The Role of TLR4 in Chemotherapy-Driven Metastasis.
The Role of TLR4 in Chemotherapy-Driven Metastasis.
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DOI：
10.1158/0008-5472.can-14-3525
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发表时间：
2015-06-15
期刊：
影响因子：
11.2
通讯作者：
Ran S
中科院分区：
文献类型：
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作者：
Ran S
肿瘤对细胞毒性药物的耐药性是成功治疗癌症的主要障碍之一。新出现的证据表明，从死亡和受损细胞释放的物质促进了化学抗性，这些物质激活了由Toll样受体4（TLR4）协调的宿主修复程序。TLR4通常在恶性和肿瘤浸润性免疫细胞中过表达。除了通过治疗诱导的肿瘤破坏释放的内源性配体之外，TLR 4还被紫杉醇直接激活，紫杉醇是针对各种人类癌症的最常用的化疗药物之一。TLR4激活促进局部和全身炎症，导致诱导多个回路，从而产生有利于局部复发和转移的再生环境。特别重要的是TLR4介导的来源于未成熟骨髓细胞的内皮祖细胞的募集。这些细胞在重建肿瘤相关的淋巴管和血管中起主要作用，从而促进淋巴和血行转移。后者进一步增强了转移前的小生境所产生的动员骨髓血管原细胞到远处的器官。本文综述了最近的证据表明，紫杉醇和其他临床使用的抗癌药物积极诱导转移，即使在缩小原发肿瘤。更好地理解TLR4依赖性化疗驱动转移的机制可能是克服癌症根除挑战的关键。
Tumor resistance to cytotoxic drugs is one of the main obstacles to successful cancer therapy. Emerging evidence suggests that chemoresistance is promoted by substances released from dead and damaged cells that activate the host repair program orchestrated by Toll-like receptor-4 (TLR4). TLR4 is often overexpressed in malignant and tumor infiltrating immune cells. In addition to endogenous ligands released by therapy-induced tumor destruction, TLR4 is directly activated by paclitaxel, one of the most commonly used chemotherapeutic drugs against various human cancers. TLR4 activation promotes local and systemic inflammation leading to induction of multiple circuits that create a regenerative environment favoring local recurrence and metastasis. Of particular importance is TLR4-mediated recruitment of endothelial progenitors derived from immature myeloid cells. These cells play a major role in rebuilding tumor-associated lymphatic and blood vessels thereby promoting lymphatic and hematogenous metastasis. The latter is further enhanced by the premetastatic niche generated by mobilization of myeloid provascular cells to distant organs. This review summarizes the recent evidence demonstrating that paclitaxel and other clinically used anticancer drugs actively induce metastasis even while shrinking the primary tumor. Better understanding of the mechanisms underlying TLR4 dependent chemotherapy-driven metastasis might be the key to overcoming challenges of cancer eradication.