Increased malignancy of neu-induced mammary tumors overexpressing active transforming growth factor β1
Increased malignancy of neu-induced mammary tumors overexpressing active transforming growth factor β1
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DOI：
10.1128/mcb.23.23.8691-8703.2003
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发表时间：
2003-12-01
影响因子：
5.3
通讯作者：
Arteaga, CL
中科院分区：
文献类型：
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作者：
Muraoka, RS;Koh, Y;Arteaga, CL
为了确定Neu是否比转化生长因子β（TGF-β）占优势，我们将小鼠乳腺肿瘤病毒（MMTV）-Neu小鼠与乳腺中表达活性TGF-β 1的MMTV-TGF-β（S223/225）小鼠杂交。Bigenic（NT）和Neu-induced乳腺肿瘤具有相似的潜伏期。双基因肿瘤及其转移的增殖性低于MMTV-Neu小鼠。然而，NT肿瘤表现出较少的细胞凋亡，更多的局部浸润性和较高的组织学分级。NT小鼠比Neu小鼠表现出更多的循环肿瘤细胞和肺转移，而NT肿瘤含有更高水平的磷酸化（活性）Smad 2，Akt，丝裂原活化蛋白激酶（MAPK）和p38，以及波形蛋白含量和Rac 1活性比肿瘤表达单独的Neu。离体培养的NT细胞中P-Akt和P-MAPK的表达水平高于Neu细胞。这些被TGF-β受体可溶性TGF-β II型受体（TbetaRII：Fc）抑制，表明它们被自分泌TGF-β激活。TGF-β刺激Neu细胞向周围基质的迁移，而可溶性TGF-β抑制剂废除NT细胞的运动性和侵袭性。这些数据表明，（i）TGF-β的抗有丝分裂和促转移作用可以同时存在，（ii）Neu不会消除TGF-β介导的抗增殖作用，但可以与TGF-β协同加速转移性肿瘤进展。
To determine if Neu is dominant over transforming growth factor beta (TGF-beta), we crossed mouse mammary tumor virus (MMTV)-Neu mice with MMTV-TGF-beta(S223/225) mice expressing active TGF-beta1 in the mammary gland. Bigenic (NT) and Neu-induced mammary tumors developed with a similar latency. The bigenic tumors and their metastases were less proliferative than those occurring in MMTV-Neu mice. However, NT tumors exhibited less apoptosis and were more locally invasive and of higher histological grade. NT mice exhibited more circulating tumor cells and lung metastases than Neu mice, while NT tumors contained higher levels of phosphorylated (active) Smad2, Akt, mitogen-activated protein kinase (MAPK), and p38, as well as vimentin content and Rac1 activity in situ than tumors expressing Neu alone. Ex vivo, NT cells exhibited higher levels of P-Akt and P-MAPK than Neu cells. These were inhibited by the TGF-beta inhibitor-soluble TGF-beta type II receptor (TbetaRII:Fc), suggesting they were activated by autocrine TGF-beta. TGF-beta stimulated migration of Neu cells into surrounding matrix, while the soluble TGF-beta inhibitor abrogated motility and invasiveness of NT cells. These data suggest that (i) the antimitogenic and prometastatic effects of TGF-beta can exist simultaneously and (ii) Neu does not abrogate TGF-beta-mediated antiproliferative action but can synergize with TGF-beta in accelerating metastatic tumor progression.