CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells.
CCL2 mediates cross-talk between cancer cells and stromal fibroblasts that regulates breast cancer stem cells.
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CCL2 介导癌细胞和基质成纤维细胞之间的串扰，从而调节乳腺癌干细胞。
DOI：
10.1158/0008-5472.can-11-3567
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发表时间：
2012-06-01
期刊：
影响因子：
11.2
通讯作者：
Wang SE
中科院分区：
文献类型：
--
作者：
Tsuyada A;Chow A;Wu J;Somlo G;Chu P;Loera S;Luu T;Li AX;Wu X;Ye W;Chen S;Zhou W;Yu Y;Wang YZ;Ren X;Li H;Scherle P;Kuroki Y;Wang SE
肿瘤干细胞(CSC)在肿瘤的发生、发展和治疗难治中起着关键作用。尽管许多研究都集中在干性相关的基因和途径上，但对肿瘤微环境中调控CSCs的因素的表征还很缺乏。在这项研究中，我们研究了间质成纤维细胞对乳腺癌干细胞的影响。我们发现，与正常成纤维细胞相比，原代肿瘤相关成纤维细胞(CAF)和共培养的乳腺癌细胞激活的成纤维细胞产生更高水平的趋化因子(C-C基序)配体2(CCL2)，它刺激乳腺癌细胞中干细胞特异性的球状形成表型和CSC的自我更新。在活化的成纤维细胞中，CCL2的表达增加需要多种乳腺癌分泌的细胞因子激活STAT3，进而诱导乳腺癌细胞中NOTCH1的表达和CSC特征，构成癌症-间质-癌症信号通路。在成对成纤维细胞和乳腺癌细胞的异种移植模型中，CCL2的丢失显著抑制了肿瘤的形成和NOTCH1的表达。此外，NOTCH1和CCL2的上调与原发乳腺癌的低分化有关，进一步支持了NOTCH1受CCL2调控的观察结果。因此，我们的研究结果表明，CCL2是一个潜在的治疗靶点，可以阻断促使CSC介导的疾病进展的癌症-宿主沟通。
Cancer stem cells (CSC) play critical roles in cancer initiation, progression, and therapeutic refractoriness. Although many studies have focused on the genes and pathways involved in stemness, characterization of the factors in the tumor microenvironment that regulate CSCs is lacking. In this study, we investigated the effects of stromal fibroblasts on breast cancer stem cells. We found that compared with normal fibroblasts, primary cancer-associated fibroblasts (CAF) and fibroblasts activated by cocultured breast cancer cells produce higher levels of chemokine (C-C motif) ligand 2 (CCL2), which stimulates the stem cell-specific, sphere-forming phenotype in breast cancer cells and CSC self-renewal. Increased CCL2 expression in activated fibroblasts required STAT3 activation by diverse breast cancer-secreted cytokines, and in turn, induced NOTCH1 expression and the CSC features in breast cancer cells, constituting a cancer-stroma-cancer signaling circuit. In a xenograft model of paired fibroblasts and breast cancer tumor cells, loss of CCL2 significantly inhibited tumorigenesis and NOTCH1 expression. In addition, upregulation of both NOTCH1 and CCL2 was associated with poor differentiation in primary breast cancers, further supporting the observation that NOTCH1 is regulated by CCL2. Our findings therefore suggest that CCL2 represents a potential therapeutic target that can block the cancer-host communication that prompts CSC-mediated disease progression.