Jernberg-Wiklund Helena, Nilsson Kenneth
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
Adv Cancer Res. 2007;97:139-65. doi: 10.1016/S0065-230X(06)97006-7.
Human multiple myeloma (MM) is characterized by the expansion of neoplastic plasmablasts/plasma cells with complex genetic aberrations and high dependence for survival and growth on cytokines produced in the bone marrow microenvironment. As tools in the study of MM about 80 authentic MM cell lines and a few relevant in vivo mouse models are available. The dependence on insulin-like growth factor receptor (IGF-IR) signaling in the development and maintenance of the malignant phenotype in a variety of cancers is a rationale for attempts to improve tumor treatment by selectively inhibiting the IGF-IR in malignant cells by neutralizing antibodies, dominant negative IGF-IR, and IGF-IR siRNA. Testing the hypothesis that abrogating IGF-IR-mediated signaling of survival should make MM cells more susceptible to apoptosis, our studies have so far provided proof-of-principle by the demonstration that inhibition of a signaling pathway stimulating survival renders cells susceptible to drug-induced apoptosis when the drug (dexamethasone) and inhibitor (rapamycin) converge on the same target, that is p70(S6K). The recent publication of the three-dimensional structure of the IGF-IR kinase domain has facilitated the development of IGF-IR inhibitors of the cyclolignan family, that is picropodophyllin, with capacity to distinguish also in vivo between the IGF-IR and the insulin receptor. Studies in vitro and in vivo with picropodophyllin show promising effects, that is apoptosis induction and growth arrest, and have made it possible to evaluate the biological and therapeutic effects of inhibition of the IGF-IR signaling in MM.
人类多发性骨髓瘤（MM）的特征是肿瘤性成浆细胞/浆细胞扩增，伴有复杂的基因畸变，并且在生存和生长方面高度依赖骨髓微环境中产生的细胞因子。作为MM研究的工具，现有约80种正宗的MM细胞系和一些相关的体内小鼠模型。多种癌症的恶性表型的发生和维持对胰岛素样生长因子受体（IGF-IR）信号传导存在依赖性，这为通过用中和抗体、显性负性IGF-IR和IGF-IR siRNA选择性抑制恶性细胞中的IGF-IR来改善肿瘤治疗提供了理论依据。为了验证废除IGF-IR介导的生存信号应使MM细胞更易发生凋亡这一假设，我们的研究迄今已通过以下方式提供了原理证明：当药物（地塞米松）和抑制剂（雷帕霉素）作用于同一靶点即p70(S6K)时，抑制刺激生存的信号通路会使细胞对药物诱导的凋亡敏感。IGF-IR激酶结构域三维结构的最新发表促进了环木脂素家族IGF-IR抑制剂即鬼臼苦素的开发，该抑制剂在体内也能够区分IGF-IR和胰岛素受体。对鬼臼苦素进行的体外和体内研究显示出有前景的效果，即诱导凋亡和生长停滞，并且使得评估抑制MM中IGF-IR信号传导的生物学和治疗效果成为可能。
