Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling.
Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling.
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DOI：
10.1038/nature09707
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发表时间：
2011-02-24
期刊：
影响因子：
64.8
通讯作者：
Karin, Michael
中科院分区：
文献类型：
--
作者：
Tan, Wei;Zhang, Weizhou;Strasner, Amy;Grivennikov, Sergei;Cheng, Jin Q.;Hoffman, Robert M.;Karin, Michael
炎症机制影响肿瘤发展和转移进展。感兴趣的是这些机制在肿瘤转移扩散中的作用，这些肿瘤的病因不涉及预先存在的炎症或感染，例如乳腺癌和前列腺癌。我们发现前列腺癌转移与淋巴细胞浸润进展期肿瘤和肿瘤坏死因子（TNF）家族成员NF-κB受体激活因子（RANK）配体（RANKL）和光敏素（LT）表达升高相关。但RANKL的来源及其在肿瘤转移中的作用尚不明确。RANKL及其受体RANK通过激活IκB激酶α（IKKα，一种乳腺癌祖细胞自我更新和前列腺癌转移所需的蛋白激酶）控制妊娠期间乳腺小叶肺泡细胞的增殖。因此，我们研究了RANKL、RANK和IKKα是否也参与乳腺癌/乳腺癌转移。事实上，过度表达ErbB 2（c-Neu）原癌基因（在转移性人乳腺癌中经常扩增）的乳腺癌细胞中的RANK信号传导对肺转移很重要。ErbB 2转化的癌细胞的转移扩散也依赖于CD 4 + CD 25 + T细胞，其主要的促转移功能似乎是RANKL的产生。产生RANKL的T细胞主要是FoxP 3+，并在小鼠和人乳腺癌中发现与平滑肌肌动蛋白（SMA）阳性基质细胞非常接近。肺转移的T细胞依赖性被外源性RANKL给药所取代，这一过程也刺激了RANK阳性人乳腺癌细胞的肺转移。这些结果与肿瘤浸润性CD 4+或FoxP 3 + T细胞对人乳腺癌的不良预后影响一致，并表明RANKL-RANK信号转导靶向可与其他治疗联合使用，以预防后续转移性疾病。
Inflammatory mechanisms influence tumor development and metastatic progression. Of interest is the role of such mechanisms in metastatic spread of tumors whose etiology does not involve pre-existing inflammation or infection, such as breast and prostate cancers. We found that prostate cancer metastasis is associated with lymphocyte infiltration into advanced tumors and elevated expression of the tumor necrosis factor (TNF) family members receptor activator of NF-κB (RANK) ligand (RANKL) and lymphotoxin (LT). But the source of RANKL and its role in metastasis were not established. RANKL and its receptor RANK control proliferation of mammary lobuloalveolar cells during pregnancy through activation of IκB kinase α (IKKα), a protein kinase that is required for self-renewal of mammary cancer progenitors and prostate cancer metastasis. We therefore examined whether RANKL, RANK and IKKα are also involved in mammary/breast cancer metastasis. Indeed, RANK signaling in mammary carcinoma cells that overexpress the ErbB2 (c-Neu) proto-oncogene, which is frequently amplified in metastatic human breast cancers, was important for pulmonary metastasis. Metastatic spread of ErbB2-transformed carcinoma cells was also dependent on CD4+CD25+ T cells, whose major pro-metastatic function appeared to be RANKL production. RANKL-producing T cells were mainly FoxP3+ and found in close proximity to smooth muscle actin (SMA)-positive stromal cells in mouse and human breast cancers. The T cell-dependence of pulmonary metastasis was replaced by administration of exogenous RANKL, a procedure that also stimulated pulmonary metastasis of RANK-positive human breast carcinoma cells. These results are consistent with the adverse prognostic impact of tumor-infiltrating CD4+ or FoxP3+ T cells on human breast cancer and suggest that targeting of RANKL-RANK signaling can be used in conjunction with other therapies to prevent subsequent metastatic disease.
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DOI：
10.1084/jem.20042167
发表时间：
2005-05-16
期刊：
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影响因子：
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