明数据。该项目的成功结果将支持Gal3用于治疗恶性胶质瘤和可能的其他癌症的临床翻译，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 Unpublished studies in our lab have revealed a new bystander effect for tumor suppressor p53.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.