Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis.
Breast cancer cells condition lymphatic endothelial cells within pre-metastatic niches to promote metastasis.
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DOI：
10.1038/ncomms5715
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发表时间：
2014-09-02
影响因子：
16.6
通讯作者：
Popel, Aleksander S.
中科院分区：
文献类型：
--
作者：
Lee, Esak;Fertig, Elana J.;Jin, Kideok;Sukumar, Saraswati;Pandey, Niranjan B.;Popel, Aleksander S.
乳腺癌转移除了血行播散外还涉及淋巴播散。虽然间质淋巴管（LV）作为最初的转移途径，器官驻留LV的作用研究不足。在这里，我们表明淋巴管内皮细胞（LECs）是转移前小生境中LV的组成部分，它受到三阴性乳腺癌（TNBC）细胞的调节，以加速转移。肺和淋巴结内的LEC，由肿瘤分泌因子调节，表达在正常LEC或癌细胞中不表达的CCL 5，并指导肿瘤扩散到这些组织中。此外，肿瘤调节的LEC促进这些器官中的血管生成，允许肿瘤外渗和定植。从机制上讲，肿瘤细胞分泌的IL 6导致LEC中的Stat 3磷酸化。该pStat 3诱导HIF-1α和VEGF，并且pStat 3-pc-Jun-pATF-2三元复合物诱导LEC中的CCL 5表达。这项研究证明了多种再利用药物的抗转移活性，阻断了乳腺癌细胞和LEC之间的自我增强旁分泌回路。
Breast cancer metastasis involves lymphatic dissemination in addition to hematogenous spreading. Although stromal lymphatic vessels (LVs) serve as initial metastatic routes, roles of organ-residing LVs are under-investigated. Here we show that lymphatic endothelial cells (LECs), a component of LVs within pre-metastatic niches, are conditioned by triple-negative breast cancer (TNBC) cells to accelerate metastasis. LECs within the lungs and lymph nodes, conditioned by tumor-secreted factors express CCL5 that is not expressed either in normal LECs or cancer cells, and direct tumor dissemination into these tissues. Moreover, tumor-conditioned LECs promote angiogenesis in these organs, allowing tumor extravasation and colonization. Mechanistically, tumor cell-secreted IL6 causes Stat3 phosphorylation in LECs. This pStat3 induces HIF-1α and VEGF, and a pStat3-pc-Jun-pATF-2 ternary complex induces CCL5 expression in LECs. This study demonstrates anti-metastatic activities of multiple repurposed drugs, blocking a self-reinforcing paracrine loop between breast cancer cells and LECs.
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DOI：
10.1186/bcr1026
发表时间：
2005
期刊：
Breast cancer research : BCR
影响因子：
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DOI：
10.1016/j.biocel.2011.08.020
发表时间：
2011-12-01
影响因子：
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作者：
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通讯作者：
Popel, Aleksander S.