Gallicchio M A, Kneen M, Hall C, Scott A M, Bach L A
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre (Austin Campus) Heidelberg, Victoria, Australia.
Int J Cancer. 2001 Dec 1;94(5):645-51. doi: 10.1002/ijc.1519.
Rhabdomyosarcoma is the most common soft-tissue sarcoma of childhood. Rhabdomyosarcoma cell lines overexpress insulin-like growth factor-II (IGF-II), an autocrine growth factor that is inhibited by insulin-like growth factor binding protein-6 (IGFBP-6). IGFBP-6 is associated with myoblast quiescence, and expression in rhabdomyosarcoma cells is low. The effect of IGFBP-6 on 2 rhabdomyosarcoma cell lines, RD and Rh30, was studied. IGFBP-6 inhibited anchorage-dependent growth of RD and Rh30 cells in a dose-dependent manner (p < 0.0001). IGFBP-6 also inhibited anchorage-independent growth of RD cells in soft agar in a dose-dependent manner (p < 0.01). Anchorage-independent growth of RD cells on polyhydroxyethylmethacrylate-coated plates was decreased to a minimum of 48% of control after treatment with IGFBP-6 (p < 0.001). In this system, IGFBP-6 increased apoptosis 4-fold (p < 0.001). IGF-II partially reversed the IGFBP-6-induced decrease in growth and increase in apoptosis. Rh30 cells were stably transfected with an IGFBP-6 cDNA and subcutaneous xenografts established in BALB/c nude mice. After 18 days, sizes of 2 independent clones of IGFBP-6-overexpressing Rh30 cells were reduced to 12% and 26% of vector control-transfected tumors (p = 0.0006 and 0.002, respectively). IGFBP-6 therefore inhibits proliferation and promotes apoptosis of rhabdomyosarcoma in vitro and dramatically inhibits xenograft growth in vivo, at least in part by inhibiting IGF-II. Low expression of IGFBP-6 may therefore contribute to rhabdomyosarcoma growth and metastasis.
横纹肌肉瘤是儿童期最常见的软组织肉瘤。横纹肌肉瘤细胞系过度表达胰岛素样生长因子-II（IGF-II），这是一种自分泌生长因子，可被胰岛素样生长因子结合蛋白-6（IGFBP-6）抑制。IGFBP-6与成肌细胞静止相关，在横纹肌肉瘤细胞中的表达较低。研究了IGFBP-6对两种横纹肌肉瘤细胞系RD和Rh30的影响。IGFBP-6以剂量依赖方式抑制RD和Rh30细胞的贴壁依赖性生长（p<0.0001）。IGFBP-6还以剂量依赖方式抑制RD细胞在软琼脂中的非贴壁依赖性生长（p<0.01）。用IGFBP-6处理后，RD细胞在聚甲基丙烯酸羟乙酯包被平板上的非贴壁依赖性生长降至对照组的最低48%（p<0.001）。在该系统中，IGFBP-6使细胞凋亡增加4倍（p<0.001）。IGF-II部分逆转了IGFBP-6诱导的生长抑制和凋亡增加。用IGFBP-6 cDNA稳定转染Rh30细胞，并在BALB/c裸鼠中建立皮下异种移植物。18天后，两个独立的过表达IGFBP-6的Rh30细胞克隆的大小分别降至载体对照转染肿瘤的12%和26%（分别为p=0.0006和0.002）。因此，IGFBP-6在体外抑制横纹肌肉瘤的增殖并促进其凋亡，在体内显著抑制异种移植物生长，至少部分是通过抑制IGF-II实现的。因此，IGFBP-6的低表达可能有助于横纹肌肉瘤的生长和转移。
