NEGATIVE REGULATION OF IGF-11 BY THE IGF-11R IN CANCER

胰岛素样生长因子II在恶性肿瘤中的重要作用 通过激活IGF-I受体进行转化。激活的IGF-IR促进 通过刺激细胞增殖和抑制细胞恶性生长 细胞凋亡。IGF-II还与甘露糖6-磷酸/IGF-II受体结合 (IGF-IIR)，一种控制IGF-II在体内的可用性的运输分子 胚胎发生。我们假设IGF-IIR也限制了IGF-II 在恶性细胞中发出信号。在IGF-II信令的自分泌模型中， 我们证明了IGF-IIR抑制了细胞外的 IGF-II，从而减少IGF-IR依赖的细胞增殖和 锚地--独立增长。 这些观察导致我们提出以下研究目标：L) 通过过度表达确认IGF-IIR作为IGF-II拮抗剂的作用 IGF-IIR与一组突变的IGF突变多肽的结合 受体亲和力。我们预计IGF-IIR的过度表达只有在 与高IGF-IIR亲和力的配体共表达，将抑制细胞外 IGF的可用性；2)IGF-IIR过表达，抑制IGF-II 信号传递可以提供一种逆转或抑制IGF-II依赖的机制 恶毒。我们将在表达IGF-II的肉瘤细胞中验证这一假设 LINES，3)第三个目标将进一步探讨 IGF-IIR，使用配体结合改变的受体突变体和 传输属性。 鉴于自分泌IGF-II的表达是肉瘤的一个显著特征， 对于治疗选择有限的患者，一项新的研究 抑制生长因子的机制服务于长期目标 设计新的治疗方法。

Insulin-like growth factor II plays a prominent role in malignant transformation by activating the IGF-I receptor. Activated IGF-IR promotes malignant growth by stimulating cellular proliferation and by inhibiting apoptosis. IGF-II also binds to the mannose 6-phosphate/IGF-II receptor (IGF-IIR), a transport molecule controlling IGF-II availability during embryogenesis. We hypothesize that the IGF-IIR also limits IGF-II signalling in malignant cells. In an autocrine model of IGF-II signalling, we demonstrated that IGF-IIR inhibited the extracellular accumulation of IGF-II, thereby reducing IGF-IR-dependent cellular proliferation and anchorage-independent growth. These observations lead us to propose the following research aims: l) To confirm that the IGF-IIR acts as an IGF-II antagonist by overexpressing the IGF-IIR with a panel of mutant IGF mutant peptides with altered receptor affinity. We anticipate that IGF-IIR overexpression, only when coexpressed with high IGF-IIR avidity ligands, will repress extracellular IGF availability; 2) IGF-IIR overexpression, suppressing IGF-II signalling, may provide a mechanism to reverse or inhibit IGF-II-dependent malignancy. We will test this hypothesis in IGF-II expressing sarcoma cell lines, 3) The third aim will further explore the antagonistic actions of IGF-IIR, employing receptor mutants with altered ligand binding and transport properties. Given that autocrine IGF-II expression is a prominent feature of sarcomas, for which treatment options are limited, investigation of a novel mechanism of growth factor suppression serves the long term goal of designing new therapeutic approaches.