CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis

Abstract

CXCR4 and its ligand CXCL12 can promote the proliferation, survival, and invasion of cancer cells. They have been shown to play an important role in regulating metastasis of breast cancer to specific organs. High CXCR4 expression was also correlated to poor clinical outcome. Previous study also showed that tumor cells express a high level of CXCR4 and that tumor metastasis target tissues (lung, liver, and bone) express high levels of the ligand CXCL12, allowing tumor cells to directionally migrate to target organs via a CXCL12-CXCR4 chemotactic gradient. However, the exact mechanisms of how CXCR4 and CXCL12 enhance metastasis and/or tumor growth and their full implications on breast cancer progression are unknown. Yet it is likely that chemokine receptor signaling may provide more than just a migrational advantage by also helping the metastasized cells establish and survive in secondary environments. In this study, we investigated CXCR4 and CXCL12 expression in breast cancer and analyzed its association with clinicopathological factors by immunohistochemistry first. Then, we detected the mRNA and protein expression of CXCR4 and CXCL12 in breast cancer cell lines by Western blot and RT-PCR. The MDA-MB-231 has CXCR4 expression and very weak CXCL12 expression. So, we constructed the functional CXCL12 expression in MDA-MB-231 using a gene transfection technique. Further experiments were conducted to evaluate the effect of CXCL12 transfection on the biological behaviors of MDA-MB-231. The cell proliferation of MDA-MB-231–CXCL12 was accessed by MTT assay; the apoptosis was analyzed by an AnnexinV-FITC/propidium iodide double staining of flow cytometry method; and the cell invasive ability was examined by Matrigel invasion assay. Immunohistochemical analysis showed the co-expression of CXCR4 and CXCL12 correlated with lymph node metastasis and TNM stage (p < 0.01). It suggested that the chemokine CXCL12 and its sole ligand CXCR4 play important role in the malignance of breast cancer. To gain a deeper insight into it, we picked CXCR4-expressing cells MDA-MB-231 to be transfected with CXCL12 stably. The decreased cellular proliferation, increased apoptosis, and invasive ability were found in MDA-MB-231 with successful CXCL12 transfection (p < 0.05). Our findings underlined the CXCL12-CXCR4 axis correlated tightly with breast cancer metastasis. CXCL12-CXCR4 axis can increase the invasion and apoptosis of MDA-MB-231 simultaneously. These data strongly support the hypothesis that CXCL12-CXCR4 axis promotes the natural selection of breast cancer cell metastasis. Our findings could have significant implications in terms of breast cancer aggressiveness and the effectiveness of targeting the receptors and downstream signaling pathways for the treatment of breast cancer.

CXCR‐4 Targeted, Short Wave Infrared (SWIR) Emitting Nanoprobes for Enhanced Deep Tissue Imaging and Micrometastatic Cancer Lesion Detection

“…Effective targeting of fReANCs was determined by cellular association of AMD3100 functionalized probes using three breast cancer cell lines with varying levels of CXCR4 expression: 1) 4175‐TR (a highly aggressive, lung‐tropic subpopulation of the MDA‐MB‐231 cancer cell line with low CXCR4 expression, 2) MDA‐MB‐231, with moderate levels of CXCR4 expression, and 3) MCF‐7, with relatively high levels of CXCR4 expression . We observed a threefold increase in cellular association of fReANCs when compared to ReANCs by both receptor positive cell lines as determined by flow cytometry, with no significant change in association with receptor negative 4175‐TR cells (Figure 2 (Supporting Information) and Figure A,B,E).…”

CXCR4 or CXCR7 antagonists treat endometriosis by reducing bone marrow cell trafficking

“…CXCR7 has been demonstrated to regulate cell migration and survival through several pathways that include ligand scavenging, direct signal transduction and direct interaction with CXCR45 . CXCR4 activation promotes tumour growth and metastasis in cancer, and recent preclinical studies have shown similar effects for CXCR7 . Agents blocking chemokine signalling by binding to these receptors are currently being developed for cancer therapy (eg ClinicalTrials.gov identifier NCT02179970, NCT02737072), supporting an evaluation of their efficacy in endometriosis.…”

Overexpression of SDF-1 activates the NF-κB pathway to induce epithelial to mesenchymal transition and cancer stem cell-like phenotypes of breast cancer cells

“…Clinical research reported that the expression of SDF-1 was elevated significantly in various carcinomas associated with tumor grade, lymph node metastasis, TNM stage and prognosis (11)(12)(13) with constitutive SDF-1 secretion, such as liver, lung, lymph nodes, and bone marrow, are also the most common sites for secondary metastasis of breast cancer (14)(15)(16). On the contrary, as a potent leukocytic chemokines, CXCL12 also has a potential to promote anticancer immunity by inducing CD8 + T cell activity, enhancing cytotoxicity, increasing the number of CD11c + cells in the tumor-draining lymph nodes and reducing the accumulation of myeloid-derived suppressor cells in the spleen (17).…”