Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Department of Pancreatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China.
Cell Death Dis. 2018 May 1;9(5):453. doi: 10.1038/s41419-018-0486-0.
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 cells in 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.
肿瘤相关巨噬细胞（TAMs）常存在于胰腺癌细胞附近，但尚不清楚其是否参与胰腺癌的进展和瓦博格效应。在这里，我们表明 TAMs 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 CCL18 通过旁分泌诱导了胰腺癌细胞中 VCAM-1 的表达。相反，VCAM-1 诱导增强有氧糖酵解的胰腺癌细胞产生的乳酸会激活巨噬细胞向 TAM 样表型转化，形成正反馈回路。研究发现 VCAM-1 在人胰腺导管腺癌（PDAC）组织和细胞系中高度表达，与疾病进展相关，并可预测 PDAC 患者的临床预后。流式细胞术分析进一步表明，VCAM-1 下调诱导 PDAC 细胞在 G0/G1 期积累，同时 S 期显著减少。VCAM-1 下调显著抑制 PDAC 细胞在体外的增殖、集落形成、迁移和侵袭，而 VCAM-1 的异位表达则产生相反的效果。VCAM-1 可能通过与受体相互作用将 THP-1 单核细胞锚定在癌细胞上，为浸润白细胞丰富的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模型中的肿瘤生长。特别是，我们的研究结果强调了 VCAM-1 对 PDAC 细胞中瓦博格效应维持的贡献。最后，我们研究了人 PDAC 标本中 CCL18 和 VCAM-1 的临床相关性。总之，这些发现表明 CCL18/PITPNM3/NF-κB/VCAM-1 调控网络可能为 PDAC 提供一种新的潜在治疗策略。
