Targeting CXC motif chemokine receptor 4 inhibits the proliferation, migration and angiogenesis of lung cancer cells

Abstract

An increasing volume of data indicates that disrupting the interaction between CXC motif chemokine receptor 4 (CXCR4) and its specific ligand, CXC motif chemokine 12 (CXCL12), may reduce tumor growth and metastasis. However, the translation from bench to bedside must be performed with extreme caution, as the CXCR4/CXCL12 axis is crucial for the normal development and maintenance of tissues and organs. In the present study, Cell Counting Kit-8 and Transwell migration assays were used to detect proliferation and chemotaxis of CXCR4-expressing A549 cells, a cell strain originating from human non-small-cell lung cancer (NSCLC), with or without the presence of AMD3100, a small-molecule inhibitor specific to CXCR4 signaling. In a xenograft model established by injecting nude mice with A549 cells, tumor growth, CXCR4 expression and microvessel density (MVD) in the tumor mass were determined through tumor size measurements and immunohistochemical staining following intraperitoneal administration of AMD3100 or vehicle. The results demonstrated that CXCR4 blockade inhibited the proliferation of A549 cells and their migration towards CXCL12. Tumor growth, CXCR4 expression and MVD were markedly reduced in nude mice treated with AMD3100 compared with mice treated with the vehicle. In conclusion, the present data demonstrated that CXCR4 targeting impaired NSCLC cell growth, angiogenesis and metastatic spread, indicating that it may represent a novel treatment strategy for NSCLC.

The clinicopathological and prognostic value of CXCR4 expression in patients with lung cancer: a meta-analysis

“…Lee et al [ 64 ] found that blocking the CXCL12/CXCR4 axis with anti-CXCR4 antibodies could decrease breast cancer cell migration to the brain. It has been reported in an experimental study that blocking CXCR4 inhibited the proliferation of lung cancer cells and the migration to CXCL12 [ 65 ]. In recent experimental studies, CXCR4 expression was shown to mediate cisplatin resistance in a cytochrome P450 1B1 (CYP1B1)-dependent manner way and paclitaxel resistance by increasing the expression of antiapoptotic proteins [ 26 , 66 ].…”

Chemokine signaling in cancer-stroma communications

“…Forcing CXCR4 overexpression in A549 cells leads to increased invasiveness through the increased expression of VEGF-C, MMP2, and phosphorylation of AKT (Zeng et al 2017). A different group repeated the experiment and found similar results that could be reversed by treatment with a CXCR4 inhibitor (He et al 2018). The co-culture of CAFs with PDAC cells similarly increases invasiveness, which can be nullified by the inhibition of CXCR4 (Bhagat et al 2019), although the authors left the responsible pathway unspecified.…”

The autocrine CXCR4/CXCL12 axis contributes to lung fibrosis through modulation of lung fibroblast activity

“…A number of studies have demonstrated that CXCR4/ CXCL12 participates in cancer development (6,8,(15)(16)(17)(18). CXCR4 is the only chemokine receptor expressed by the majority of cancer cells, and its ligand CXCL12 can be secreted by tumor cells and stromal cells, including tumor-associated fibroblasts (24,25).…”

“…Chemokine expression is stimulated by infection and inflammation, which serves an important role in the attraction, recruitment and activation of leukocytes and immune cells (4,5). C-X-C Motif Chemokine Ligand 12 (CXCL12) represents the natural ligand for C-X-C motif chemokine receptor 4 (CXCR4) and has been indicated to play a role in the metastasis of CXCR4-expressing cells (6)(7)(8). Fibrocytes originate from the bone marrow, and express hematopoietic (CD34+) and mesenchymal markers [collagen I+ (ColI+) and vimentin+] (9).…”