Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma.
Tumor-associated macrophages promote progression and the Warburg effect via CCL18/NF-kB/VCAM-1 pathway in pancreatic ductal adenocarcinoma.
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肿瘤相关巨噬细胞通过 CCL18/NF-kB/VCAM-1 通路促进胰腺导管腺癌的进展和 Warburg 效应
DOI：
10.1038/s41419-018-0486-0
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发表时间：
2018-05-01
影响因子：
9
通讯作者：
Chen R
中科院分区：
文献类型：
--
作者：
Ye H;Zhou Q;Zheng S;Li G;Lin Q;Wei L;Fu Z;Zhang B;Liu Y;Li Z;Chen R
肿瘤相关巨噬细胞（tumor associated macrophages, tam）常见于胰腺癌细胞附近，但尚不清楚它们是否参与胰腺癌的进展和Warburg效应。在这里，我们发现tam分泌的CCL18促进了胰腺癌的恶性进展并诱导了糖酵解表型，部分原因是胰腺癌细胞中VCAM-1的旁分泌诱导。反过来，vcam -1诱导的胰腺癌细胞乳酸生成与增强的有氧糖酵解激活巨噬细胞到tam样表型，形成一个正反馈回路。研究发现，VCAM-1在人类胰腺导管腺癌（PDAC）组织和细胞系中高度表达，并与PDAC患者的疾病进展相关，并预测临床结果。流式细胞术分析进一步表明，VCAM-1下调诱导PDAC细胞在G0/G1期聚集，S期明显减少。下调VCAM-1可显著抑制PDAC细胞的增殖、集落形成、迁移和侵袭，而异位表达VCAM-1则具有相反的作用。胰腺癌细胞上的VCAM-1可能通过反受体相互作用将THP-1单核细胞束缚在癌细胞上，为浸润富白细胞微环境的胰腺癌细胞提供生存优势。此外，下调VCAM-1可抑制小鼠异种移植瘤模型的肿瘤生长。特别是，我们的研究结果强调了VCAM-1对维持PDAC细胞中的Warburg效应的贡献。最后，我们研究了CCL18和VCAM-1在人类PDAC标本中的临床相关性。综上所述，这些发现表明CCL18/PITPNM3/NF-kB/VCAM-1调控网络可能为PDAC提供一种潜在的新治疗策略。
Tumor-associated macrophages (TAMs) are frequently found near pancreatic cancer cells, but it is uncertain whether they are involved in pancreatic cancer progression and the Warburg effect. Here, we show that CCL18 secreted by TAMs facilitates malignant progression and induced a glycolytic phenotype in pancreatic cancer, partially owing to paracrine induction of VCAM-1 in pancreatic cancer cells. Reciprocally, VCAM-1-induced lactate production from pancreatic cancer cells with enhanced aerobic glycolysis activates macrophages to a TAM-like phenotype, forming a positive feedback loop. VCAM-1 was found to be highly expressed in human pancreatic ductal adenocarcinoma (PDAC) tissues and cell lines, and is associated with disease progression and predicts clinical outcome in PDAC patients. Flow cytometry analysis further demonstrated that VCAM-1 downregulation induced an accumulation of PDAC cells in G0/G1 phase, accompanied by a significant decrease in S phase. Downregulation of VCAM-1 significantly inhibited proliferation, colony formation, migration, and invasion of PDAC cellsin vitro, whereas the ectopic expression of VCAM-1 had the opposite effect. VCAM-1 on pancreatic cancer cells might tethers THP-1 monocytes to cancer cells via counter–receptor interaction, providing a survival advantage to pancreatic cancer cells that infiltrate leukocyte-rich microenvironments. Furthermore, downregulation of VCAM-1 could repress tumor growth in mouse xenograft models. In particular, our results highlighted the contribution of VCAM-1 to the maintenance of the Warburg effect in PDAC cells. Finally, we investigated the clinical correlations of CCL18 and VCAM-1 in human PDAC specimens. In summary, these findings indicate that the CCL18/PITPNM3/NF-kB/VCAM-1 regulatory network might provide a potential new therapeutic strategy for PDAC.
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影响因子：
4.3
作者：
Ding, YB;Chen, GY;Yang, L
通讯作者：
Yang, L
间充质样癌细胞和巨噬细胞之间的正反馈回路对于乳腺癌转移至关重要。
影响因子：
50.3
作者：
Su, Shicheng;Liu, Qiang;Song, Erwei
通讯作者：
Song, Erwei
DOI：
10.1073/pnas.1219555110
发表时间：
2013-03-05
影响因子：
11.1
作者：
Guillaumond, Fabienne;Leca, Julie;Vasseur, Sophie
通讯作者：
Vasseur, Sophie
影响因子：
50.3
作者：
Chen Q;Zhang XH;Massagué J
通讯作者：
Massagué J
影响因子：
64.5
作者：
Qian BZ;Pollard JW
通讯作者：
Pollard JW