Macrophage Migration Inhibitory Factor (MIF) Upregulates CXCR7 and Contributes to Chemotherapy Resistance in Colorectal Cancer.

Colorectal cancer is one of the most common malignant tumors worldwide, with high incidence and mortality rates making it a focus of research. Chemotherapy is a primary treatment modality for colon cancer, but chemotherapy resistance severely impacts treatment efficacy. MIF has been found to promote tumor progression and resistance in various cancers. This study aims to investigate the role of MIF in chemotherapy resistance in colon cancer and its potential mechanisms, particularly through the upregulation of CXCR7 expression, affecting the metabolism and drug sensitivity of colon cancer cells. The expression levels of MIF in colon cancer tissues and its association with patient prognosis were evaluated by analyzing TCGA and HPA data. Subsequently, the expression levels of MIF in colon cancer cell lines and resistant cell lines were detected by qRT-PCR and immunohistochemistry, and the effect of MIF on oxaliplatin sensitivity was assessed. The impact of MIF on the metabolic activity of colon cancer cells was measured using a cellular energy metabolism analyzer. Further experiments explored the mechanism by which MIF affects the metabolic activity of colon cancer cells through the upregulation of CXCR7 expression, and the role of CTCF in regulating CXCR7 transcription was validated by silencing CTCF. Finally, the effect of MIF on drug sensitivity of colon cancer cells was verified in a mouse xenograft tumor model. In this study, we found that the expression of MIF in colon cancer tissues was significantly higher than in normal tissues, and high MIF expression was associated with poor prognosis in patients. The expression levels of MIF in resistant colon cancer cell lines were significantly higher than in parental cell lines, and MIF overexpression significantly increased the resistance of colon cancer cells to oxaliplatin. Conversely, silencing MIF significantly reduced the IC50 value of resistant cells and increased apoptosis. MIF overexpression significantly increased the ECAR and OCR levels of colon cancer cells, while MIF knockdown significantly reduced these metabolic indicators. Further studies indicated that MIF affects the metabolic activity of colon cancer cells by upregulating CXCR7 expression. CTCF binding peaks at the CXCR7 promoter region and luciferase activity assays indicated that CTCF regulates CXCR7 transcription, and silencing CTCF significantly enhanced the sensitivity of colon cancer cells to oxaliplatin. In vivo experiments in mice showed that MIF silencing combined with oxaliplatin treatment significantly inhibited tumor growth and increased the necrotic area of tumor tissues. In conclusion, this study reveals the crucial role of MIF in chemotherapy resistance in colon cancer through the upregulation of CXCR7 expression, with CTCF playing an important regulatory role in this process. Our findings provide new theoretical insights and potential therapeutic targets for overcoming chemotherapy resistance in colon cancer. Future research should further explore the roles of MIF and CXCR7 in other types of cancers and the potential of MIF and CXCR7 as therapeutic targets.

ACKR3 Antagonism Enhances the Repair of Demyelinated Lesions Through Both Immunomodulatory and Remyelinating Effects.

Addressing inflammation, demyelination, and associated neurodegeneration in inflammatory demyelinating diseases like multiple sclerosis (MS) remains challenging. ACT-1004-1239, a first-in-class and potent ACKR3 antagonist, currently undergoing clinical development, showed promise in preclinical MS models, reducing neuroinflammation and demyelination. However, its effectiveness in treating established disease and impact on remyelination after the occurrence of demyelinated lesions remain unexplored. This study assessed the therapeutic effect of ACT-1004-1239 in two demyelinating disease models. In the proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE) model, ACT-1004-1239 administered upon the detection of the first signs of paralysis, resulted in a dose-dependent reduction in EAE disease severity, concomitant with diminished immune cell infiltrates in the CNS and reduced demyelination. Notably, efficacy correlated with elevated plasma concentrations of CXCL11 and CXCL12, two pharmacodynamic biomarkers of ACKR3 antagonism. Combining ACT-1004-1239 with siponimod, an approved immunomodulatory treatment for MS, synergistically reduced EAE severity. In the cuprizone-induced demyelination model, ACT-1004-1239 administered after 5 weeks of cuprizone exposure, significantly accelerated remyelination, already quantifiable one week after cuprizone withdrawal. Additionally, ACT-1004-1239 penetrated the CNS, elevating brain CXCL12 concentrations. These results demonstrate that ACKR3 antagonism significantly reduces the severity of experimental demyelinating diseases, even when treatment is initiated therapeutically, after the occurrence of lesions. It confirms the dual mode of action of ACT-1004-1239, exhibiting both immunomodulatory effects by reducing neuroinflammation and promyelinating effects by accelerating myelin repair. The results further strengthen the rationale for evaluating ACT-1004-1239 in clinical trials for patients with demyelinating diseases.

Bilayer lipids modulate ligand binding to atypical chemokine receptor 3.

Chemokine receptors belong to the large class of G protein-coupled receptors (GPCRs) and are involved in a number of (patho)physiological processes. Previous studies highlighted the importance of membrane lipids for modulating GPCR structure and function. However, the underlying mechanisms of how lipids regulate GPCRs are often poorly understood. Here, we report that anionic lipid bilayers increase the binding affinity of the chemokine CXCL12 for the atypical chemokine receptor 3 (ACKR3) by modulating the CXCL12 binding kinetics. Notably, the anionic bilayer favors CXCL12 over the more positively charged chemokine CXCL11, which we explained by bilayer interactions orienting CXCL12 but not CXCL11 for productive ACKR3 binding. Furthermore, our data suggest a stabilization of active ACKR3 conformations in anionic bilayers. Taken together, the described regulation of chemokine selectivity of ACKR3 by the lipid bilayer proposes an extended version of the classical model of chemokine binding including the lipid environment of the receptor.

Protective Effect of CXCR7 Against Hypoxia/Reoxygenation Injury in Renal Tubular Epithelial Cells.

Acute kidney injury (AKI) is a multifactorial syndrome with complex pathophysiology and prognosis. Ischaemia‒reperfusion injury (IRI) is a major cause of induced AKI. The aim of this study was to investigate the effect of upregulated CXCR7 expression on renal tubular epithelial cell apoptosis induced by hypoxia/reoxygenation (H/R). HK-2 cells were divided into three groups: control group (pcDNA3.1), hypoxia/reoxygenation + pcDNA3.1 group (H/R+pcDNA3.1) and CXCR7 overexpression + hypoxia/reoxygenation group (H/R+ Flag-CXCR7). Protein levels of renal tubular epithelial cell injury-, apoptosis- and autophagy-related markers were assessed by qRT‒PCR, Western blotting, flow cytometry (FCM), immunofluorescence and transmission electron microscopy (TEM). In addition, HK-2 cells were treated with the autophagy inhibitor 3-MA and divided into 3 groups: control group, 3-MA + pcDNA3.1 group, and 3-MA + Flag-CXCR7 group. Changes in autophagy and apoptosis in renal tubule epithelial cells were assessed by Western blotting and FCM. Compared with those in the control group, the protein and mRNA expression levels of CXCR7 in HK-2 cells were significantly lower under H/R conditions. Under H/R conditions, CXCR7 overexpression in HK-2 cells significantly downregulated the expression of NGAL. Moreover, CXCR7 overexpression significantly decreased H/R-induced cleaved PARP-1 and cleaved Caspase 3 levels, increased the level of the antiapoptotic protein BCL-2 and the autophagy-related molecules ATG5 and LC3B II, and significantly inhibited the expression of P62. Autophagy flow and TEM also showed that CXCR7 significantly promoted autophagy. CXCR7 significantly alleviated the 3-MA-induced inhibition of autophagy and increase in apoptosis. Upregulated CXCR7 expression can inhibit renal tubular epithelial cell apoptosis and damage by regulating autophagy. In conclusion, CXCR7 is a promising target for the prevention and/or treatment of AKI.

The effect of CXCL12 on survival outcomes of patients with viral hepatitis-associated hepatocellular carcinoma after hepatectomy.

Background: The CXCL12-CXCR4/CXCR7 axis is garnering growing attention. But the comprehension of its function in the progression of HCC remains controversial. The purpose of this study was to investigate the effects of CXCL12 and its receptor on the prognosis of patients with viral hepatitis-associated HCC after hepatectomy. Methods: A total of 86 patients had been enrolled who had undergone hepatectomy for HCC and followed up to July 31, 2019, and their clinicopathological and follow-up data were recorded. Tumor and peritumoral tissues were obtained to detect the expression of CXCL12, CXCR4, and CXCR7 using immunohistochemistry. Real-time polymerase chain reaction was utilized to detect hepatitis B or C virus loads, while survival analysis was performed using the Kaplan-Meier method. Furthermore, the Cox proportional hazards regression model was employed to analyze the factors affecting the prognosis. Results: The results revealed that the CXCL12, CXCR4, and CXCR7 expression in tumor tissues was lower than in the corresponding non-tumor tissues in 20.93 %, 22.09 %, and 23.26 % of the patients, respectively, and that only CXCL12 was found to be related to the extrahepatic invasion of HCC. The survival analysis and Cox regression showed that only CXCL12 was associated with the postoperative survival of patients with HCC, and that it was an independent prognostic risk factor in the CXCL12-CXCR4/CXCR7 axis. The CXCL12low group represented shorter progression-free survival and lower overall survival rates. However, the subgroup analysis displayed that the survival difference associated with CXCL12 was only manifested in patients with higher expression of CXCR4 or CXCR7 in HCC, as compared to the surrounding tissues. Conclusions: Our findings suggest that, when assessing the prognostic significance of CXCL12 in HCC, it is essential to consider the expression level of its receptor. Nevertheless, CXCL12 can potentially serve as a promising prognostic marker for HCC.

CXCR7 promotes pulmonary vascular remodeling via targeting p38/MMP2 pathway in pulmonary arterial hypertension.

Background: A hallmark feature of pulmonary arterial hypertension (PAH) is the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) in the pulmonary arteries. The exact role of C-X-C motif chemokine ligand 12 (CXCL12)/chemokine receptor type 7 (CXCR7) in the PASMCs remains unknown. This study was conducted to investigate CXCR7's role in p38/MMP2 pathway and its effect on PASMCs. Methods: In this study, we examined the expression profile of CXCL12/CXCR7 in both hypoxic rats and PASMCs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) was used to measure the level of proliferation in PASMCs. Enzyme-linked immunosorbent assay (ELISA) and western blotting assays were applied to investigate the protein expression of the related molecules. Results: We found that a high level of CXCR7 was correlated with remodeled pulmonary arterioles in hypoxic rats. Moreover, CXCR7 protein levels were significantly increased by the induction of CXCL12, indicating that the CXCL12-CXCR7 axis participates in PAH. During hypoxia-PAH, CXCR7 inhibition reduces right ventricular systolic pressure (RVSP), the Fulton index, and pulmonary arteriosclerosis remodeling. Further study indicated inhibition CXCR7 reduced PASMCs by downregulating MMP2, via p38 MAPK pathway. It was additionally found that CXCL12/CXCR7 stimulated the phosphorylation of the p38 MAPK pathway, which was a contributing factor to the decrease in MMP2 expression following preconditioning with SB203580, which inhibited p38 MAPK. Conclusions: In summary, these findings suggest that CXCL12/CXCR7 plays a critical role in PAH, the therapy of which can be developed further by targeting its potential targets.

Crosstalk between purinergic receptor P2Y11 and chemokine receptor CXCR7 is regulated by CXCR4 in human macrophages.

P2Y11 is a G protein-coupled ATP receptor that activates IL-1 receptor (IL-1R) in a cyclic AMP dependent manner. In human macrophages, P2Y11/IL-1R crosstalk with CCL20 as a prime target is controlled by phosphodiesterase 4 (PDE4), which mediates breakdown of cyclic AMP. Here, we used gene expression analysis to identify activation of CXCR4 and CXCR7 as a hallmark of P2Y11 signaling. We found that PDE4 inhibition with rolipram boosts P2Y11/IL-1R-induced upregulation of CXCR7 expression and CCL20 production in an epidermal growth factor receptor dependent manner. Using an astrocytoma cell line, naturally expressing CXCR7 but lacking CXCR4, P2Y11/IL-1R activation effectively induced and CXCR7 agonist TC14012 enhanced CCL20 production even in the absence of PDE4 inhibition. Moreover, CXCR7 depletion by RNA interference suppressed CCL20 production. In macrophages, the simultaneous activation of P2Y11 and CXCR7 by their respective agonists was sufficient to induce CCL20 production with no need of PDE4 inhibition, as CXCR7 activation increased its own and eliminated CXCR4 expression. Finally, analysis of multiple CCL chemokines in the macrophage secretome revealed that CXCR4 inactivation and CXCR7 activation selectively enhanced P2Y11/IL-1R-mediated secretion of CCL20. Altogether, our data establish CXCR7 as an integral component of the P2Y11/IL-1R-initiated signaling cascade and CXCR4-associated PDE4 as a regulatory checkpoint.

ACKR3 in olfactory glia cells shapes the immune defense of the olfactory mucosa.

Barrier-forming olfactory glia cells, termed sustentacular cells, play important roles for immune defense of the olfactory mucosa, for example as entry sites for SARS-CoV-2 and subsequent development of inflammation-induced smell loss. Here we demonstrate that sustentacular cells express ACKR3, a chemokine receptor that functions both as a scavenger of the chemokine CXCL12 and as an activator of alternative signaling pathways. Differential gene expression analysis of bulk RNA sequencing data obtained from WT and ACKR3 conditional knockout mice revealed upregulation of genes involved in immune defense. To map the regulated genes to the different cell types of the olfactory mucosa, we employed biocomputational methods utilizing a single-cell reference atlas. Transcriptome analysis, PCR and immunofluorescence identified up-regulation of NF-κB-related genes, known to amplify inflammatory signaling and to facilitate leukocyte transmigration, in the gliogenic lineage. Accordingly, we found a marked increase in leukocyte-expressed genes and confirmed leukocyte infiltration into the olfactory mucosa. In addition, lack of ACKR3 led to enhanced expression and secretion of early mediators of immune defense by Bowman's glands. As a result, the number of apoptotic cells in the epithelium was decreased. In conclusion, our research underlines the importance of sustentacular cells in immune defense of the olfactory mucosa. Moreover, it identifies ACKR3, a druggable G protein-coupled receptor, as a promising target for modulation of inflammation-associated anosmia.

Unveiling the oncogenic role of CLDN11-secreting fibroblasts in gastric cancer peritoneal metastasis through single-cell sequencing and experimental approaches.

BACKGROUND: Fibroblasts are necessary to the progression of cancer. However, the role of fibroblasts in peritoneal metastasis (PM) of gastric cancer (GC) remains elusive. In this study, we would explore the role of fibroblasts mediated cell interaction in PM of GC. METHODS: Single-cell sequencing data from public database GSE183904 was used to explore the specific fibroblast cluster. Fibroblasts were extracted from PM and GC tissues. The expression level of CXCR7 was verified by western blot, immunohistochemistry. The role of CLDN11 was investigate through in vitro and in vivo study. Multiple immunohistochemistry was used to characterize the tumor microenvironment. RESULTS: CXCR7-positive fibroblasts were significantly enriched in PM of GC. CXCR7 could promote the expression of CLDN11 through activation of the AKT pathway in fibroblasts. Fibroblasts promote the GC proliferation and peritoneal metastasis by secreting CLDN11 in vitro and in vivo. Furthermore, it was revealed that CXCR7-positive fibroblasts were significantly associated with M2-type macrophages infiltration in tissues. CONCLUSION: CXCR7-positive fibroblasts play an essential role in PM of GC via CLDN11. Therapy targeting CXCR7-positive fibroblasts or CLDN11 may be helpful in the treatment of GC with PM.

CXC chemokine receptor 7 ameliorates renal fibrosis by inhibiting ß-catenin signaling and epithelial-to-mesenchymal transition in tubular epithelial cells.

Renal fibrosis is a common feature of various chronic kidney diseases. However, the underlying mechanism remains poorly understood. The CXC chemokine receptor (CXCR) family plays a role in renal fibrosis; however, the detailed mechanisms have not been elucidated. In this study, we investigated the potential role of CXCR7 in mediating renal fibrosis. CXCR7 expression is decreased in unilateral ischemia-reperfusion injury (UIRI) and unilateral ureteral obstruction mouse models. Furthermore, CXCR7 was specifically expressed primarily in the Lotus Tetragonolobus Lectin-expressing segment of tubules, was slightly expressed in the peanut agglutinin-expressing segment, and was barely expressed in the Dolichos biflorus agglutinin-expressing segment. Administration of pFlag-CXCR7, an overexpression plasmid for CXCR7, significantly inhibited the activation of ß-catenin signaling and protected against the progression of epithelial-to-mesenchymal transition (EMT) and renal fibrosis in a UIRI mouse model. Using cultured HKC-8 cells, we found that CXCR7 significantly downregulated the expression of active ß-catenin and fibrosis-related markers, including fibronectin, Collagen I, and α-SMA. Furthermore, CXCR7 significantly attenuated TGF-ß1-induced changes in ß-catenin signaling, EMT and fibrosis. These results suggest that CXCR7 plays a crucial role in inhibiting the activation of ß-catenin signaling and the progression of EMT and renal fibrosis. Thus, CXCR7 could be a novel therapeutic target for renal fibrosis.

An emerging paradigm of CXCL12 involvement in the metastatic cascade.

The chemokine CXCL12, also known as stromal cell-derived factor 1 (SDF1), has emerged as a pivotal regulator in the intricate molecular networks driving cancer progression. As an influential factor in the tumor microenvironment, CXCL12 plays a multifaceted role that spans beyond its traditional role as a chemokine inducing invasion and metastasis. Indeed, CXCL12 has been assigned functions related to epithelial-to-mesenchymal transition, cancer cell stemness, angiogenesis, and immunosuppression, all of which are currently viewed as specialized biological programs contributing to the "metastatic cascade" among other cancer hallmarks. Its interaction with its cognate receptor, CXCR4, initiates a cascade of events that not only shapes the metastatic potential of tumor cells but also defines the niches within the secondary organs that support metastatic colonization. Given the profound implications of CXCL12 in the metastatic cascade, understanding its mechanistic underpinnings is of paramount importance for the targeted elimination of rate-limiting steps in the metastatic process. This review aims to provide a comprehensive overview of the current knowledge surrounding the role of CXCL12 in cancer metastasis, especially its molecular interactions rationalizing its potential as a therapeutic target.

Regulation of the Hippo/YAP axis by CXCR7 in the tumorigenesis of gastric cancer.

BACKGROUND: The Hippo pathway is crucial in organ size control and tumorigenesis. Dysregulation of the Hippo/YAP axis is commonly observed in gastric cancer, while effective therapeutic targets for the Hippo/YAP axis are lacking. Identification of reliable drug targets and the underlying mechanisms that could inhibit the activity of the Hippo/YAP axis and gastric cancer progression is urgently needed. METHODS: We used several gastric cancer cell lines and xenograft models and performed immunoblotting, qPCR, and in vivo studies to investigate the function of CXCR7 in gastric cancer progression. RESULTS: In our current study, we demonstrate that the membrane receptor CXCR7 (C-X-C chemokine receptor 7) is an important modulator of the Hippo/YAP axis. The activation of CXCR7 could stimulate gastric cancer cell progression through the Hippo/YAP axis in vitro and in vivo, while pharmaceutical inhibition of CXCR7 via ACT-1004-1239 could block tumorigenesis in gastric cancer. Molecular studies revealed that the activation of CXCR7 could dephosphorylate YAP and facilitate YAP nuclear accumulation and transcriptional activation in gastric cancer. CXCR7 functions via G-protein Gαq/11 and Rho GTPase to activate YAP activity. Interestingly, ChIP assays showed that YAP could bind to the promoter region of CXCR7 and facilitate its gene transcription, which indicates that CXCR7 is both the upstream signalling and downstream target of the Hippo/YAP axis in gastric cancer. CONCLUSION: In general, we identified a novel positive feedback loop between CXCR7 and the Hippo/YAP axis, and blockade of CXCR7 could be a plausible strategy for gastric cancer.

Molecular characterization of the CXCR4 / CXCR7 axis in germ cell tumors and its targetability using nanobody-drug-conjugates.

Being stimulated by the chemokine CXCL12, the CXCR4 / CXCR7 cascade is involved in tumor proliferation, migration, and metastasis. The interaction between CXCL12, secreted by cells from the microenvironment, and its receptors is complex and has been ascribed to promote chemotherapy resistance. However, the role of this signaling axis and its targetability in germ cell tumors (GCT) is not fully understood. Thus, this study investigated the therapeutic efficacy of a nanobody-drug-conjugate targeting CXCR4 (CXCR4-NDC) and functionally characterized this signaling pathway in GCT using small molecule inhibitors and nanobodies. As shown by diminished cell viability, enhanced apoptosis induction, and detection of mitotic catastrophes, we confirmed the cytotoxic efficacy of the CXCR4-NDC in CXCR4+-GCT cells (i.e. seminoma and yolk-sac tumor), while non-malignant CXCR4--fibroblasts, remained largely unaffected. Stimulation of CXCR4+ / CXCR7+-GCT cells with CXCL12 resulted in an enhanced proliferative and migratory capacity, while this effect could be reverted using CXCR4 inhibitors or a CXCR7-nanobody. Molecularly, the CXCR4 / CXCR7-signaling cascade could be activated independently of MAPK (ERK1 / 2)-phosphorylation. Although, in CXCR4- / CXCR7--embryonal carcinoma cells, CXCR7-expression was re-induced upon inhibition of ERK1 / 2-signaling. This study identified a nanobody-drug-conjugate targeting CXCR4 as a putative therapeutic option for GCT, i.e. seminoma and yolk-sac tumors. Furthermore, this study shed light on the functional role of the CXCR4 / CXCR7 / CXCL12-signaling cascade in GCT, demonstrating an important influence on proliferation and migration.

CXCR7 promotes the migration of fibroblasts derived from patients with acquired laryngotracheal stenosis by NF-κB signaling.

Background: Laryngotracheal stenosis (LTS) is a life-threatening disease that commonly results in airway obstruction in children. Traditional treatments such as laryngotracheal reconstruction and balloon dilation all have the risk of laryngotracheal restenosis. It is of great importance to spare patients the morbidity of LTS and risks of restenosis associated with these treatments. Laboratory and clinical trials have focused on fibrosis, the crucial pathological process of LTS. This study was undertaken to investigate the function of CXC chemokine receptor-7 (CXCR7) in the fibroblasts derived from LTS. Methods: RNA sequencing was performed on acquired human LTS and normal trachea tissues to analyze differentially expressed genes. Fibroblasts from LTS and normal trachea tissues were isolated and cultured. CXCR7 knockdown was performed using specific small interfering RNAs (siRNAs) and activated by CXCR7 agonist VUF11207. The assessment of cell proliferation and migration was conducted using EdU proliferation, wound healing, and transwell assays. The assessment of cell proliferation and migration was conducted using EdU proliferation, wound healing, and transwell assays. The expressions of CXCR7, E-cadherin and NF-κB signaling pathway were analyzed by quantitative polymerase chain reaction (qPCR), western blotting, immunohistochemistry, and immunofluorescence. Results: RNA sequencing showed that CXCR7 was among the most differentially expressed genes. LTS had an increased CXCR7 expression but decreased E-cadherin expression in vivo. CXCR7 agonist stimulated the migration of LTS derived fibroblasts significantly in vitro, with no significant influence on the cell proliferation and apoptosis. CXCR7 agonist inhibited the expression of E-cadherin by activating the NF-κB signaling pathway. The effects of CXCR7 on cell migration and E-cadherin expression were blocked by CXCR7 siRNA. Conclusions: LTS had an increased CXCR7 expression but decreased E-cadherin expression. CXCR7 activation inhibited E-cadherin expression by NF-κB signaling pathway and thereby promoted the migration of LTS derived fibroblasts.

Glia Cells Control Olfactory Neurogenesis by Fine-Tuning CXCL12.

Olfaction depends on lifelong production of sensory neurons from CXCR4 expressing neurogenic stem cells. Signaling by CXCR4 depends on the concentration of CXCL12, CXCR4's principal ligand. Here, we use several genetic models to investigate how regulation of CXCL12 in the olfactory stem cell niche adjusts neurogenesis. We identify subepithelial tissue and sustentacular cells, the olfactory glia, as main CXCL12 sources. Lamina propria-derived CXCL12 accumulates on quiescent gliogenic stem cells via heparan sulfate. Additionally, CXCL12 is secreted within the olfactory epithelium by sustentacular cells. Both sustentacular-cell-derived and lamina propria-derived CXCL12 are required for CXCR4 activation. ACKR3, a high-affinity CXCL12 scavenger, is expressed by mature glial cells and titrates CXCL12. The accurate adjustment of CXCL12 by ACKR3 is critical for CXCR4-dependent proliferation of neuronal stem cells and for proper lineage progression. Overall, these findings establish precise regulation of CXCL12 by glia cells as a prerequisite for CXCR4-dependent neurogenesis and identify ACKR3 as a scavenger influencing tissue homeostasis beyond embryonic development.

Expression of CXCL12-CXCR4/CXCR7 chemokines in splenic fibrosis of cirrhotic spleen and its therapeutic significance.

Introduction: To investigate the expression and treatment of chemokine CXCL12 and its receptor CXCR4/CXCR7. Methods: The liver cirrhosis hypersplenism model of rats was made with CCL4, and then was detected by immunohistochemistry, Western blot and qRT-PCR. Results: The area of spleen fibrosis in the model group was significantly larger than that in the control group (p < 0.01), and the expression of CXCL12, CXCR4 and CXCR7 in the model group was significantly higher than that in the control group (p < 0.01). Conclusions: CXCL12-CXCR4/CXCR7 is abnormally high in splenic fibrosis, and blocking its high expression can slow down the occurrence of hypersplenism.

Tamoxifen as a modulator of CXCL12-CXCR4-CXCR7 chemokine axis: A breast cancer and glioblastoma view.

The chemokine stromal cell-derived-factor 1 (SDF)-1/CXCL12 acts by binding to its receptors, the CXC-4 chemokine receptor (CXCR4) and the CXC-7 chemokine receptor (CXCR7). The binding of CXCL12 to its receptors results in downstream signaling that leads to cell survival, proliferation and migration of tumor cells. CXCL12 and CXCR4 are highly expressed in breast cancer (BC) and glioblastoma (GBM) compared to normal cells. High expression of this chemokine axis correlates with increased therapy resistance and grade, tumor spread and poorer prognosis in these tumors. Tamoxifen (TMX) is a selective estrogen receptor modulator (SERM) that inhibits the expression of estrogen-regulated genes, including growth and angiogenic factors secreted by tumor cells. Additionally, TMX targets several proteins, such as protein kinase C (PKC), phospholipase C (PLC), P-glycoprotein (PgP), phosphatidylinositol-3-kinase (PI3K) and ion channels. This drug showed promising antitumor activity against both BC and GBM cells. In this review, we discuss the role of the CXCL12-CXCR4-CXCR7 chemokine axis in BC and GBM tumor biology and propose TMX as a potential modulator of this axis in these tumors. TMX modulates the CXCL12-CXCR4-CXCR7 axis in BC, however, there are no studies on this in GBM. We propose that studying this axis in GBM cells/patients treated with TMX might be beneficial for these patients. TMX inhibits important signaling pathways in these tumors and the activation of this chemokine axis is associated with increased therapy resistance.

CXCL12/CXCR4/CXCR7 axis in placenta tissues of patients with placenta previa.

CXCR4 and CXCR7 have been revealed to be receptors of CXCL12. This research was designed to probe the expression of chemokine CXCL12 and its receptors CXCR4 and CXCR7 in placental tissues of patients with placenta previa and the effect of CXCL12/CXCR4/CXCR7 axis on the biological functions of human trophoblast cells. CXCL12, CXCR4, and CXCR7 expression in placental tissue from patients with placenta previa and healthy puerperae was detected. CXCL12, CXCR4, and CXCR7 expression in human trophoblast cell lines (HTR8/SVneo cells) was assessed after suppression or overexpression of CXCL12, CXCR4, and CXCR7. The cell proliferative, invasive, and migratory capacities were also evaluated in HTR8/SVneo cells after suppression or overexpression of CXCL12, CXCR4, and CXCR7. CXCL12, CXCR4, and CXCR7 expression was elevated in placental tissues from patients with placenta previa. Downregulation of CXCL12, CXCR4, and CXCR7 could lead to decreased mRNA levels of CXCL12, CXCR4, and CXCR7 in HTR-8/SVneo cells, which was accompanied by diminished cell proliferative, migratory, and invasive capabilities. Overexpression of CXCL12, CXCR4, and CXCR7 genes presented an opposite tendency. CXCL12, CXCR4, and CXCR7 are highly expressed in placental tissues of patients with placenta previa and induce the biological activities of HTR8/SVneo cells.

CXCL12-CXCR4/CXCR7 Axis in Cancer: from Mechanisms to Clinical Applications.

Cancer is a multi-step disease caused by the accumulation of genetic mutations and/or epigenetic changes, and is the biggest challenge around the world. Cytokines, including chemokines, exhibit expression changes and disorders in all human cancers. These cytokine abnormalities can disrupt homeostasis and immune function, and make outstanding contributions to various stages of cancer development such as invasion, metastasis, and angiogenesis. Chemokines are a superfamily of small molecule chemoattractive cytokines that mediate a variety of cellular functions. Importantly, the interactions of chemokine members CXCL12 and its receptors CXCR4 and CXCR7 have a broad impact on tumor cell proliferation, survival, angiogenesis, metastasis, and tumor microenvironment, and thus participate in the onset and development of many cancers including leukemia, breast cancer, lung cancer, prostate cancer and multiple myeloma. Therefore, this review aims to summarize the latest research progress and future challenges regarding the role of CXCL12-CXCR4/CXCR7 signaling axis in cancer, and highlights the potential of CXCL12-CXCR4/CXCR7 as a biomarker or therapeutic target for cancer, providing essential strategies for the development of novel targeted cancer therapies.

New pairings and deorphanization among the atypical chemokine receptor family - physiological and clinical relevance.

Atypical chemokine receptors (ACKRs) form a small subfamily of receptors (ACKR1-4) unable to trigger G protein-dependent signaling in response to their ligands. They do, however, play a crucial regulatory role in chemokine biology by capturing, scavenging or transporting chemokines, thereby regulating their availability and signaling through classical chemokine receptors. ACKRs add thus another layer of complexity to the intricate chemokine-receptor interaction network. Recently, targeted approaches and screening programs aiming at reassessing chemokine activity towards ACKRs identified several new pairings such as the dimeric CXCL12 with ACKR1, CXCL2, CXCL10 and CCL26 with ACKR2, the viral broad-spectrum chemokine vCCL2/vMIP-II, a range of opioid peptides and PAMP-12 with ACKR3 as well as CCL20 and CCL22 with ACKR4. Moreover, GPR182 (ACKR5) has been lately proposed as a new promiscuous atypical chemokine receptor with scavenging activity notably towards CXCL9, CXCL10, CXCL12 and CXCL13. Altogether, these findings reveal new degrees of complexity of the chemokine network and expand the panel of ACKR ligands and regulatory functions. In this minireview, we present and discuss these new pairings, their physiological and clinical relevance as well as the opportunities they open for targeting ACKRs in innovative therapeutic strategies.