Fibroblast Growth Factor-2 Is an Important Factor that Maintains Cellular Immaturity and Contributes to Aggressiveness of Osteosarcoma
Fibroblast Growth Factor-2 Is an Important Factor that Maintains Cellular Immaturity and Contributes to Aggressiveness of Osteosarcoma
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DOI：
10.1158/1541-7786.mcr-11-0347
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发表时间：
2012-03-01
影响因子：
5.2
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
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作者：
Shimizu, Takatsune;Ishikawa, Tomoki;Saya, Hideyuki
骨肉瘤是最常见的非造血的原发性骨恶性肿瘤。在组织病理学上，骨肉瘤的特点是不同类型的细胞与骨形成的复杂混合物。环境因素在骨肉瘤这种复杂组织结构形成中的作用仍有待阐明。本研究利用新建立的小鼠骨肉瘤模型，阐明了成纤维细胞生长因子-2 （Fgf2）或白血病抑制因子（liff）等环境因素在维持骨肉瘤细胞处于未成熟状态中的作用。这些因子在肿瘤环境基质细胞中而不是在骨肉瘤细胞中高表达，它们在体外和体内均能有效抑制骨肉瘤细胞的成骨分化。进一步研究发现，这些因素诱导的细胞外信号调节激酶（Erk）1/2的高激活参与了骨肉瘤的分化过程。此外，Fgf2增强骨肉瘤细胞的增殖和迁移活性，并调节细胞对抗癌药物的敏感性。本研究结果提示骨肉瘤肿瘤的组织学由未成熟的肿瘤细胞和病理骨形成组成，可能取决于这些环境因素的分布。联合阻断几种生长因子的信号通路，包括Fgf2，可能有助于控制骨肉瘤的侵袭性。Mol - Cancer Res；10 (3);454 - 68。AACR (C) 2012。
Osteosarcoma is the most frequent, nonhematopoietic, primary malignant tumor of bone. Histopathologically, osteosarcoma is characterized by complex mixtures of different cell types with bone formation. The role of environmental factors in the formation of such a complicated tissue structure as osteosarcoma remains to be elucidated. Here, a newly established murine osteosarcoma model was used to clarify the roles of environmental factors such as fibroblast growth factor-2 (Fgf2) or leukemia-inhibitory factor (Lif) in the maintenance of osteosarcoma cells in an immature state. These factors were highly expressed in tumor environmental stromal cells, rather than in osteosarcoma cells, and they potently suppressed osteogenic differentiation of osteosarcoma cells in vitro and in vivo. Further investigation revealed that the hyperactivation of extracellular signal-regulated kinase (Erk)1/2 induced by these factors affected in the process of osteosarcoma differentiation. In addition, Fgf2 enhanced both proliferation and migratory activity of osteosarcoma cells and modulated the sensitivity of cells to an anticancer drug. The results of the present study suggest that the histology of osteosarcoma tumors which consist of immature tumor cells and pathologic bone formations could be generated dependent on the distribution of such environmental factors. The combined blockade of the signaling pathways of several growth factors, including Fgf2, might be useful in controlling the aggressiveness of osteosarcoma. Mol Cancer Res; 10(3); 454-68. (C)2012 AACR.