Arg/Abl2 promotes invasion and attenuates proliferation of breast cancer in vivo.
Arg/Abl2 promotes invasion and attenuates proliferation of breast cancer in vivo.
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DOI：
10.1038/onc.2012.284
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发表时间：
2013-05-23
期刊：
影响因子：
8
通讯作者：
Koleske, A. J.
中科院分区：
文献类型：
--
作者：
Gil-Henn, H.;Patsialou, A.;Wang, Y.;Warren, M. S.;Condeelis, J. S.;Koleske, A. J.
肿瘤进展是一个复杂的多步骤过程，涉及遗传畸变的积累和基因表达模式的改变，导致不受控制的细胞分裂，侵入周围组织，最终扩散和转移。我们先前已经表明，Arg/Arg 2非受体酪氨酸激酶在EGF受体和Src酪氨酸激酶的下游起作用，以促进乳腺癌细胞中的侵袭功能，从而促进其侵袭性。然而，精氨酸是否以及如何有助于肿瘤的发展和传播，在体内从来没有调查。使用小鼠异种移植模型，我们表明，敲低乳腺癌细胞中的精氨酸导致肿瘤细胞增殖增加和肿瘤大小显着扩大。尽管具有较大的肿瘤，但Arg敲除荷瘤小鼠表现出肿瘤细胞侵袭、血管内渗和自发转移至肺的显著减少。有趣的是，我们发现在Arg敲低的乳腺癌细胞中，Ras-MAPK通路中的增殖相关基因上调，Ras-MAPK信号传导也是如此，而侵袭相关基因则显著下调。这些数据表明，精氨酸促进肿瘤细胞的侵袭和扩散，同时抑制肿瘤生长。我们认为Arg在转移性癌细胞中起着开关的作用，它决定着“生长或消失”（分裂或入侵）。
Tumor progression is a complex, multistep process involving accumulation of genetic aberrations and alterations in gene-expression patterns leading to uncontrolled cell division, invasion into surrounding tissue and finally dissemination and metastasis. We have previously shown that the Arg/Abl2 non-receptor tyrosine kinase acts downstream of the EGF receptor and Src tyrosine kinases to promote invadopodium function in breast cancer cells, thereby promoting their invasiveness. However, whether and how Arg contributes to tumor development and dissemination in vivo has never been investigated. Using a mouse xenograft model, we show that knocking down Arg in breast cancer cells leads to increased tumor cell proliferation and significantly enlarged tumor size. Despite having larger tumors, the Arg knockdown tumor-bearing mice exhibit significant reductions in tumor cell invasion, intravasation into blood vessels, and spontaneous metastasis to lungs. Interestingly, we found that proliferation-associated genes in the Ras-MAPK pathway are upregulated in Arg-knockdown breast cancer cells, as is Ras-MAPK signaling, while invasion-associated genes are significantly downregulated. These data suggest that Arg promotes tumor cell invasion and dissemination, while simultaneously inhibiting tumor growth. We propose that Arg acts as a switch in metastatic cancer cells that governs the decision to “grow or go” (divide or invade).
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