CCL3–CCR5 axis contributes to progression of esophageal squamous cell carcinoma by promoting cell migration and invasion via Akt and ERK pathways

Abstract

Tumor-associated macrophages (TAMs) contribute to the progression and mortality of various malignancies. We reported that high numbers of infiltrating TAMs were significantly associated with tumor progression and poor prognosis in esophageal squamous cell carcinoma (ESCC). In our previous investigation of TAMs’ actions in ESCC, we compared gene expression profiles between peripheral blood monocyte (PBMo)-derived macrophages and TAM-like macrophages stimulated with conditioned media of ESCC cell lines. Among the upregulated genes in the TAM-like macrophages, we focused on CC chemokine ligand 3 ( CCL3 ), which was reported to contribute to tumor progression in several malignancies. Herein, we observed that not only TAMs but also ESCC cell lines expressed CCL3. A CCL3 receptor, CC chemokine receptor 5 (CCR5) was expressed in the ESCC cell lines. Treating the ESCC cell lines with recombinant human (rh)CCL3 induced the phosphorylations of Akt and ERK, which were suppressed by CCR5 knockdown. Migration and invasion of ESCC cells were promoted by treatment with rhCCL3 and co-culture with TAMs. TAMs/rhCCL3-promoted cell migration and invasion were suppressed by inhibition of the CCL3–CCR5 axis, PI3K/Akt, and MEK/ERK pathways. Treatment with rhCCL3 upregulated MMP2 and VEGFA expressions in ESCC cell lines. Our immunohistochemical analysis of 68 resected ESCC cases showed that high expression of CCL3 and/or CCR5 in ESCC tissues was associated with poor prognosis. High CCR5 expression was associated with deeper invasion, presence of vascular invasion, higher pathological stage, higher numbers of infiltrating CD204 + TAMs, and higher microvascular density. High expression of both CCL3 and CCR5 was an independent prognostic factor for disease-free survival. These results suggest that CCL3 derived from both TAMs and cancer cells contributes to the progression and poor prognosis of ESCC by promoting cell migration and invasion via the binding of CCR5 and the phosphorylations of Akt and ERK. The CCL3–CCR5 axis could become the target of new therapies against ESCC.

CC Chemokines in a Tumor: A Review of Pro-Cancer and Anti-Cancer Properties of Receptors CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10 Ligands

“…Their expression has been found in tumor-associated and cancer cells. In a tumor, they are produced by TAM [ 69 , 124 , 125 , 126 , 127 ], MDSC [ 68 ], and MSC [ 66 ], which promotes tumor growth. The expression of CCL4 may also occur in tumor-associated neutrophils (TAN) [ 128 ].…”

“…The expression of CCL4 may also occur in tumor-associated neutrophils (TAN) [ 128 ]. CCL3 may be expressed in a cancer cell [ 127 ]. The immune response reduces the expression of CCL3 in cancer cells via the activation of β-catenin [ 129 ].…”

“…CCL3 causes migration and invasion of cancer cells via CCR5 [ 124 , 127 , 144 ]. This is related, among other things, to the activation of PI3K→Akt/PKB and ERK MAPK pathways [ 127 ]. Both CCL3 and CCL4 may also participate in metastasis.…”

“…CCL3 and CCL4 also indirectly cause angiogenesis. CCL3 [ 127 , 155 ] and CCL4 [ 156 ] cause increased expression of VEGF in a cancer cell, a growth factor causing angiogenesis. CCL4 also increases the expression of VEGF-C in a cancer cell, which leads to lymphangiogenesis and lymph node metastasis [ 157 ].…”

Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor–A Literature Review

“…Chemokines are also crucial for the migration, invasion, and metastasis of cancer cells [3]. An important function of chemokines in cancer is to support the course of angiogenesis [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and lymphangiogenesis [15,[20][21][22][23][24]. Another important role of chemokines in cancer processes is the recruitment of cells to a cancer niche, in particular cancer-associated fibroblasts (CAF) [25,26], eosinophils [27][28][29], regulatory T cells (Treg) [30][31][32][33][34], T helper type 17 (Th17) [35][36][37], tumor-associated neutrophils (TAN) [38], tumor-associated macrophages (TAM) [11,[39][40][41][42][43][44][45][46][47]…”