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调节性 T 细胞（Tregs）在淋巴结中分泌的 TGF-β1 通过上调 IL-17RB 促进乳腺癌恶性进展。

TGF-β1 secreted by Tregs in lymph nodes promotes breast cancer malignancy via up-regulation of IL-17RB.

机构信息

Genomics Research Center, Academia Sinica, Taipei, Taiwan.

Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.

出版信息

EMBO Mol Med. 2017 Dec;9(12):1660-1680. doi: 10.15252/emmm.201606914.

DOI:10.15252/emmm.201606914
PMID:28993429
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5709760/
Abstract

Lymph node (LN) metastasis is commonly associated with systemic distant organ metastasis in human breast cancer and is an important prognostic predictor for survival of breast cancer patients. However, whether tumor-draining LNs (TDLNs) play a significant role in modulating the malignancy of cancer cells for distant metastasis remains controversial. Using a syngeneic mouse mammary tumor model, we found that breast tumor cells derived from TDLN have higher malignancy and removal of TDLNs significantly reduced distant metastasis. Up-regulation of oncogenic Il-17rb in cancer cells derived from TDLNs contributes to their malignancy. TGF-β1 secreted from regulatory T cells (Tregs) in the TDLNs mediated the up-regulation of Il-17rb through downstream Smad2/3/4 signaling. These phenotypes can be abolished by TGF-β1 neutralization or depletion of Tregs. Consistently, clinical data showed that the up-regulation of IL-17RB in cancer cells from LN metastases correlated with the increased prevalence of Tregs as well as the aggressive growth of tumors in mouse xenograft assay. Together, these results indicate that Tregs in TDLNs play an important role in modulating the malignancy of breast cancer cells for distant metastasis. Blocking IL-17RB expression could therefore be a potential approach to curb the process.

摘要

淋巴结（LN）转移通常与人类乳腺癌的全身远处器官转移相关，是乳腺癌患者生存的重要预后预测因子。然而，肿瘤引流淋巴结（TDLNs）是否在调节远处转移的癌细胞恶性方面发挥重要作用仍存在争议。我们使用同种小鼠乳腺肿瘤模型发现，源自 TDLN 的乳腺肿瘤细胞具有更高的恶性，并且去除 TDLN 可显著降低远处转移。源自 TDLN 的肿瘤细胞中癌基因 Il-17rb 的上调有助于其恶性。TDLNs 中的调节性 T 细胞（Tregs）分泌的 TGF-β1 通过下游 Smad2/3/4 信号传导介导 Il-17rb 的上调。这些表型可以通过 TGF-β1 中和或 Treg 耗竭来消除。一致地，临床数据表明，来自淋巴结转移的癌细胞中 IL-17RB 的上调与 Tregs 的增加以及在小鼠异种移植模型中肿瘤的侵袭性生长相关。总之，这些结果表明 TDLNs 中的 Tregs 在调节乳腺癌细胞的远处转移恶性方面发挥重要作用。因此，阻断 IL-17RB 的表达可能是抑制该过程的一种潜在方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a81a/5709760/c33f162e6662/EMMM-9-1660-g015.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a81a/5709760/8bf23f01a6e5/EMMM-9-1660-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a81a/5709760/d131c2697341/EMMM-9-1660-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a81a/5709760/7bd5677a749a/EMMM-9-1660-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a81a/5709760/855fcbd0e41f/EMMM-9-1660-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a81a/5709760/8bf23f01a6e5/EMMM-9-1660-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a81a/5709760/c912939143ca/EMMM-9-1660-g012.jpg
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