Chen Kevin, Fallen Shannon, Abaan Hatice Ozel, Hayran Mutlu, Gonzalez Corina, Wodajo Felasfa, MacDonald Tobey, Toretsky Jeffrey A, Uren Aykut
Georgetown University School of Medicine, Washington, District of Columbia, USA.
Pediatr Blood Cancer. 2008 Sep;51(3):349-55. doi: 10.1002/pbc.21595.
Osteosarcoma (OS) is a primary malignant tumor of the bone that typically presents in the second decade of life and has a poor prognosis, especially in metastatic cases. Wnt signaling contributes to the pathogenesis of tumors such as colon cancer and malignant melanoma. Wnt signaling controls normal bone formation during embryogenesis and homeostasis in adult organisms, thus we evaluated Wnt signaling in OS.
We surveyed the expression of Wnts, their receptors, Frizzleds and LRPs, and soluble Wnt inhibitors (sFRPs) in four OS cell lines by RT-PCR. We also tested biological response of OS cell lines to exogenous Wnts by measuring beta-catenin stabilization, Dvl phosphorylation, TOPFLASH activity and chemotaxis. Human OS tumor microarrays were evaluated for expression of Wnt10b by immunohistochemistry.
All cell lines tested showed expression of at least three Wnts and one Frizzled. Exogenous Wnt3a and Wnt10b treatment induced Dvl phosphorylation, beta-catenin stabilization and TCF4 transcriptional activity in both metastatic and non-metastatic murine OS cell lines. Metastatic OS cell lines showed better chemotaxis response to Wnts than the non-metastatic OS cell lines. Immunohistochemistry studies of 44 human OS samples demonstrated that Wnt10b expression correlated with decreased overall survival.
These results further supports a possible autocrine or paracrine Wnt pathway in metastatic potential of OS.
骨肉瘤（OS）是一种原发性骨恶性肿瘤，通常在生命的第二个十年出现，预后较差，尤其是在转移病例中。Wnt信号通路参与结肠癌和恶性黑色素瘤等肿瘤的发病机制。Wnt信号通路在胚胎发育过程中控制正常的骨形成，并在成年生物体中维持内环境稳定，因此我们评估了骨肉瘤中的Wnt信号通路。
我们通过逆转录聚合酶链反应（RT-PCR）检测了四种骨肉瘤细胞系中Wnts、其受体、卷曲蛋白（Frizzleds）和低密度脂蛋白受体相关蛋白（LRPs）以及可溶性Wnt抑制剂（sFRPs）的表达。我们还通过测量β-连环蛋白的稳定性、Dishevelled（Dvl）磷酸化、TOPFLASH活性和趋化性来测试骨肉瘤细胞系对外源性Wnts的生物学反应。通过免疫组织化学评估人骨肉瘤肿瘤微阵列中Wnt10b的表达。
所有测试的细胞系均显示至少三种Wnts和一种卷曲蛋白的表达。外源性Wnt3a和Wnt10b处理在转移性和非转移性小鼠骨肉瘤细胞系中均诱导了Dvl磷酸化、β-连环蛋白稳定性和TCF4转录活性。转移性骨肉瘤细胞系对Wnts的趋化反应比非转移性骨肉瘤细胞系更好。对44个人骨肉瘤样本的免疫组织化学研究表明，Wnt10b表达与总体生存率降低相关。
这些结果进一步支持了Wnt信号通路在骨肉瘤转移潜能中可能存在的自分泌或旁分泌途径。
