ADAM17-regulated CX3CL1 expression produced by bone marrow endothelial cells promotes spinal metastasis from hepatocellular carcinoma

Abstract

Spinal metastasis occurs in 50-75% of bone metastases caused by hepatocellular carcinoma (HCC), and HCC-derived spinal metastasis can lead to a less favorable prognosis. Recently, several studies have demonstrated that C-X3-C motif chemokine ligand 1 (CX3CL1) is closely associated with cancer metastasis, and its secretion is modulated by a disintegrin and metalloproteinase 17 (ADAM17). Bone marrow endothelial cells (BMECs) are an essential component of bone marrow. However, little is known about the roles in and effects of BMECs on HCC spinal metastasis. The present study demonstrated that CX3CL1 and C-X-C motif chemokine receptor 3 (CXCR3) expression was upregulated in HCC spinal metastases, and that CX3CL1 promoted the migration and invasion of HCC cells to the spine. Western blot analysis revealed that the Src/protein tyrosine kinase 2 (PTK2) axis participated in CX3CL1-induced HCC cell invasion and migration. CX3CL1 also increased the expression of M2 macrophage markers in THP-1 monocytes. BMECs promoted the migration and invasion of Hep3B and MHCC97H cells by secreting soluble CX3CL1, whereas the neutralization of CX3CL1 inhibited this enhancement. CX3CL1 enhanced the activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA)/AKT serine/threonine kinase 1 (AKT1) and Ras homolog family member A (RHOA)/Rho associated coiled-coil containing protein kinase 2 (ROCK2) signaling pathways through the Src/PTK2 signaling pathway. Furthermore, ADAM17 was activated by mitogen-activated protein kinase (MAPK) z14 in BMECs and significantly promoted the secretion of CX3CL1. HCC cells enhanced the recruitment and proliferation of BMECs. The overexpression of CX3CR1 facilitated the spinal metastasis of HCC in a mouse model in vivo. In addition, in vivo experiments revealed that BMECs promoted the growth of HCC in the spine. The present study demonstrated that CX3CL1 participates in HCC spinal metastasis, and that BMECs play an important role in the regulation of CX3CL1 in the spinal metastatic environment.

Bone Vasculature and Bone Marrow Vascular Niches in Health and Disease

“…EC-specific deletion of VEGFR2 results in reduction and disorganization of blood vessels in the metaphyseal region closed to the growth plate. (75) VEGFA exists in multiple isoforms-VEGF 120 , VEGF 164 , and VEGF 188 in mouse and VEGF 121 , VEGF 145 , VEGF 165 , VEGF 183 , VEGF 186 , VEGF 189 , and VEGF 206 in human, which elicit diverse biological processes. (76,77) Nevertheless, reduced endochondral angiogenesis and mineralization occurs in mice expressing only VEGF 120 isoform.…”

“…( 182 ) A recent study shows that ADAM17‐regulated C‐X3‐C motif chemokine ligand 1 (CX3CL1) expression produced by bone marrow ECs promotes spinal metastasis from hepatocellular carcinoma. ( 183 ) Although sinusoids and low blood flow facilitate more significant interactions between tumor cells and ECs in bone, ( 180 ) type H vessels with higher speed of blood flow and more abundant oxygen, cytokine, and growth factors may promote tumor cell survival. Reduced blood flow leads to a reduction of type H vessels and inhibition of pericyte expansion, which regulate EC‐derived PDGF‐B signaling, rendering DTCs susceptible to irradiation and chemotherapy.…”

Role of chemokines in hepatocellular carcinoma (Review)

“…In addition, the mucin-like domain of CX3CL1 contains a cleavage site that allows metalloproteinases (such as ADAM10) to cleave and release proteins in a soluble form ( 33 ). CXCR3 is the only receptor of CX3CL1, and CX3CL1/CX3CR1 regulates the chemotaxis of inflammatory cells, as well as the proliferation, migration and invasion of cancer cells ( 34 , 35 ). It has been reported that CX3CL1 is closely associated with the metastasis of prostate ( 36 ) and breast cancer ( 37 ).…”

“…Additionally, these studies confirmed that inhibition of CX3CL1 was an effective strategy to prevent spinal metastasis of breast and prostate cancer ( 36 , 37 ). Sun et al ( 34 ) revealed that CX3CL1/CX3CR1 expression in HCC spinal metastases was upregulated. Bone marrow endothelial cells promote the migration and invasion of Hep3B and MHCC97H cells to the spine by secreting soluble CX3CL1 and this is inhibited following neutralization of CX3CL1 ( 34 ).…”

Transforming growth factor‐β‐regulated fractalkine as a marker of erosive bone invasion in oral squamous cell carcinoma

“…In contrast, fractalkine expression was correlated with increased tumor‐infiltrating lymphocytes and poorer overall survival in patients with breast cancer (15) and pancreatic ductal adenocarcinoma (16). Fractalkine promoted cell proliferation, migration, and/or invasion in osteosarcoma, breast cancer, and hepatocellular carcinoma cells (17‐19). A recent study indicated that microRNA‐29b promoted OSCC cell migration by downregulating fractalkine (20).…”