Sturla L M, Westwood G, Selby P J, Lewis I J, Burchill S A
Candlelighter's Children's Cancer Research Laboratory, St. James's University Hospital, Leeds, United Kingdom.
Cancer Res. 2000 Nov 1;60(21):6160-70.
Ewing's sarcoma is thought to arise after developmental arrest of primitive neural cells during embryogenesis. Because basic fibroblast growth factor (bFGF) has a critical role in the regulation of cell survival, proliferation, and differentiation during embryogenesis, we have tested the hypothesis that bFGF and FGF receptors may contribute to the development of Ewing's sarcoma and may provide a mechanism for the modulation of their behavior. All four of the Ewing's sarcoma cell lines examined expressed bFGF and FGF receptors, which were detected by immunofluorescence and Western blotting. bFGF-induced a significant dose-dependent decrease in Ewing's sarcoma cell proliferation on plastic and reduced anchorage-independent growth in soft agar. Unexpectedly, this decrease in cell number reflected bFGF-induced apoptosis and necrosis, as demonstrated by electron microscopy, binding of annexin V, and staining with acridine orange. Induction of cell death was dependent on dosage of, and period of exposure to, bFGF. bFGF did not induce differentiation of Ewing's sarcoma cells in either the presence or the absence of serum or nerve growth factor. Treatment of NuNu mice with bFGF decreased growth of the highly tumorigenic Ewing's sarcoma cell lines. Histologically tumors grown in the NuNu mice treated with bFGF were less cellular than those in control mice, and showed an increased level of apoptotic nuclei. This is in contrast to the mitogenic effect bFGF has in most other cancer cells. In summary, bFGF decreases Ewing's sarcoma growth in vitro and in vivo by the induction of cell death. This novel observation may provide a new therapeutic strategy for Ewing's sarcomas.
尤因肉瘤被认为是在胚胎发育过程中原始神经细胞发育停滞之后发生的。由于碱性成纤维细胞生长因子（bFGF）在胚胎发育期间的细胞存活、增殖和分化调节中起关键作用，我们检验了这样一个假说，即bFGF和FGF受体可能促成尤因肉瘤的发生，并可能为调节其行为提供一种机制。所检测的所有四种尤因肉瘤细胞系均表达bFGF和FGF受体，通过免疫荧光和蛋白质印迹法可检测到。bFGF在塑料培养皿上可显著剂量依赖性地降低尤因肉瘤细胞的增殖，并减少其在软琼脂中的非贴壁依赖性生长。出乎意料的是，细胞数量的减少反映了bFGF诱导的凋亡和坏死，这通过电子显微镜、膜联蛋白V结合以及吖啶橙染色得以证实。细胞死亡的诱导取决于bFGF的剂量和暴露时间。无论有无血清或神经生长因子，bFGF均未诱导尤因肉瘤细胞分化。用bFGF处理NuNu小鼠可降低高致瘤性尤因肉瘤细胞系的生长。组织学检查显示，用bFGF处理的NuNu小鼠体内生长的肿瘤细胞数量比对照小鼠体内的少，且凋亡细胞核水平升高。这与bFGF在大多数其他癌细胞中的促有丝分裂作用形成对比。总之，bFGF通过诱导细胞死亡在体外和体内降低尤因肉瘤的生长。这一新颖的观察结果可能为尤因肉瘤提供一种新的治疗策略。
