HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo
HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo
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DOI：
10.1074/jbc.m508136200
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发表时间：
2005-12-02
影响因子：
4.8
通讯作者：
Sanderson, RD
中科院分区：
文献类型：
--
作者：
Dai, YM;Yang, Y;Sanderson, RD
硫酸乙酰肝素作为辅助受体参与生长因子信号传导，必须具有特定的结构特征。最近的研究表明，当硫酸乙酰肝素的6-O-硫酸化水平被细胞外硫酸乙酰肝素6-O-内硫酸酯酶（Sulfs）、成纤维细胞生长因子2-、肝素结合表皮生长因子-和肝细胞生长因子-介导的信号传导减弱时。这代表了一种调节细胞生长的新机制，特别是在已知硫被错误调节的肿瘤微环境中。为了直接测试Sulfs在体内肿瘤生长控制中的作用，用编码两种已知的人内硫酸酯酶HSulf-1或HSulf-2中的任一种的cDNA转染人骨髓瘤细胞系。当植入到严重的联合免疫缺陷（SCID）小鼠，这些肿瘤的生长显着减少了约5至10倍，与对照组相比。除了抑制肿瘤生长外，这些研究还揭示了以下内容。（i）HSulf-1和HSulf-2在体内具有相似的功能。（ii）Sulfs的细胞外活性仅限于局部肿瘤细胞表面。（iii）硫促进肿瘤内细胞外基质沉积的显著增加，这可能沿着减弱的生长因子信号传导，有助于肿瘤生长的减少。这些发现表明，肿瘤微环境中存在的硫对硫酸乙酰肝素结构的动态调节可以对体内恶性细胞的生长和进展产生巨大影响。
To participate as co-receptor in growth factor signaling, heparan sulfate must have specific structural features. Recent studies show that when the levels of 6-O-sulfation of heparan sulfate are diminished by the activity of extracellular heparan sulfate 6-O-endosulfatases ( Sulfs), fibroblast growth factor 2-, heparin binding epidermal growth factor-, and hepatocyte growth factor- mediated signaling are attenuated. This represents a novel mechanism for regulating cell growth, particularly within the tumor microenvironment where the Sulfs are known to be misregulated. To directly test the role of Sulfs in tumor growth control in vivo, a human myeloma cell line was transfected with cDNAs encoding either of the two known human endosulfatases, HSulf-1 or HSulf-2. When implanted into severe combined immunodeficient ( SCID) mice, the growth of these tumors was dramatically reduced on the order of 5- to 10-fold as compared with controls. In addition to an inhibition of tumor growth, these studies revealed the following. ( i) HSulf-1 and HSulf-2 have similar functions in vivo. ( ii) The extracellular activity of Sulfs is restricted to the local tumor cell surface. ( iii) The Sulfs promote a marked increase in extracellular matrix deposition within tumors that may, along with attenuated growth factor signaling, contribute to the reduction in tumor growth. These findings demonstrate that dynamic regulation of heparan sulfate structure by Sulfs present within the tumor microenvironment can have a dramatic impact on the growth and progression of malignant cells in vivo.