CCL18 from tumor-associated macrophages promotes angiogenesis in breast cancer

Abstract

The infiltration of tumor-associated macrophages (TAMs) is associated with extensive angiogenesis, which contributes to a poor prognosis in breast cancer. However, anti-angiogenic therapy with VEGF-specific monotherapy has been unsuccessful in treating breast cancer, and the molecular mechanisms associated with chemoresistance remain unclear. Here, we investigated whether CCL18, a chemokine produced by TAMs, can stimulate angiogenesis in breast cancer, as well as the underlying mechanisms. Double immunohistochemical staining for CCL18 and CD34/CD31/vWF was performed in 80 breast cancer samples to study the correlation between CCL18+ TAMs and microvascular density (MVD). Cocultures of TAMs with human umbilical vein endothelial cells (HUVECs) were used to model the inflammatory microenvironment, and CCL18-induced angiogenesis was evaluated both in vitro and in vivo. We demonstrated that CCL18+ TAM infiltration positively associated with MVD in breast cancer samples, which was correlated with tumor metastasis and poor prognosis. We confirmed, both in vitro and in vivo, that CCL18 and VEGF synergistically promoted endothelial cell migration and angiogenesis. Conversely, blocking CCL18 or VEGF with neutralizing antibodies synergistically inhibited the promigratory effects of TAMs. Silencing PITPNM3, a putative CCL18 receptor, on the surface of HUVECs abrogated CCL18-mediated promigration and the enhancement of HUVEC tube formation, independently of VEGFR signaling. Moreover, CCL18 exposure induced the endothelial-mesenchymal transformation and activated ERK and Akt/GSK-3β/Snail signaling in HUVECs, thereby contributing to its pro-angiogenic effects. In conclusion, our findings suggest that CCL18 released from TAMs promotes angiogenesis and tumor progression in breast cancer; thus, CCL18 may serve as a novel target for anti-angiogenic therapies.

New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy

“…CCL18 released from TAMs can induce EndMT in endothelial cells to produce a different differentiated phenotype, which may lead to a loss of cell-cell junctions as well as enhanced invasiveness and migratory capacity [77]. These data confirm a strong cross-talk between macrophages and tumor progression, mainly through stimulation of EMT.…”

The contribution of tumor-associated macrophages in glioma neo-angiogenesis and implications for anti-angiogenic strategies

“…IL-6 is able to promote epithelial-mesenchymal transition of cancer cells, which is typically operative in high-grade gliomas. 51 Other paracrine factors that influence the sprouting process include TAM-derived WNT7b and M-CSF in breast cancer and glioma, which can activate the canonical WNT/β-catenin and insulin-like growth factor binding protein pathways, respectively, in endothelial cells, thereby increasing the expression of VEGFA and contributing to vascular sprouting 52,53 (Fig. 2C).…”

“…For example, CCL18 secretion by (M2) type TAMs in breast cancer has been reported to bind to PITPNM3, a membrane-associated phosphatidylinositol transfer domain-containing protein located on endothelial cells. This interaction triggers downstream extracellular signal-regulated kinase and Akt/glycogen synthase kinase 3β/Snail signaling and promotes the endoMT process, thereby increasing the migration ability of endothelial cells 51 (Fig. 2H).…”

A Comparative Approach of Tumor-Associated Inflammation in Mammary Cancer between Humans and Dogs

“…Specifically, the infiltration of TAMs that express the chemokine CCL18 was positively associated with microvessel density in breast cancer. In fact, the synergistic expression of CCL18 and VEGF by the TAMs promoted endothelial cell migration and angiogenesis in this type of cancer [51]. …”