Live imaging of tumor initiation in zebrafish larvae reveals a trophic role for leukocyte-derived PGE₂.
Live imaging of tumor initiation in zebrafish larvae reveals a trophic role for leukocyte-derived PGE₂.
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DOI：
10.1016/j.cub.2012.05.010
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发表时间：
2012-07-10
期刊：
影响因子：
9.2
通讯作者：
Martin, Paul
中科院分区：
文献类型：
--
作者：
Feng, Yi;Renshaw, Stephen;Martin, Paul
流行病学研究和临床试验表明，使用包括阿司匹林在内的非甾体抗炎药（NSAIDs）能够显著降低许多癌症的发病率以及相关死亡率，并且肿瘤微环境中COX2 - PGE2通路的上调可能推动癌症进展的多个方面。基于这些原因，COX阻断与癌症预防相关的机制长期以来一直是一个活跃的研究领域。在致癌过程中，恶性上皮细胞以及包括巨噬细胞在内的肿瘤相关基质细胞都会表达COX - 2，但有观察发现，如果从受孕开始对APCmin/+小鼠进行治疗，NSAIDs在癌症预防方面最为有效，这表明COX - 2/PGE2通路在肿瘤发展的最早阶段可能也至关重要。在这项研究中，我们利用斑马鱼幼体的透明性和遗传可操作性来研究在癌症起始阶段（当转化细胞首次在组织中出现时）炎症细胞的参与情况。我们之前已经表明，先天免疫细胞为早期转化细胞提供增殖信号，并且通过使用互补的药理学和遗传学实验，我们现在表明前列腺素E2（PGE2）是这种转化细胞扩增所必需的营养信号。我们在癌症起始这些早期阶段的体内观察为为什么长期使用低剂量的NSAIDs（包括阿司匹林）可能会减少癌症发病提供了一种潜在的机制解释。
►在斑马鱼幼体中，COX - 2抑制阻止了Ras转化细胞的早期生长
►中性粒细胞和巨噬细胞都对转化细胞的营养支持有贡献
►dmPGE2处理在白细胞耗竭后挽救了转化细胞的生长
►炎症衍生的PGE2可能是NSAIDs/阿司匹林预防癌症的一个靶点
Epidemiology studies and clinical trials have suggested that the use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, can significantly reduce the incidence of and mortality associated with many cancers, and upregulation of the COX2-PGE2 pathway in tumor microenvironments might drive several aspects of cancer progression. For these reasons, the mechanisms linking COX blockade and cancer prevention have long been an area of active investigation. During carcinogenesis, COX-2 is expressed both by malignant epithelial cells and by tumor-associated stromal cells, including macrophages, but the observation that NSAIDs are most effective in cancer prevention in APCmin/+ mice if the mice are treated from conception suggests that the COX-2/PGE2 pathway might also be critical at the earliest stages of tumor development. In this study we take advantage of the translucency and genetic tractability of zebrafish larvae to investigate the involvement of inflammatory cells at cancer initiation, when transformed cells first arise in tissues. We previously showed that innate immune cells supply early transformed cells with proliferative cues and, by using complementary pharmacological and genetic experiments, we now show that prostaglandin E2 (PGE2) is the trophic signal required for this expansion of transformed cells. Our in vivo observations at these early stages of cancer initiation provide a potential mechanistic explanation for why long-term use of low doses of NSAIDs, including aspirin, might reduce cancer onset. ►COX-2 inhibition halts early growth of Ras-transformed cells in zebrafish larvae ► Both neutrophils and macrophages contribute to trophic support of transformed cells ► dmPGE2 treatment rescues growth of transformed cells after leukocyte depletion ► Inflammation-derived PGE2 could be a target for cancer prevention by NSAIDs/aspirin
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影响因子：
9.8
作者：
Ruder, Elizabeth H.;Laiyemo, Adeyinka O.;Graubard, Barry I.;Hollenbeck, Albert R.;Schatzkin, Arthur;Cross, Amanda J.
通讯作者：
Cross, Amanda J.
DOI：
10.1073/pnas.112217799
发表时间：
2002-06-11
影响因子：
11.1
作者：
Grosser, T;Yusuff, S;FitzGerald, GA
通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
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影响因子：
7.3
作者：
Elder, DJE;Baker, JA;Paraskeva, C
通讯作者：
Paraskeva, C
影响因子：
10.5
作者：
Cha, YI;Kim, SH;DuBois, RN
通讯作者：
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