Insulin Receptor Isoform A and Insulin-like Growth Factor II as Additional Treatment Targets in Human Osteosarcoma
Insulin Receptor Isoform A and Insulin-like Growth Factor II as Additional Treatment Targets in Human Osteosarcoma
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DOI：
10.1158/0008-5472.can-08-2645
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Baldini, Nicola
中科院分区：
文献类型：
--
作者：
Avnet, Sofia;Sciacca, Laura;Baldini, Nicola
尽管骨肉瘤（OS）中经常存在胰岛素样生长因子I受体（IGFIR）介导的自分泌环，但在临床前研究中干扰该靶点仅中度有效。在这里，我们认为其他成员的IGF系统，可能参与的分子病理学OS。我们发现，在45例OS患者中，IGF-I和IGFBP-3血清水平显着降低，IGF-II血清水平显着高于健康对照组。IGF-II值升高与无病生存率降低相关。肿瘤切除后，IGF-I和IGF-II水平均恢复至正常值。在45例患者中的23例中，我们获得了组织标本，发现所有患者均表达高水平的IGF-Ⅱ和> IGF-Ⅰ mRNA。此外，除了IGFIR和IR-A/IGFIR杂合受体（HR（A））之外，胰岛素受体的同种型A（IR-A）也以高水平表达。这些受体也在OS细胞系中表达，并且通过单克隆抗体、siRNA或酪氨酸激酶抑制剂BMS-536924（其阻断IGFIR和IR）同时损害IGFIR、IR和Hybrid-Rs比选择性抗IGFIR策略更有效。此外，在低血清条件下，抗IGF-II-siRNA治疗显著抑制了具有IGF-II自分泌回路的MG-63 OS细胞。总之，IGF-II而不是IGF-I是OS细胞产生的主要生长因子，并且除了先前显示的IGF 1 R/IGF-I回路之外，三种不同的受体（IR-A、HR（A）和IGF 1 R）对IGF-II介导的组成性自分泌回路起互补作用。共靶向IGF 1 R和HI-A在抑制OS生长方面比单独靶向IGF-IR更有效。[Cancer Res 2009;69（6）：2443-52]
Despite the frequent presence of an insulin-like growth factor I receptor (IGFIR)-mediated autocrine loop in osteosarcoma (OS), interfering with this target was only moderately effective in preclinical studies. Here, we considered other members of the IGF system that might be involved in the molecular pathology of OS. We found that, among 45 patients with OS, IGF-I and IGFBP-3 serum levels were significantly lower, and IGF-II serum levels significantly higher, than healthy controls. Increased IGF-II values were associated with a decreased disease-free survival. After tumor removal, both IGF-I and IGF-II levels returned to normal values. In 23 of 45 patients, we obtained tissue specimens and found that all expressed high mRNA level of IGF-II and >IGF-I. Also, isoform A of the insulin receptor (IR-A) was expressed at high level in addition to IGFIR and IR-A/IGFIR hybrids receptors (HR(A)). These receptors were also expressed in OS cell lines, and simultaneous impairment of IGFIR, IR, and Hybrid-Rs by monoclonal antibodies, siRNA, or the tyrosine kinase inhibitor BMS-536924, which blocks both IGFIR and IR, was more effective than selective anti-IGFIR strategies. Also, anti-IGF-II-siRNA treatment in low-serum conditions significantly inhibited MG-63 OS cells that have an autocrine circuit for IGF-II. In summary, IGF-II rather than IGF-I is the predominant growth factor produced by OS cells, and three different receptors (IR-A, HR(A), and IGFIR) act complementarily for an IGF-II-mediated constitutive autocrine loop, in addition to the previously shown IGFIR/IGF-I circuit. Cotargeting IGFIR and HI-A is more effective than targeting IGF-IR alone in inhibiting OS growth. [Cancer Res 2009;69(6):2443-52]