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: 7482494
• 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/7482494
• 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; 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-L（IGF-I）信号传导与乳腺癌和其他癌症的发病机理有关。 IGF-I受体（IGF-IR）激活了调节与肿瘤发生过度增殖，增强生存和迁移相关的关键过程的途径。我使用体外3-D乳腺上皮模型研究特异性调节这些过程的IGF-IR途径，我观察到IGF-I高刺激会导致形成具有填充管腔的超增殖结构。这些结构类似于现场癌。使用此模型，我发现了与IGF-I有关的AKT和其他信号传导蛋白的新型活性刺激了对生存，迁移和入侵的影响，并计划研究基本机制。在特定目标1中，我将研究负责调节IGF-I迁移和入侵的机制。观察到AKT1抑制IGF-I-I和EGF刺激的迁移，而AKT2则需要迁移。将执行这些对比，同工型特异性功能的研究，并确定AKT的同工型特异性靶标。在特定的目标2中，我将检查通过IGF-I调节管腔存活和填充细胞存活的细胞途径。虽然发现AKT2对于与IGF-L诱导的腔内填充有关的抗凋亡活性至关重要，但雷帕霉素介导的MTOR抑制MTOR是Akt信号的下游靶标，但不能抑制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-1介导的细胞存活的贡献。该项目利用基于候选的方法和筛选方法，旨在识别这些途径以及其他对IGF-1介导的细胞存活和腔内归档至关重要的未表征的新型分子。特别抑制肿瘤中激活的分子的靶向疗法正在成为一种常见策略，靶向IGF-IR/PI-3K/AKT的抑制剂正在早期临床发育中。鉴于肿瘤细胞中信号网络之间相互作用的复杂性，对这些蛋白质功能的透彻理解对于最佳使用新生物疗法至关重要。鉴定新目标的策略也至关重要，因为肿瘤细胞利用多种机制逃避治疗性抑制作用。汉娜·艾里（Hanna Irie）是一名研究人员，也是一名专门研究乳腺癌的医学肿瘤学家，他致力于成为一名独立的基于实验室的科学家，致力于了解生长因子在乳腺肿瘤中的作用。