AMD3100 (Plerixafor) is an antagonist of CXCR4, receptor for stromal cell-derived factor-1 (SDF-1).It disrupts binding of SDF-1 to CXCR4 by competing binding site, thus blocking the physiological function of SDF-1/CXCR4 axis. SDF-1/CXCR4 axis has been shown to play critical roles in stem cell mobilization, migration and homing, and in immunoregulation, inflammatory disease, autoimmune disorder, embryonic development, and tumor cell proliferation, migration and location. AMD3100 has been confined effective for the mobilization of HSC and MSC, inhibition of carcinoma growth and metastasis, suppression of some inflammatory and autoimmune disorder. Therefore, further research on AMD3100 will be helpful to understand the effects of bone marrow microenvironment on the pathogenesis of neoplasm, and to restore the traumatic tissues by mobilizing HSC effectively, that might provide a new idea and measure for the treatment of certain neoplasms. Some research progress of basic research and application on AMD3100 are summarized in this review.
Heterocyclic Compounds ; pharmacology ; Receptors, CXCR4 ; antagonists & inhibitors

OBJECTIVE: To evaluate the change of cell surface CXC chemokine receptor 4 (CXCR4) expression of stem cells from apical papilla (SCAP) after the inhibition of endocytotic pathway, thus to provide experimental basis for the mechanism of SCAP migration. METHODS: The immunofluorescence analysis was conducted to examine the co-expression of CXCR4 and endocytotic compartments, including early endosomes, recycling endosomes and lysosomes in SCAP. Several Rab proteins were applied as markers of organelles in the endocytotic pathway, including Rab5 for early endosomes, Rab11A for recycling endosomes, and Lamp1 for lysosomes. The co-localization of CXCR4 with these endodontic compartments was further observed by proximity ligation assay (PLA). SCAP was treated with two kinds of endocytotic inhibitors, Blebbistatin and Dynasore, at a concentration of 80 μmol/L, respectively. The conditioning time was 1 hour. Flow cytometry was carried out to evaluate the proportion of SCAP that expressed CXCR4 on cell surface. The data were analysed by analysis of variance (ANOVA). RESULTS: The red staining of CXCR4 on immunofluorescence confocal microscopy predominantly overlapped with the green staining of Rab5 and Rab11A, and partly overlapped with Lamp1. It indicated that most CXCR4 molecules were located in early endosomes and recycling endosomes, and some were located in lysosomes. The PLA results revealed that the co-localizaiton of CXCR4 with endocytotic compartments could be observed in early endosomes, recycling endosomes and lysosomes. According to the results of flow cytometry, the proportion of SCAP that expressed CXCR4 on cell surface was as low as 0.13%±0.10%. After the inhibition of endocytosis by pretreating the cells with the following two inhibitors, Blebbistatin and Dynasore, the percentage of SCAP that positively expressed CXCR4 on cell surface was significantly increased to 13.34%±1.31% in Blebbistatin group and 4.03%±0.92% in Dynasore group (F=16.721, P<0.001). Moreover, the number of SCAP that expressed CXCR4 on cell surface in Blebbistatin group was significantly higher than that in Dynasore group (P<0.001). CONCLUSION The inhibition of endocytotic pathway could increase the number of SCAP that expressed CXCR4 on cell surface, and provide potency for the migration of SCAP.
Endocytosis ; Endosomes ; Lysosomes ; Receptors, CXCR4 ; Stem Cells

Chemokine CXCL12 ; Child ; Humans ; Neoplasm Metastasis ; Neoplasms ; pathology ; Receptors, CXCR4

BACKGROUND: Tumor associated macrophages (TAMs) and CXC chemokine receptor 4 (CXCR4) have emerged as potential biomarkers in various human cancers. The aims of this study were to investigate the clinical characteristics of anaplastic thyroid cancer (ATC) patients according to the TAM numbers in the tumor tissue, and to evaluate the associations between CXCR4 expressions and macrophage densities in ATC tumor microenvironment. METHODS: Total 14 ATC samples from thyroid tissue microarray were used. Immunohistochemical staining was performed using anti-CD163 and anti-CXCR4 antibodies. According to the immunoreactivity of CD163, all subjects were divided into two groups: low-CD163 (n=8) and high-CD163 (n=6) groups. RESULTS: The mean diagnostic age was 65±7 years and the median tumor size was 4.3 cm, ranging 2.5 to 15 cm. Clinicopathological characteristics were not significantly different between low-CD163 and high-CD163 groups, while age of diagnosis was younger in high-CD163 group than that of low-CD163 group with marginal significance (56.9±5.5 years vs. 67.5±6.8 years, P=0.09). However, overall survival was significantly reduced in high-CD163 group (5.5 months [range, 1 to 10]) compared with low-CD163 groups (8.8 months [range, 6 to 121); log-rank test, P=0.0443). Moreover, high-CD163 group showed strong CXCR4 expressions in both cancer and stromal compartments, while low-CD163 group showed relatively weak, stromal-dominant CXCR4 expressions. Additionally, CD163 and CXCR4 expressions showed a strong positive correlation (γ²=0.432, P=0.013). CONCLUSION: Increased number of TAMs showed poor overall survival in ATC, suggesting TAMs are potentially a prognostic biomarker for ATC. CXCR4 expression was significantly correlated with CD163-positive TAM densities, which suggest the possible role of CXCR4 in TAM recruitments.
Antibodies ; Biomarkers ; Diagnosis ; Humans ; Macrophages* ; Receptors, CXCR* ; Receptors, CXCR4* ; Thyroid Carcinoma, Anaplastic* ; Thyroid Gland ; Tumor Microenvironment

BACKGROUND AND OBJECTIVES: Follicular tumors can present a difficult diagnostic challenge for cytological evaluation and ultrasound findings. Therefore, new methods which could help distinguish follicular adenoma from follicular carcinoma simply and accurately are greatly desired. This study investigated the usefulness of immnunohistochemical expression of CXC chemokine receptor 4 (CXCR4) and galectin-3 as marker of differentiated thyroid carcinomas. MATERIALS AND METHODS: Expression of CXCR4 and galectin-3 were examined immunohistochemically in the 60 paraffin embedded tissues which were already diagnosed as follicular adenoma (n=20), follicullar carcinoma (n=20), and papillary carcinoma (n=20) of thyroid. RESULTS: Galatin-3 was expressed significantly high in follicular carcinoma than follicular adenoma (p=0.022). CXCR4 was also expressed significantly high in follicular carcinoma than follicular adenoma (p=0.027). The sensitivity of CXCR4 and galectin-3 was 70% and 80% and specificity, 65% and 60% for differential diagnosis of follicular tumors. CONCLUSION: An immunohistochemical panel, including galatin-3 and CXCR4, could be useful in the differential diagnosis between follicular adenoma from follicular carcinoma.
Adenoma ; Carcinoma, Papillary ; Diagnosis, Differential ; Galectin 3 ; Paraffin ; Receptors, CXCR ; Receptors, CXCR4 ; Sensitivity and Specificity ; Thyroid Gland

PURPOSE: Experimental studies have suggested that the stromal-derived factor-1 (SDF-1)/CXCR4 axis is associated with tumor aggressiveness and metastasis in several malignancies. We performed a meta-analysis to elucidate the relationship between CXCR4 expression and the clinicopathological features of prostate cancer. MATERIALS AND METHODS: Data were collected from studies comparing Gleason score, T stage, and the presence of metastasis with CXCR4 levels in human prostate cancer samples. The studies were pooled, and the odds ratio (OR) of CXCR4 expression for clinical and pathological variables was calculated. RESULTS: Five articles were eligible for the current meta-analysis. We found no relationship between CXCR4 expression and Gleason score (<7 vs. > or =7). The forest plot using the fixed-effects model indicated an OR of 1.585 (95% confidence interval [CI]: 0.793~3.171; p=0.193). Further, CXCR4 expression was not associated with the T stage ( or =T3), and the relevant meta-analysis showed OR=1.803 (95% CI: 0.756~4.297, p=0.183). However, increased CXCR4 expression was strongly associated with metastatic disease with a fixed-effects pooled OR of 7.459 (95% CI: 2.665~20.878, p<0.001). CONCLUSIONS: Our meta-analysis showed that the higher CXCR4 protein expression in prostate cancer specimens is significantly associated with the presence of metastatic disease. This supports previous experimental data supporting the role played by the SDF-1/CXCR4 axis in metastasis.
Axis, Cervical Vertebra ; Humans ; Neoplasm Grading ; Neoplasm Metastasis* ; Odds Ratio ; Prostatic Neoplasms* ; Receptors, CXCR4

The study on biological effects of SDF-1/CXCR4 axis composed of stromal cell derived factor-1 (SDF-1) and its receptor CXCR4 is progressing rapidly in the recent years. The SDF-1/CXCR4 axis plays an important role in occurrence and development of tumors and closely correlate with angiogenesis of tumors. This review focuses the progress of study on SDF-1/CXCR4 axis and angiogenesis in leukemia including SDF-1/ and its receptor CXCR4, the expression of SDF-1/CXCR4 axis in leukemic cells, the mechanism of relation between SDF-1/CXCR4 axis and angiogenesis in leukemia, the application of inhibitors against SDF-1/CXCR4 in treatment of angiogenesis and so on.
Chemokine CXCL12 ; metabolism ; physiology ; Humans ; Leukemia ; metabolism ; Neovascularization, Pathologic ; Receptors, CXCR4 ; metabolism ; physiology

Multiple myeloma (MM) is a plasma cell malignancy characterized by the high capacity to induce bone destruction. Osteolytic bone lesions in MM patients mainly result from an increased bone resorption related to the stimulation of osteoclast recruitment and activity. SDF-1a would represent a potential role and may provide a suitable therapeutic target for MM-mediated osteolysis. In this article the structure of SDF-1/CXCR4, the expression of SDF-1/CXCR4 in bone microenvironment of MM patients and its effect on osteoclasts, relation of SDF-1/CXCR expression with osteolytic bone lesions and prognosis of MM, SDF-1/CXCR4 as potential target for treatment of myeloma-osteopathia were reviewed.
Chemokine CXCL12 ; metabolism ; physiology ; Humans ; Multiple Myeloma ; complications ; metabolism ; Osteolysis ; etiology ; Receptors, CXCR4 ; metabolism ; physiology

OBJECTIVEThis study further explores the stromal cell-derived factor-1 (SDF-1)/chemokine receptor 4 (CXCR4) signaling axis mechanism in temporomandibular joint osteoarthritis (OA) by detecting the changes in CXCR4, interleukin (IL)-6, and collagen X expression in the ATDC5 cell line stimulated by the cyclic tensile strain and SDF-1.

METHODSInsulin-transferrin-selenium (ITS) was used to induce ATDC5 cells to differentiate into chondrocyte-like cells. After three weeks, the cells were divided into two groups: those with and without cyclic tensile strain. These groups were further divided into the negative control and SDF-1 groups. Strain force of 20% was applied. After 12 h, the total proteins were extracted from cells of the four groups, and Western blot analysis was used to detect the changes in CXCR4, IL-6, and collagen X expression.

RESULTSSDF-1 could enhance CXCR4, IL-6, and collagen X expressions in the chondrocytes, and 20% tensile strain force could further upregulate the three factors.

CONCLUSIONUnder abnormal tensile force, SDF-1 can upregulate its specific receptor CXCR4, thus increasing its-binding efficiency and resulting in the activation of the SDF-1/CXCR4 axis. This condition enhances the expressions of IL-6 and other inflammatory factors and directly damages to cartilage tissue. Such damage directly promotes chondrocyte hypertrophy, which enhances collagen X expression.

Stromal cell derived factor (SDF), expressing on bone marrow stromal cells is a CXC-type chemokine, which specifically chemoattracts hematopoietic stem cells (HSCs) expressing CXCR4. SDF plays important roles in homing and mobilizing of HSCs. In this paper the regulatory mechanism of SDF/CXCR4 in the HSC migration process is mainly reviewed.
Chemokine CXCL12 ; Chemokines, CXC ; physiology ; Hematopoietic Stem Cell Mobilization ; Humans ; Receptors, CXCR4 ; physiology ; Signal Transduction