Transforming growth factor-β regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment
Transforming growth factor-β regulates mammary carcinoma cell survival and interaction with the adjacent microenvironment
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DOI：
10.1158/0008-5472.can-07-5597
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发表时间：
2008-03-15
期刊：
影响因子：
11.2
通讯作者：
Moses, Harold L.
中科院分区：
文献类型：
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作者：
Bierie, Brian;Stover, Daniel G.;Moses, Harold L.
转化生长因子(TGF)- β信号与早期肿瘤抑制和晚期肿瘤进展有关；然而，介导这些过程的许多机制尚不清楚。利用Cre/LoxP技术，利用乳清酸性蛋白启动子驱动Cre重组酶（WAP-Cre）的转基因表达，我们现在已经在小鼠乳腺泡祖细胞中特异性地消融了11型tgf - β受体（T β RII）的表达。在小鼠乳腺肿瘤病毒增强子/启动子的控制下，转基因表达多瘤病毒中间T抗原，在缺乏或存在Cre （T β RII(fI/fI)）的情况下产生乳腺肿瘤；PY和T β RII(fI/fI)；PY；WC,分别)。tgf - β信号的缺失显著降低了肿瘤潜伏期，增加了肺转移率。tgf - β信号的缺失与肿瘤大小的增加和癌细胞存活率的提高显著相关。此外，我们观察到间质纤维血管的丰度和组成存在显著差异，并伴有T β RII(fI/fI)；PY；WC小鼠与T β RII（fI/fI）比较；PY控制。F4/80（+）细胞的募集与已知炎症基因（包括Cxcll、Cxcl5和Ptgs2（环氧化酶-2））的表达增加相关。值得注意的是，我们还在原代T β RII（fI/fI）、PY、PY中发现了丰富的K5(+) dNp63（+）细胞群。WC肿瘤和相应的肺转移，提示在这部分癌细胞中tgf - β信号的缺失可以促进转移。总之，我们目前的研究结果表明，乳腺肺泡祖细胞中tgf - β信号的缺失可能通过调节体内固有细胞信号和邻近基质-上皮相互作用来影响肿瘤的发生、进展和转移。
Transforming growth factor (TGF)-beta signaling has been associated with early tumor suppression and late tumor progression; however, many of the mechanisms that mediate these processes are not known. Using Cre/LoxP technology, with the whey acidic protein promoter driving transgenic expression of Cre recombinase (WAP-Cre), we have now ablated the type 11 TGF-beta receptor (T beta RII) expression specifically within mouse mammary alveolar progenitors. Transgenic expression of the polyoma virus middle T antigen, under control of the mouse mammary tumor virus enhancer/promoter, was used to produce mammary tumors in the absence or presence of Cre (T beta RII(fI/fI);PY and T beta RII(fI/fI);PY;WC, respectively). The loss of TGF-beta signaling significantly decreased tumor latency and increased the rate of pulmonary metastasis. The loss of TGF-beta signaling was significantly correlated with increased tumor size and enhanced carcinoma cell survival. In addition, we observed significant differences in stromal fibrovascular abundance and composition accompanied by increased recruitment of F4/80(+) cell populations in T beta RII(fI/fI);PY;WC mice when compared with T beta RII(fI/fI);PY controls. The recruitment of F4/80(+) cells correlated with increased expression of known inflammatory genes including Cxcll, Cxcl5, and Ptgs2 (cyclooxygenase-2). Notably, we also identified an enriched K5(+) dNp63(+) cell population in primary T beta RII(fI/fI);PY;WC tumors and corresponding pulmonary metastases, suggesting that loss of TGF-beta signaling in this subset of carcinoma cells can contribute to metastasis. Together, our current results indicate that loss of TGF-beta signaling in mammary alveolar progenitors may affect tumor initiation, progression, and metastasis through regulation of both intrinsic cell signaling and adjacent stromal-epithelial interactions in vivo.