Avnet Sofia, Sciacca Laura, Salerno Manuela, Gancitano Giovanni, Cassarino Maria Francesca, Longhi Alessandra, Zakikhani Mahvash, Carboni Joan M, Gottardis Marco, Giunti Armando, Pollak Michael, Vigneri Riccardo, Baldini Nicola
Laboratory for Pathophysiology, Rizzoli Orthopaedic Institute, Bologna, Italy.
Cancer Res. 2009 Mar 15;69(6):2443-52. doi: 10.1158/0008-5472.CAN-08-2645. Epub 2009 Mar 3.
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 IR-A is more effective than targeting IGF-IR alone in inhibiting OS growth.
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的效果仅为中等。在此，我们考虑了IGF系统中可能参与OS分子病理学的其他成员。我们发现，在45例OS患者中，IGF-I和IGFBP-3血清水平显著低于健康对照，而IGF-II血清水平显著高于健康对照。IGF-II值升高与无病生存期缩短相关。肿瘤切除后，IGF-I和IGF-II水平均恢复至正常水平。在45例患者中的23例，我们获取了组织标本，发现所有标本均高表达IGF-II mRNA水平且>IGF-I。此外，除了IGFIR和IR-A/IGFIR杂交受体（HR(A)）外，胰岛素受体（IR-A）的A亚型也高表达。这些受体也在OS细胞系中表达，通过单克隆抗体、siRNA或酪氨酸激酶抑制剂BMS-536924（其可同时阻断IGFIR和IR）同时损害IGFIR、IR和杂交受体，比选择性抗IGFIR策略更有效。此外，在低血清条件下进行抗IGF-II-siRNA治疗可显著抑制具有IGF-II自分泌回路的MG-63 OS细胞。总之，IGF-II而非IGF-I是OS细胞产生的主要生长因子，除了先前显示的IGFIR/IGF-I回路外，三种不同的受体（IR-A、HR(A)和IGFIR）对IGF-II介导的组成型自分泌环起互补作用。在抑制OS生长方面，同时靶向IGFIR和IR-A比单独靶向IGF-IR更有效。
