Abstract
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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the main pathological type of pancreatic cancer, and it has a 5-year survival rate of ~ 6%1,2
It was recently reported that pancreatic Tumor-associated macrophages (TAMs) are primarily polarized M2 macrophages that are associated with cancer progression and metastasis[10,11]
Compared with M0 macrophages incubated with conditioned medium derived from si-NC pancreatic ductal adenocarcinoma (PDAC) cells, M0 macrophages incubated with conditioned medium derived from si-VCAM-1 PDAC cells or treated with quercetin alone had significantly lower mRNA level of CD206, CD163, fibronectin, CCL18, CCL22, and IL-10 and showed a markedly lower protein levels of CCL18, CCL22, and IL-10 (Fig. 6b–e)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the main pathological type of pancreatic cancer, and it has a 5-year survival rate of ~ 6%1,2. (see figure on previous page) Fig. 1 Differences and characterizations in mRNA expression profiles between pancreatic cancer cell line PANC-1-alone control groups (NPC groups) and the PANC-1-co-cultured TAMs groups (NPM groups). A Scatter plots are used to evaluate the difference in the expression of mRNAs between the NPC groups and the NPM groups. The middle green line refers to no difference between the two groups, and the flanking green lines represent twofold changes. B Box plots for the normalized gene expression data of the NPC groups and the NPM groups. The red points in plot represent the differentially expressed mRNAs with statistical significance. E Hierarchical cluster analysis of the top 30 up and downregulated mRNAs. Red and green colors represent up- and downregulated genes, respectively. Until now, the biological effects of TAMs on pancreatic cancer progression and metabolic dysregulation remain largely unknown
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