Monocytes/Macrophages promote vascular CXCR4 expression via the ERK pathway in hepatocellular carcinoma

Abstract

We recently identified CXCR4 as a novel vascular marker for vessel sprouting in hepatocellular carcinoma (HCC) tissues. Thus, CXCR4 endothelial cells (ECs) could serve as a potential predictor for patients who may benefit from sorafenib treatment; however, the mechanism that regulates vascular CXCR4 expression in HCC remains largely unknown. Here, we revealed a large number of monocytes/macrophages (Mo/Mϕ) to be selectively enriched in the perivascular areas of CXCR4 vessels in HCC samples. The depletion of Mo/Mϕ with gadolinium chloride (GdCl) or zoledronic acid (ZA) treatment significantly reduced vascular CXCR4 expression in HCC tumors. This phenomenon was also confirmed in CCR2-KO mice, which exhibited reduced infiltration of inflammatory Mo/Mϕ in tumor tissues. Mechanistic studies revealed that inflammatory cytokines derived from tumor conditioned Mo/Mϕ, especially TNF-α, could up-regulate CXCR4 expression on ECs. TNF-α-induced activation of the Raf-ERK pathway, but not Notch signaling, was responsible for the expression of CXCR4. Moreover, the combination treatment of sorafenib with ZA was associated with improved anti-tumor efficacy by significantly reducing vascular CXCR4 expression. These findings revealed that Mo/Mϕ could regulate CXCR4 expression in the tumor vasculature. Thus, the inhibition of Mo/Mϕ inflammation might enhance the treatment efficacy of sorafenib in HCC.

Profiles of m6A RNA methylation regulators for the prognosis of hepatocellular carcinoma

“…The RNA m 6 A methylation function within the tumor was recently confirmed, and certain biological processes were found to be affected by it, including tumor stem cell growth, tumorigenesis and self-renewal (25,26), as well as DNA damage response secondary to radiotherapy or chemotherapy (27,28). Herein, the expression levels of m 6 A RNA methylation regulators in HCC were found to be correlated with HCC-related biological processes, such as ATM_PATHWAY (29), CXCR4_PATHWAY (30) and IL6_PATHWAY (31).…”

Human hepatocellular carcinoma: Protection by melatonin

“…There are other signaling pathways related to HCC including Notch (Nowell & Radtke, 2017) and CXCR4 (Meng et al, 2018). Notch signaling has a tumor-repressive function in HCC (Nowell & Radtke, 2017).…”

Support of Tumor Endothelial Cells by Chemokine Receptors

“…TNF-α induces activation of the Raf-ERK pathway and induces expression of CXCR4 on activated endothelial cells. CCR2 KO mice showed reduced infiltration of inflammatory Mo/Mϕ in tumor tissues and reduced vascular CXCR4 expression in HCC tumors (62). CXCR4 is among the genes enriched in tip cells vs. stalk endothelial cells, along with VEGFR2, platelet-derived growth factor (PDGF)- B, Dll4, and matrix metalloproteinase (MMP)14 (16, 28, 63).…”