Role of IGF-I Receptor Signaling Pathways in Cell Survival and Migration

IGF-I 受体信号通路在细胞存活和迁移中的作用

• 批准号: 7679137
• 负责人: HANNA Y IRIE
• 金额: $ 13.51万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679137
• 关键词: 3-Dimensional; Anoikis; Apoptosis; Apoptotic; Biological Response Modifier Therapy; Breast; Carcinoma in Situ; Cell Survival; Clinical; Commit; Development; Epithelial; Growth Factor; Immigration; In Vitro; Insulin-Like Growth Factor I; Insulin-Like-Growth Factor I Receptor; Laboratories; Malignant Neoplasms; Mediating; Medical Oncologist; Modeling; Pathogenesis; Pathway interactions; Process; Protein Isoforms; Receptor Signaling; Regulation; Research Personnel; Role; Scientist; Screening procedure; Signal Pathway; Signal Transduction; Signaling Protein; Sirolimus; Small Interfering RNA; Somatomedins; Structure; Substrate Domain; Therapeutic; base; breast tumorigenesis; c new; inhibitor/antagonist; mTOR inhibition; malignant breast neoplasm; migration; neoplastic cell; novel; programs; protein function; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Insulin-like growth factor-l (IGF-I) signaling has been implicated in the pathogenesis of breast and other cancers. The IGF-I receptor (IGF-IR) activates pathways that regulate key processes associated with tumorigenesis- hyperproliferation, enhanced survival and migration. Using an in vitro 3-D breast epithelial model to investigate IGF-IR pathways that specifically regulate these processes, I observed that IGF-I hyper-stimulation leads to formation of hyperproliferative structures with filled lumen; these structures resemble carcinoma-in-situ. Using this model, I uncovered novel activities of Akt and other signaling proteins involved in IGF-I stimulated effects on survival, migration and invasion and I plan to investigate the underlying mechanisms. In Specific Aim 1, I will investigate mechanisms responsible for regulation of migration and invasion by IGF-I. Akt1 was observed to suppress IGF-I- and EGF-stimulated migration whereas Akt2 is required for migration. Studies to elucidate the underlying basis for these contrasting, isoform-specific functions and to identify isoform-specific targets of Akt will be performed. In Specific Aim 2, I will examine the cellular pathways that regulate cell survival and filling of the lumen by IGF-I. While Akt2 was found to be critical for anti-apoptotic activity associated with IGF-l-induced luminal filling, rapamycin-mediated inhibition of mTOR, a downstream target of Akt signaling, does not suppress the anti-apoptotic effects of IGF-I. These results revealed the contribution of rapamycin-insensitive pathway(s) to IGF-I mediated cell survival. Utilizing both candidate-based and screening approaches, this project aims to identify these pathways, as well as other uncharacterized, novel molecules critical for IGF-I mediated cell survival and luminal filing. Targeted therapies, which specifically inhibit molecules activated in tumors, are becoming a common strategy and inhibitors targeting IGF-IR/PI-3K/Akt are in early clinical development. Given the complexity of interactions between signaling networks in tumor cells, a thorough understanding of the functions of these proteins is critical for optimal use of new biological therapies. Strategies to identify novel targets are also critical as tumor cells utilize multiple mechanisms to evade therapeutic inhibition. Hanna Irie is a researcher and a medical oncologist specializing in breast cancer who is committed to becoming an independent laboratory-based scientist dedicated to understanding the role of growth factors in breast tumorigenesis.

描述（由申请人提供）：胰岛素样生长因子-I（IGF-I）信号转导与乳腺癌和其他癌症的发病机制有关。IGF-I受体（IGF-IR）激活调节与肿瘤发生相关的关键过程的途径-过度增殖，增强存活和迁移。使用体外3-D乳腺上皮模型来研究专门调节这些过程的IGF-IR通路，我观察到IGF-I过度刺激导致管腔填充的过度增殖结构的形成;这些结构类似于原位癌。利用这个模型，我发现了Akt和其他信号蛋白的新活性，这些蛋白参与了IGF-I对生存、迁移和侵袭的刺激作用，我计划研究潜在的机制。在具体目标1中，我将研究IGF-I调节迁移和侵袭的机制。观察到Akt 1抑制IGF-I和EGF刺激的迁移，而Akt 2是迁移所必需的。将进行研究，以阐明这些对比，亚型特异性功能的基础，并确定亚型特异性Akt的目标。在具体目标2中，我将研究调节细胞存活和IGF-I填充管腔的细胞通路。虽然发现Akt 2对于与IGF-I诱导的管腔填充相关的抗凋亡活性是关键的，但是雷帕霉素介导的mTOR（Akt信号传导的下游靶标）的抑制不抑制IGF-I的抗凋亡作用。这些结果揭示了雷帕霉素不敏感途径对IGF-I介导的细胞存活的贡献。利用基于候选人的方法和筛选方法，该项目旨在确定这些途径，以及其他未表征的，对IGF-I介导的细胞存活和管腔填充至关重要的新型分子。特异性抑制肿瘤中活化分子的靶向治疗正在成为一种常用策略，靶向IGF-IR/PI-3 K/Akt的抑制剂处于早期临床开发中。鉴于肿瘤细胞中信号网络之间相互作用的复杂性，彻底了解这些蛋白质的功能对于最佳使用新的生物疗法至关重要。识别新靶点的策略也至关重要，因为肿瘤细胞利用多种机制逃避治疗抑制。Hanna Irie是一名研究人员和专门研究乳腺癌的医学肿瘤学家，她致力于成为一名独立的实验室科学家，致力于了解生长因子在乳腺肿瘤发生中的作用。