Targeting the CXCR4/CXCL12 axis in treating epithelial ovarian cancer

Abstract

Ovarian carcinoma is the most crucial and difficult target for available therapeutic treatments among gynecological malignancies, and great efforts are required to find an effective solution. Molecular studies showed that the chemokine stromal cell-derived factor-1 (also known as CXCL12) and its receptor, CXCR4, are key determinants of tumor initiation, progression and metastasis in ovarian carcinomas. Hence, it is generally believed that blocking the CXCR4/CXCL12 pathway could serve as a potential therapy for patients with ovarian cancer. Herein, we investigated the role of the CXCR4/CXCL12 axis in regulating ovarian cancer progression. Using flow cytometry, a real-time PCR and western blot analyses, we showed that the chemokine receptor CXCR4 protein and mRNA were overexpressed in human epithelial ovarian cancer cell lines, and these were closely correlated with poor outcomes. Moreover, silencing CXCR4 by small hairpin RNA in HTB75 cells reduced cell proliferation, migration and invasion and significantly reduced RhoA and Rac-1/Cdc42 expressions, whereas overexpression of CXCR4 in SKOV3 cells significantly increased cell migration and markedly increased RhoA, Rac-1/Cdc42 levels. Silencing CXCR4 also led to decreased in vitro cytotoxicity of AMD3100, a specific antagonist of CXCR4, which exerts its effect upon CXCR4 expression. Remarkably, knockdown of CXCR4 in HTB75 cells led to a significantly decreased capability to form tumors in vivo, and the Ki67 proliferation index of xenograft tumors showed a dramatic reduction. Our results revealed that the CXCR4/CXCL12 pathway represents a promising therapeutic target for epithelial ovarian carcinoma.

Adenosine A2A receptor activation reduces brain metastasis via SDF‐1/CXCR4 axis and protecting blood‐brain barrier

“…Therefore, small molecular antagonists targeting CXCR4, such as BKT140, plerixafor and AMD3100, have been widely used in cancer treatment. 13 In conclusion, we have firstly demonstrated the activation of adenosine A2A receptor inhibits the proliferation, migration and invasion ability of PC-9 cells in this research. We have revealed that adenosine A2A receptor modulates the lung-to-brain metastasis via regulating the tight junction protein levels to regulate the integrity and function of BBB.…”

“…Besides, the link between inflammation and cancer, as well as the role CXCR4 plays in the transformation between the two sides, has drawn great attention of oncological researchers. Therefore, small molecular antagonists targeting CXCR4, such as BKT140, plerixafor and AMD3100, have been widely used in cancer treatment 13 …”

“…12 Stromal cell-derived factor-1 (SDF-1) is a small preinflammatory chemoattractant cytokine, which interacts with G protein coupled transmembrane receptors such as C-X-C motif chemokine receptor 4 (CXCR4). 13 The interaction between SDF-1 and CXCR4 has been proved to modulate abundant physiological processes including cell adhesion, chemotaxis, energy metabolism, and transcription regulation. 14 It has been reported that SDF-1 is prevalently upregulated in cancer cells and CXCR4 is mainly expressed in CD43 + cancer stem cells.…”

Immune mediator expression signatures are associated with improved outcome in ovarian carcinoma

“…60 Moreover, binding of CXCL-12 to its receptor CXCR4 has been shown to induce tumor proliferation and cancer progression, and these effects were attenuated when this pathway was knocked down in pre-clinical in vivo models. 61 PDGFA is a potent activator for mesenchymal-origin cells, and stimulates chemotaxis, proliferation and angiogenesis in cancer, 62 engaging several pathways such as Ras-MAPK, PI3K, PLCγ and inducing VEGF production. 62,63 Plasma CRP concentration is increased in response to inflammation, tissue damage and infection, and may promote tumor growth and metastasis by causing low-grade inflammation in breast cancer, although the exact pathogenesis is still uncertain.…”

Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes

“…This would provide in vivo validation of eRNA function and describe pre-clinical models for future eRNA-targeted therapies. Indeed, the feasibility of targeting tissue-specific and disease-relevant enhancers using LNA or CRISPR-based strategies might have clinical importance [168,169].…”