Specific chemotherapeutic agents induce metastatic behaviour through stromal- and tumour-derived cytokine and angiogenic factor signalling
Specific chemotherapeutic agents induce metastatic behaviour through stromal- and tumour-derived cytokine and angiogenic factor signalling
复制标题
特定的化疗药物通过基质和肿瘤来源的细胞因子和血管生成因子信号传导诱导转移行为。
DOI：
10.1002/path.4564
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发表时间：
2015-10-01
影响因子：
7.3
通讯作者：
Luo, Yongzhang
中科院分区：
文献类型：
--
作者：
Liu, Guanghua;Chen, Yang;Luo, Yongzhang
最近的研究表明，化疗可通过宿主反应增强转移，如内皮细胞黏附分子表达增强和髓系细胞数量增加。然而，目前还不清楚肿瘤细胞是如何参与这一过程的。在这里，我们观察到紫杉醇和卡铂加速了荷瘤小鼠的肺转移，而阿霉素和氟尿嘧啶则没有。从机制上讲，紫杉醇和卡铂引起了类似的细胞因子和血管生成因子的变化。紫杉醇可使荷瘤小鼠血清或原发瘤组织中CXCR2、CXCR4、S1P/S1PR1、PlGF和PDGF-BB水平升高。卡铂还可提高血清中CXCL1、PDGF-BB水平和组织中CXCR4水平。而阿霉素和氟尿嘧啶则不能引起这种变化。化疗诱导的细胞因子和血管生成因子的变化也在化疗后患者的基因表达数据中得到证实。这些化疗增强的细胞因子和血管生成因子进一步诱导血管生成，破坏血管完整性，招募BMDCs到转移器官，并介导肿瘤细胞的增殖、迁移和上皮向间充质的转变。有趣的是，这些因子的抑制剂抑制了静脉注射B16F10-GFP细胞的荷瘤小鼠和正常小鼠的化疗促进的转移。特别是，阻断SDF-1-CXCR4和S1P-S1PR1轴不仅可以抑制化疗诱导的转移，而且可以分别延长33.9%和40.3%的中位生存期。本研究阐明了化疗诱导转移的机制，并通过联合抗细胞因子/抗血管生成治疗，为对抗化疗药物的促转移作用提供了新的治疗策略。版权所有(C)2015年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
Recent studies reveal that chemotherapy can enhance metastasis due to host responses, such as augmented expression of adhesion molecules in endothelial cells and increased populations of myeloid cells. However, it is still unclear how tumour cells contribute to this process. Here, we observed that paclitaxel and carboplatin accelerated lung metastasis in tumour-bearing mice, while doxorubicin and fluorouracil did not. Mechanistically, paclitaxel and carboplatin induced similar changes in cytokine and angiogenic factors. Increased levels of CXCR2, CXCR4, S1P/S1PR1, PlGF and PDGF-BB were identified in the serum or primary tumour tissues of tumour-bearing mice treated by paclitaxel. The serum levels of CXCL1 and PDGF-BB and the tissue level of CXCR4 were also elevated by carboplatin. On the other hand, doxorubicin and fluorouracil did not induce such changes. The chemotherapy-induced cytokine and angiogenic factor changes were also confirmed in gene expression datasets from human patients following chemotherapy treatment. These chemotherapy-enhanced cytokines and angiogenic factors further induced angiogenesis, destabilized vascular integrity, recruited BMDCs to metastatic organs and mediated the proliferation, migration and epithelial-to-mesenchymal transition of tumour cells. Interestingly, inhibitors of these factors counteracted chemotherapy-enhanced metastasis in both tumour-bearing mice and normal mice injected intravenously with B16F10-GFP cells. In particular, blockade of the SDF-1-CXCR4 or S1P-S1PR1 axes not only compromised chemotherapy-induced metastasis but also prolonged the median survival time by 33.9% and 40.3%, respectively. The current study delineates the mechanism of chemotherapy-induced metastasis and provides novel therapeutic strategies to counterbalance pro-metastatic effects of chemo-drugs via combination treatment with anti-cytokine/anti-angiogenic therapy. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.