The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression.
The role of proto-oncogene Fra-1 in remodeling the tumor microenvironment in support of breast tumor cell invasion and progression.
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DOI：
10.1038/onc.2009.308
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发表时间：
2010-02-04
期刊：
影响因子：
8
通讯作者：
Reisfeld, R. A.
中科院分区：
文献类型：
--
作者：
Luo, Y. P.;Zhou, H.;Krueger, J.;Kaplan, C.;Liao, D.;Markowitz, D.;Liu, C.;Chen, T.;Chuang, T-H;Xiang, R.;Reisfeld, R. A.
越来越多的证据表明，肿瘤微环境（TME）中肿瘤细胞和肿瘤相关巨噬细胞（tam）之间的相互作用对促进肿瘤细胞的侵袭和进展至关重要。巨噬细胞在这些过程中发挥着不明确的作用，因为M1表型与肿瘤杀伤能力相关，而M2表型的tam则发挥促肿瘤作用。在这里，我们提供的证据表明，小鼠乳腺肿瘤细胞与tam之间的相互作用重塑了TME，导致FOS转录因子家族成员Fra-1的上调。反过来，这个原癌基因启动IL-6/JAK/Stat3信号通路的激活。这在乳腺肿瘤细胞中产生了恶性转换，导致肿瘤细胞中促血管生成因子MMP-9、VEGF和TGF-β的释放增加，加剧了乳腺癌的侵袭和进展。在小鼠乳腺癌模型中，通过siRNA特异性敲低Fra-1，可以显著抑制肿瘤细胞的侵袭、血管生成和转移，从而证实转录因子Fra-1在调节这些过程中发挥关键作用的概念。这种策略最终可能导致转移性乳腺癌的有效治疗。
A growing body of evidence indicates that interactions between neoplastic cells and tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are crucial in promoting tumor cell invasion and progression. Macrophages play an ambiguous role in these processes since this M1 phenotype correlates with tumoricidal capacity whereas TAMs of M2 phenotype exert tumor-promoting effects. Here, we provide evidence that interactions between mouse breast tumor cells and TAMs remodel the TME, leading to upregulation of Fra-1, a member of the FOS family of transcription factor. In turn, this proto-oncogene initiates activation of the IL-6/JAK/Stat3 signaling pathway. This creates a malignant switch in breast tumor cells, leading to increased release of pro-angiogenic factors MMP-9, VEGF and TGF-β from tumor cells and intensified invasion and progression of breast cancer. Proof of concept for the crucial role played by transcription factor Fra-1 in regulating these processes was established by specific knockdown of Fra-1 with siRNA which resulted in marked suppression of tumor cell invasion, angiogenesis and metastasis in a mouse breast cancer model. Such a strategy could eventually lead to future efficacious treatments of metastatic breast cancer.
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影响因子：
20.3
作者：
FRASER, CC;CHEN, BP;KRAAL, G
通讯作者：
KRAAL, G
影响因子：
6.6
作者：
Lin, Elaine Y.;Li, Jiu-feng;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.
影响因子：
15.9
作者：
Gao, Sizhi Paul;Mark, Kevin G.;Bromberg, Jacqueline F.
通讯作者：
Bromberg, Jacqueline F.
影响因子：
3.1
作者：
Martinez, Fernando Oneissi;Sica, Antonio;Locati, Massimo
通讯作者：
Locati, Massimo
影响因子：
21.3
作者：
Hiratsuka, Sachie;Watanabe, Akira;Maru, Yoshiro
通讯作者：
Maru, Yoshiro