Blockade of transforming growth factor-beta signaling suppresses progression of androgen-independent human prostate cancer in nude mice.
Blockade of transforming growth factor-beta signaling suppresses progression of androgen-independent human prostate cancer in nude mice.
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阻断转化生长因子-β信号传导可抑制裸鼠中雄激素非依赖性人类前列腺癌的进展。
DOI：
10.1158/1078-0432.ccr-04-2571
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Dong,Zhongyun
中科院分区：
文献类型：
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作者：
Zhang,Fahao;Lee,Juwon;Lu,Shan;Pettaway,CurtisA;Dong,Zhongyun
我们研究了转化生长因子-β (TGF-β) 信号在 PC-3MM2 人前列腺癌细胞生长和转移中的作用。高度转移的 PC-3MM2 人前列腺癌细胞被设计为组成型过度表达显性失活 II 型 TGF-β 受体 (DNR)。 DNR 转染对细胞生长的直接影响很小，并且减弱了 TGF-β 诱导的细胞生长抑制和 TGF-β1 的产生。当细胞被植入裸鼠前列腺时，PC-3MM2变体的致瘤性（肿瘤发生率）没有明显差异。然而，DNR 改造的 PC-3MM2 细胞的生长率和转移率显着降低。对照肿瘤中的大多数细胞被增殖细胞核抗原抗体呈阳性染色，极少数细胞被末端脱氧核苷酸转移酶介导的切口末端标记（TUNEL）染色。与此形成鲜明对比的是，由PC-3MM2-DNR细胞形成的肿瘤含有较少的增殖细胞核抗原阳性细胞和更多的TUNEL阳性细胞。 CD31抗体染色显示对照肿瘤比PC-3MM2-DNR肿瘤含有更多血管。 Northern 印迹和 ELISA 均显示，PC-3MM2 细胞形成的肿瘤中白介素 8 (IL-8) 的表达显着降低。最后，反义IL-8 cDNA的转染显着降低了PC-3MM2细胞的IL-8产生，并且与亲本和对照载体转染的细胞相比，反义IL-8转染的PC-3MM2细胞生长得更慢。综上所述，我们的数据表明，TGF-β信号通过调节肿瘤细胞中IL-8的表达从而调节肿瘤血管生成，对于裸鼠前列腺中PC-3MM2细胞的渐进生长至关重要。
We investigated the role of transforming growth factor-β (TGF-β) signaling in the growth and metastasis of PC-3MM2 human prostate cancer cells. Highly metastatic PC-3MM2 human prostate cancer cells were engineered to constitutively overexpress a dominant-negative type II TGF-β receptor (DNR). Transfection of DNR had minimal direct effects on cell growth and attenuated TGF-β-induced cell growth inhibition and TGF-β1 production. There were no discernable differences in tumorigenicity (tumor incidence) among PC-3MM2 variants when the cells were implanted into the prostates of nude mice. Growth rate and metastatic incidence of DNR-engineered PC-3MM2 cells, however, were significantly reduced. Most cells in the control tumors were positively stained by an antibody to proliferation cell nuclear antigen and very few cells were stained by terminal deoxynucleotidyl transferase–mediated nick-end labeling (TUNEL). In sharp contrast, tumors formed by PC-3MM2-DNR cells contained fewer proliferation cell nuclear antigen–positive cells and many more TUNEL-positive cells. Staining with antibody against CD31 showed that control tumors contained more blood vessels than PC-3MM2-DNR tumors. Expression of interleukin-8 (IL-8) in tumors formed by PC-3MM2 cells was significantly reduced as revealed by both Northern blotting and ELISA. Finally, transfection of antisense IL-8 cDNA significantly reduced IL-8 production by PC-3MM2 cells and antisense IL-8-transfected PC-3MM2 cells grew slower in comparison with parental and control vector-transfected cells. Taken together, our data suggest that TGF-β signaling, by regulating IL-8 expression in tumor cells and hence tumor angiogenesis, is critical for progressive growth of PC-3MM2 cells in the prostate of nude mice.