PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors
PLCγ contributes to metastasis of in situ-occurring mammary and prostate tumors
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DOI：
10.1038/sj.onc.1210115
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发表时间：
2007-05-10
期刊：
影响因子：
8
通讯作者：
Wells, A.
中科院分区：
文献类型：
--
作者：
Shepard, C. R.;Kassis, J.;Wells, A.
磷脂酶C-γ（PLC γ）与肿瘤细胞侵袭和转移所需的运动性有关。在异种移植模型中已经证明了肿瘤扩散的减少，但是缺乏对自然发生的肿瘤的研究，这受到干预时机的限制。因此，我们产生了表达PLC γ的多西环素（DOX）诱导型显性阴性片段PLC z的小鼠;这种方法避免了由于PLC γ的缺乏而引起的子宫内致死性。当我们靶向乳腺（MMT驱动的多瘤中T抗原模型，PyVmT）和前列腺（TRAMP模型）的两种新生癌时，我们通过从前列腺素C3启动子驱动DOX反式激活因子来限制这些上皮细胞的表达。这避免了可能消除基质和内皮细胞运动性的混杂变量。这些小鼠在DOX存在下正常发育，除了如果在6周龄之前治疗则乳房发育有限和如果在2周龄之前治疗则前列腺不成熟。在PyVmT小鼠中，DOX介导的8至16周龄的PLCz诱导使肺转移的数量减少> 10倍（P < 0.06），而对原位肿瘤细胞增殖或肿瘤大小没有可检测的影响。在表达PLCz片段的小鼠的TRAMP模型中，肺转移也显著减少（P < 0.05）。DOX治疗本身对对照小鼠的肿瘤大小或转移没有影响，也不影响非转基因小鼠的肿瘤传播。总之，废除PLC γ信号通路可以限制癌的转移潜力。
Phospholipase C-gamma ( PLC gamma) has been implicated in tumor cell motility required for invasiveness and metastasis. Diminished tumor dissemination has been demonstrated in xenograft models, but studies in naturally-occurring tumors are lacking, having been limited by the timing of the interventions. Therefore, we generated mice that express a doxycycline ( DOX)-inducible dominant-negative fragment of PLC gamma, PLCz; this approach avoids the in utero lethality caused by the absence of PLC gamma. As we targeted two de novo-occurring carcinomas of the mammary ( MMTV-driven polyoma middle T antigen model, PyVmT) and prostate ( TRAMP model) glands, we limited expression to these epithelial cells by driving DOX transactivator from the prostatein C3 promoter. This avoids the confounding variable of potentially abrogating motility in stromal and endothelial cells. These mice developed normally in the presence of DOX, except for limited mammary development if treated before 6 weeks and immaturity of the prostate gland if treated before 2 weeks of age. DOX-mediated induction of PLCz from age 8 to 16 weeks in PyVmT mice decreased the number of lung metastases by > 10-fold ( P < 0.06) without a detectable effect on in situ tumor cell proliferation or tumor size. Lung metastases were also significantly decreased in the TRAMP model in which the mice expressed the PLCz fragment ( P < 0.05). DOX treatment itself had no effect on tumor size or metastasis in control mice, nor did it affect tumor dissemination in nontransgenic littermates. In conclusion, abrogation of the PLC gamma signaling pathway can limit the metastatic potential of carcinomas.