c‐Met identifies a population of matrix metalloproteinase 9‐producing monocytes in peritumoural stroma of hepatocellular carcinoma

Abstract

Macrophages (Mϕ) are prominent components of solid tumours and exhibit distinct phenotypes in different microenvironments. Previously, we found that tumours could alter the normal developmental process of Mϕ to trigger transient activation of monocytes in the peritumoural stroma of human hepatocellular carcinoma (HCC). In the present study, we showed that a fraction of monocytes in the peritumoural stroma, but not in HCC cancer nests, expressed surface c-Met molecules. Monocytes exposed to tumours strongly expressed c-Met proteins with kinetics similar to their activation status, and significant correlations were found between c-Met levels and HLA-DR expression on tumour-infiltrating monocytes. NF-κB-mediated autocrine TNF-α stimulated the expression of c-Met on activated monocytes, and by interacting with its ligand hepatocyte growth factor (HGF), c-Met increased the motility and matrix metalloproteinase (MMP) 9-producing capacity of tumour-associated monocytes. The intensity of c-Met expression on tumour-infiltrating monocytes was associated with high mortality and reduced survival of patients with HCC. Therefore, the expression of c-Met on activated monocytes/Mϕ may represent a novel mechanism by which a tumour actively and precisely regulates the distribution and functions of these cells to facilitate disease progression.

CD169 identifies an anti-tumour macrophage subpopulation in human hepatocellular carcinoma

“…For example, we previously identified a c‐Met + monocyte population that accumulated in the peri‐tumoural stroma of HCC. These cells could facilitate disease progression by producing large amounts of MMP‐9 after they interacted with environmental HGF . In the present study, we newly defined a population of Mϕ, CD169 + Mϕ, which accumulated in non‐tumour areas of HCC tissues.…”

“…Mφ are highly plastic, which allows them to interpret the complex and even contradictory signals that can be present in the tumour stroma [13]. Although classically activated Mφ can suppress tumour initiation by acting as both antigen-presenting cells (APCs) and effector cells, tumour-associated Mφ act to facilitate tumour progression via diverse mechanisms [14][15][16][17][18][19][20][21]. For example, our recent studies showed that intra-tumoural interleukin (IL)-10 + Mφ could induce immune tolerance, whereas peri-tumoural PD-L1 + monocytes/Mφ could attenuate anti-tumour immune responses and promote angiogenesis in human hepatocellular carcinoma (HCC) patients [17][18][19][20].…”

Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications

“…These macrophages activated by the tumor microenvironment express tumor necrosis factor α (TNF-α), which induces c-Met-expression on their surface. These macrophages also express MMP-9, which increases the remodeling of the tumor microenvironment of HCC[ 49 ].…”

Tumor-infiltrating macrophages express interleukin-25 and predict a favorable prognosis in patients with gastric cancer after radical resection

“…Peripheral blood mononuclear cells (PBMC) were isolated from buffy coats acquired from healthy donors using a Ficoll density gradient as previously described [ 13 ]. The monocytes were purified from PBMCs using anti-CD14 magnetic beads (Miltenyi Biotechnology; Surrey, UK) according to the manufacturer's instructions [ 15 ]. CD14 + monocytes were cultured for seven days in DMEM supplemented with 10% AB serum in the presence 15% TSN or TGF-β1 (10 ng/mL; R & D Systems) or in medium alone to obtain TSN-treated Mφs, TGF-β1-treated Mφs or control Mφs (Med).…”

“…Macrophages (Mφs) constitute a major component of immune cell infiltrates in nearly all tumors [ 8 – 9 ]. Studies have demonstrated that they could promote tumor angiogenesis, metastasis and induce T cell differentiation and activation through the production of cytokines [ 10 – 15 ]. Our group and others have reported that a high number of infiltrating Mφs could be correlated with both favorable and poor prognoses in different tumor types [ 11 – 19 ].…”