Prostate tumor progression is mediated by a paracrine TGF-beta/Wnt3a signaling axis.
Prostate tumor progression is mediated by a paracrine TGF-beta/Wnt3a signaling axis.
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DOI：
10.1038/onc.2008.293
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发表时间：
2008-11-27
期刊：
影响因子：
8
通讯作者：
Bhowmick, N. A.
中科院分区：
文献类型：
--
作者：
Li, X.;Placencio, V.;Iturregui, J. M.;Uwamariya, C.;Sharif-Afshar, A-R;Koyama, T.;Hayward, S. W.;Bhowmick, N. A.
转化生长因子-β是肿瘤发生过程中重要的旁分泌因子。I型和II型转化生长因子-β受体的配体结合启动下游信号传导。间质转化生长因子-β信号在前列腺癌进展中的作用尚不清楚。在小鼠中，转化生长因子-β受体II型表达的有条件间质基因敲除(Tgfbr2fspKO)导致前列腺上皮内瘤变的发展和7个月内进展为腺癌。临床上，我们观察到转化生长因子-β受体II型在69%的前列腺癌相关间质中表达缺失，而在良性组织中的表达仅为15%(p值为0.0001)。为了探讨旁分泌转化生长因子-β信号在前列腺癌进展中的作用机制，我们比较了Tgfbr2fspKO和Tgfbr2flxE2/FloxE2小鼠前列腺基质细胞对体外培养的人前列腺癌LNCaP细胞和组织重组异种移植瘤的作用。Tgfbr2fspKO前列腺基质可诱导Wnt3a表达增加，从而诱导LNCaP细胞增殖和成瘤。Wnt3a中和抗体逆转LNCaP肿瘤发生。转化生长因子β对WNT3a表达的抑制部分是通过抑制WNT3a启动子上的STAT3活性而实现的。结论：前列腺癌间质TβRII表达的频繁缺失可缓解旁分泌抑制WNT3a的表达。
TGF-β is an important paracrine factor in tumorigenesis. Ligand binding of the type I and II TGF-β receptors initiate downstream signaling. The role of stromal TGF-β signaling in prostate cancer progression is unknown. In mice the conditional stromal knockout of the TGF-β receptor type II expression (Tgfbr2fspKO) resulted in the development of prostatic intraepithelial neoplasia and progression to adenocarcinoma within seven months. Clinically, we observed a loss of TGF-β receptor type II expression in 69% of human prostate cancer-associated stroma compared to 15% of stroma associated with benign tissues (n =140, p value < 0.0001). To investigate the mechanism of paracrine TGF-β signaling in prostate cancer progression, we compared the effect of the prostatic stromal cells from Tgfbr2fspKO and Tgfbr2floxE2/floxE2 mice on LNCaP human prostate cancer cells in vitro and tissue recombination xenografts. Induction of LNCaP cell proliferation and tumorigenesis was observed by Tgfbr2fspKO prostate stroma as a result of elevated Wnt3a expression. Neutralizing antibodies to Wnt3a reversed LNCaP tumorigenesis. The TGF-β inhibition of Wnt3a expression was in part through the suppression of Stat3 activity on the Wnt3a promoter. In conclusion, the frequent loss of stromal TβRII expression in human prostate cancer can relieve the paracrine suppression of Wnt3a expression.
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影响因子：
6.6
作者：
DAVIDSON, D;BOSTWICK, DG;STILMANT, M
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