Academic literature on the topic 'CXCR4 signalling'
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Journal articles on the topic "CXCR4 signalling"
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Ray, Paramita, Sarah A. Lewin, Laura Anne Mihalko, Sasha-Cai Lesher-Perez, Shuichi Takayama, Kathryn E. Luker, and Gary D. Luker. "Secreted CXCL12 (SDF-1) forms dimers under physiological conditions." Biochemical Journal 442, no. 2 (February 13, 2012): 433–42. http://dx.doi.org/10.1042/bj20111341.
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Chemokine CXCL12 (CXC chemokine ligand 12) signalling through CXCR (CXC chemokine receptor) 4 and CXCR7 has essential functions in development and underlies diseases including cancer, atherosclerosis and autoimmunity. Chemokines may form homodimers that regulate receptor binding and signalling, but previous studies with synthetic CXCL12 have produced conflicting evidence for homodimerization. We used bioluminescence imaging with GL (Gaussia luciferase) fusions to investigate dimerization of CXCL12 secreted from mammalian cells. Using column chromatography and GL complementation, we established that CXCL12 was secreted from mammalian cells as both monomers and dimers. Secreted CXCL12 also formed homodimers in the extracellular space. Monomeric CXCL12 preferentially activated CXCR4 signalling through Gαi and Akt, whereas dimeric CXCL12 more effectively promoted recruitment of β-arrestin 2 to CXCR4 and chemotaxis of CXCR4-expressing breast cancer cells. We also showed that CXCR7 preferentially sequestered monomeric CXCL12 from the extracellular space and had minimal effects on dimeric CXCL12 in cell-based assays and an orthotopic tumour xenograft model of human breast cancer. These studies establish that CXCL12 secreted from mammalian cells forms homodimers under physiological conditions. Since monomeric and dimeric CXCL12 have distinct effects on cell signalling and function, our results have important implications for ongoing efforts to target CXCL12 pathways for therapy.
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Gonzalez-Meljem, Jose Mario, Sarah Ivins, Cynthia Lilian Andoniadou, Paul Le Tissier, Peter Scambler, and Juan Pedro Martinez-Barbera. "An expression and function analysis of the CXCR4/SDF-1 signalling axis during pituitary gland development." PLOS ONE 18, no. 2 (February 17, 2023): e0280001. http://dx.doi.org/10.1371/journal.pone.0280001.
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The chemokine SDF-1 (CXCL12) and its receptor CXCR4 control several processes during embryonic development such as the regulation of stem cell proliferation, differentiation, and migration. However, the role of this pathway in the formation of the pituitary gland is not understood. We sought to characterise the expression patterns of CXCR4, SDF-1 and CXCR7 at different stages of pituitary gland development. Our expression profiling revealed that SDF-1 is expressed in progenitor-rich regions of the pituitary anterior lobe, that CXCR4 and CXCR7 have opposite expression domains and that CXCR4 expression is conserved between mice and human embryos. We then assessed the importance of this signalling pathway in the development and function of the murine pituitary gland through conditional deletion of CXCR4 in embryonic pituitary progenitors. Successful and specific ablation of CXCR4 expression in embryonic pituitary progenitors did not lead to observable embryonic nor postnatal defects but allowed the identification of stromal CXCR4+ cells not derived from HESX1+ progenitors. Further analysis of constitutive SDF-1, CXCR7 and CXCR4 mutants of the pathway indicates that CXCR4 expression in HESX1+ cells and their descendants is not essential for normal pituitary development in mice.
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Friedman, Daniel, Antony Long, Piers EM Patten, and Robbert Hoogeboom. "Identification of a Novel Proliferating Cell Fraction in Chronic Lymphocytic Leukaemia with High Expression of IgM and Chemokine Receptors." Blood 138, Supplement 1 (November 5, 2021): 3711. http://dx.doi.org/10.1182/blood-2021-153415.
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Abstract Chronic lymphocytic leukaemia (CLL) is characterised by the accumulation of malignant CD5+ B cells in the peripheral blood (PB), secondary lymphoid tissues and bone marrow. Currently considered an incurable disease, B cell receptor (BCR) signalling plays a key role in the disease aetiology as evidenced by the therapeutic success of BCR signalling inhibitors such as ibrutinib. Previous studies using incorporation of 2H-labelling of DNA in vivo demonstrated sub-clonal heterogeneity in PB CLL cell fractions sorted based on reciprocal densities of chemokine C-X-C motif receptor 4 (CXCR4) and CD5. The CXCR4 loCD5 hi fraction was shown to be enriched in recently born proliferating cells while the CXCR4 hiCD5 lo fraction consists of resting, quiescent cells thought to reflect their migratory and BCR signalling histories in tissue. Whilst these proliferating/resting fractions have since been more closely examined, the remaining bulk PB CLL population has been left relatively unexplored leaving other therapeutically relevant cell fractions undetected. Here, we have comprehensively analysed the phenotype of subpopulations of PB cells from 11 CLL patients using flow cytometry to identify activated and proliferating cell fractions. CD19 +CD5 +cells were divided into 9 fractions based on CXCR4/CD5 densities and to permit comparisons between fractions, each cell fraction was defined as containing 1-2% of the total clonal CD19 +CD5 + population. Surprisingly, we detected enrichment for Ki67+ proliferating cells and high expression of AID in the cell fraction with highest expression levels of both CXCR4 and CD5 (CXCR4 hiCD5 hi), demonstrating that CXCR4 loCD5 hi cells are not the only proliferating fraction in the blood. Moreover, we could detect mitotic cells in the CXCR4 hiCD5 hi fraction using imaging flow cytometry of a nuclear stain. This CXCR4 hiCD5 hi fraction showed the highest surface expression levels of IgM, CD86, CCR7, CXCR3 and CXCR5 of all the fractions assessed (p<0.05), indicating they are highly activated and primed for migration to lymph nodes (LNs) for further activation and proliferation. Proliferation of CLL cells is highest in secondary lymphoid tissues, however the phenotype of proliferating cells in tissue is unknown. To examine the phenotype of proliferating CLL cells in LNs, we analysed a fine-needle aspirate obtained from an enlarged cervical node using flow cytometry and compared this to a matched PB sample. Flow cytometric gates set on the PB sample were used to define and quantify LN cell fractions. Expression levels of both Ki67 and surface IgM were highest in the CXCR4 hiCD5 hi fraction which was expanded to 20% of the CD19 +CD5 + population in the LN whilst CXCR4 loCD5 hi cells (accounting for 2% of the bulk LN population) expressed very low surface IgM and Ki67 levels, suggesting CXCR4 hiCD5 hi cells may be the most proliferative cells in CLL. The CXCR4 loCD5 hi cell fraction has been shown to be a key target of ibrutinib, however the impact of ibrutinib on the CXCR4 hiCD5 hi fraction is unknown. Administration of ibrutinib to PB CLL cells for 48hr in vitro resulted in selective targeted depletion of the CXCR4 loCD5 hi fraction, as evidenced by induction of apoptotic markers in this compartment; conversely, persistent cells after 48hr ibrutinib administration in vitro were exclusively of the CXCR4 hi phenotype. In conclusion, we have identified a potentially dangerous fraction of proliferating cells in the PB of CLL patients with high expression of CXCR4, CD5, IgM, CCR7, CXCR3 and CXCR5 open for both migration to tissue and reception of BCR signals. Furthermore, CXCR4 hiCD5 hi cells in the periphery may closely mirror tissue-resident activated cell phenotypes and may represent critical targets for therapeutic intervention, particularly in high-risk CLL patients refractory to BCR inhibitor therapies. Disclosures Patten: ROCHE: Research Funding; GILEAD SCIENCES: Honoraria, Research Funding; NOVARTIS: Honoraria; JANSSEN: Honoraria; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria.
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Barbieri, Federica, Stefano Thellung, Roberto Würth, Federico Gatto, Alessandro Corsaro, Valentina Villa, Mario Nizzari, Manuela Albertelli, Diego Ferone, and Tullio Florio. "Emerging Targets in Pituitary Adenomas: Role of the CXCL12/CXCR4-R7 System." International Journal of Endocrinology 2014 (2014): 1–16. http://dx.doi.org/10.1155/2014/753524.
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Chemokines are chemotactic regulators of immune surveillance in physiological and pathological conditions such as inflammation, infection, and cancer. Several chemokines and cognate receptors are constitutively expressed in the central nervous system, not only in glial and endothelial cells but also in neurons, controlling neurogenesis, neurite outgrowth, and axonal guidance during development. In particular, the chemokine CXCL12 and its receptors, CXCR4 and CXCR7, form a functional network that controls plasticity in different brain areas, influencing neurotransmission, neuromodulation, and cell migration, and the dysregulation of this chemokinergic axis is involved in several neurodegenerative, neuroinflammatory, and malignant diseases. CXCR4 primarily mediates the transduction of proliferative signals, while CXCR7 seems to be mainly responsible for scavenging CXCL12. Importantly, the multiple intracellular signalling generated by CXCL12 interaction with its receptors influences hypothalamic modulation of neuroendocrine functions, although a direct modulation of pituitary functioningviaautocrine/paracrine mechanisms was also reported. Both CXCL12 and CXCR4 are constitutively overexpressed in pituitary adenomas and their signalling induces cell survival and proliferation, as well as hormonal hypersecretion. In this review we focus on the physiological and pathological functions of immune-related cyto- and chemokines, mainly focusing on the CXCL12/CXCR4-7 axis, and their role in pituitary tumorigenesis. Accordingly, we discuss the potential targeting of CXCR4 as novel pharmacological approach for pituitary adenomas.
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Weissleder, Christin, Maree J. Webster, and Cynthia Shannon Weickert. "M174. REDUCED CHEMOKINE SIGNALLING CAPACITY IS ASSOCIATED WITH INHIBITORY INTERNEURON DYSFUNCTION IN SUBCORTICAL BRAIN REGIONS IN SCHIZOPHRENIA AND BIPOLAR DISORDER." Schizophrenia Bulletin 46, Supplement_1 (April 2020): S202—S203. http://dx.doi.org/10.1093/schbul/sbaa030.486.
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Abstract Background The subependymal zone (SEZ) adjacent to the lateral ventricles represents the largest reservoir of postnatally-generated cortical and striatal inhibitory interneurons in the human brain. Expression of markers representing the generation of neuronal progenitors from neural stem cells is reduced in the adult SEZ in schizophrenia and bipolar disorder; however, underlying mechanisms and relationships to inhibitory interneuron dysfunction remain unknown. Stem cell maintenance, neuronal migration and cell survival are regulated by signaling of the CXC motif chemokine 12 (CXCL12) through CXC motif chemokine receptors 4 (CXCR4) and 7 (CXCR7), which are increasingly implicated in the pathophysiology of psychiatric disorders. Methods Post-mortem tissue was obtained from 33 schizophrenia, 32 bipolar disorder and 33 control cases from the Stanley Medical Research Institute. SEZ and caudate nucleus tissue was dissected from 60 µm sections for RNA isolation and cDNA synthesis. Gene expression of CXCL12, CXCR4 and CXCR7 were determined by quantitative polymerase chain reactions. Semi-partial correlations were performed to assess whether CXC chemokine family member mRNAs may correlate with markers of neural stem cells (PROM1, GFAPD), neuronal progenitors (SOX2, ASCL1) and inhibitory interneurons (CALB2, NPY) in the SEZ and caudate nucleus. Results In the SEZ, CXCL12 mRNA was decreased in schizophrenia compared to controls and bipolar disorder (14–24%, all p≤0.03). CXCR4 and CXCR7 mRNAs were both decreased in schizophrenia and bipolar disorder compared to controls (9–33%, all p≤0.05). CXCL12, CXCR4 and CXCR7 expression positively correlated with PROM1, GFAPD, SOX2 and ASCL1 mRNAs (0.28≥sr≤0.61). In the caudate nucleus, CXCL12 mRNA was decreased in schizophrenia and bipolar disorder compared to controls (19–26%, all p≤0.05). CXCR4 mRNA was decreased in schizophrenia compared to controls (20%, p=0.01), while CXCR7 expression did not significantly differ across diagnostic groups. CALB2 and NPY mRNAs were increased in bipolar disorder compared to controls (13–27%, all p≤0.05). CXCR4 expression positively correlated with CALB2 mRNA (sr=0.26), while CXCR7 expression negatively correlated with NPY mRNA (sr=0.26). Discussion These findings provide the first molecular evidence of decreased CXC chemokine family member expression in the SEZ and caudate nucleus in psychiatric disorders, with exacerbated deficits in schizophrenia compared to bipolar disorder. Dysregulated CXC chemokine family member expression may hamper neural stem cell maintenance and neuronal differentiation, which may contribute to inhibitory interneuron dysfunction in psychiatric disorders. Future work will determine the cellular localisation of CXCR4 and CXCR7 expression in the SEZ and caudate nucleus to disentangle the regulatory role of CXCL12 signalling in the generation, migration and survival of inhibitory interneurons in the human brain.
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Willett, Brian J., Karen Adema, Nikolaus Heveker, Anne Brelot, Laurent Picard, Marc Alizon, Julie D. Turner, et al. "The Second Extracellular Loop of CXCR4 Determines Its Function as a Receptor for Feline Immunodeficiency Virus." Journal of Virology 72, no. 8 (August 1, 1998): 6475–81. http://dx.doi.org/10.1128/jvi.72.8.6475-6481.1998.
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ABSTRACT The feline homolog of the α-chemokine receptor CXCR4 has recently been shown to support cell-cell fusion mediated by CXCR4-dependent strains of human immunodeficiency virus (HIV) and strains of feline immunodeficiency virus (FIV) that have been selected for growth in the Crandell feline kidney (CrFK) cell line. In this report we demonstrate that expression of CXCR4 alone is sufficient to render cells from diverse species permissive for fusion with FIV-infected cells, suggesting that CXCR4 is the sole receptor for CrFK-tropic strains of FIV, analogous to CD4-independent strains of HIV-2. To identify the regions of CXCR4 involved in fusion mediated by FIV, we screened panels of chimeric CXCR4 molecules for the ability to support fusion with FIV-infected cells. Human CXCR4 supported fusion more efficiently than feline CXCR4 and feline/human CXCR4 chimeras, suggesting that the second and third extracellular loops of human CXCR4 contain a critical determinant for receptor function. Rat/human CXCR4 chimeras suggested that the second extracellular loop contained the principal determinant for receptor function; however, chimeras constructed between human CXCR2 and CXCR4 revealed that the first and third loops of CXCR4 contribute to the FIV Env binding site, as replacement of these domains with the corresponding domains of CXCR2 rendered the molecule nonfunctional in fusion assays. Mutation of the DRY motif and the C-terminal cytoplasmic tail of CXCR4 did not affect the ability of the molecule to support fusion, suggesting that neither signalling via G proteins nor receptor internalization was required for fusion mediated by FIV; similarly, truncation of the N terminus of CXCR4 did not affect the function of the molecule as a receptor for FIV. CXCR4-transfected feline cells were rendered permissive for infection with both the CrFK-tropic PET isolate of FIV and the CXCR4-dependent RF strain of HIV-1, and susceptibility to infection correlated well with ability to support fusion. The data suggest that the second extracellular loop of CXCR4 is the major determinant of CXCR4 usage by FIV.
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Arvidsson, Yvonne, Anders Bergström, Linda Arvidsson, Erik Kristiansson, Håkan Ahlman, and Ola Nilsson. "Hypoxia stimulates CXCR4 signalling in ileal carcinoids." Endocrine-Related Cancer 17, no. 2 (June 2010): 303–16. http://dx.doi.org/10.1677/erc-09-0085.
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Tumour hypoxia is associated with increased metastatic potential and resistance to radiotherapy and chemotherapy. Ileal carcinoids are usually metastatic at the time of diagnosis and respond poorly to chemotherapy. The aim of this study was to investigate the extent of hypoxia in ileal carcinoids and the response of tumour cells to induced hypoxia. Vascular endothelial growth factor (VEGF), carbonic anhydrase (CA-IX), hypoxia-inducible factor (HIF)-1α and HIF-2α were studied by immunohistochemistry in biopsies from 24 patients with ileal carcinoids. All hypoxic markers were shown to be highly expressed in localized areas of the tumours irrespective of tumour location or stage. However, HIF-2α expression was significantly higher in distant metastases compared to primary tumours in the same patient. Global gene expression profiling of GOT1 carcinoid cells revealed a marked response to hypoxia. Expression of genes related to epithelial-to-mesenchymal transition and development was altered including increased expression of the C-X-C chemokine receptor type 4 (CXCR4), an important regulator of invasive growth and metastasis formation. High expression of CXCR4 was confirmed by immunohistochemistry in tumour biopsies. Stimulation of GOT1 cells by the CXCR4 ligand, CXCL12 (stromal cell-derived factor 1 (SDF-1)), activated the mitogen-activated protein kinase (MAPK) p42/44 signalling pathway and increased tumour cell migration. We conclude that ileal carcinoids contain hypoxic areas expressing HIF-1α, HIF-2α and CXCR4. Signalling through the CXCL12–CXCR4 axis may contribute to the metastatic potential of ileal carcinoids. Targeting of HIFs and/or the CXCR4 signalling pathway may offer new therapeutic strategies for carcinoid tumour disease.
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Murphy, Philip T., Brendan p. Power, Patrick D. Thornton, and Judith H. Harmey. "Regulation of B-Cell Chronic Lymphocytic Leukaemia Cell Survival and Migration by the VEGF/SEMA3A Axis." Blood 112, no. 11 (November 16, 2008): 2083. http://dx.doi.org/10.1182/blood.v112.11.2083.2083.
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Abstract B-cell Chronic Lymphocytic Leukaemia (B-CLL) is characterized by the accumulation of B-CLL lymphocytes in the blood, marrow and secondary lymphoid tissues. B-CLL cells have a long survival owing to alterations in the normal pathways of apoptosis. In the marrow and lymphoid tissues CLL cells are in close contact with stromal cells that constitute distinct microenvironments. The secretion of the CXCR4 ligand, CXCL12, by stromal cells attracts B-CLL cells and provides protection from spontaneous or induced apoptosis. Studies in other cell types have shown VEGF signalling is involved in regulating CXCR4 expression levels. The aim of this study was to examine VEGF receptor expression and the role of VEGF signalling in cell survival and CXCR4 expression. Expression levels of CXCR4 and VEGF receptors, VEGFR-1 and -2, in CLL samples were determined by flow cytometry. Expression of the VEGFR co-receptor, Neuropilin-1 (NRP1), was examined by Western blot. Cell migration towards CXCL12 was assessed using CoStar Transwell chambers (5mm pore size). Informed consent was received from all patients. VEGFR1 and VEGFR2 positive cells in 22 patient samples ranged from 0–38% and 1.5–83% respectively. NRP1 expression was detected in all samples analysed thus far (n=6). The NRP1 ligand, SEMA3A, a competitive inhibitor of VEGF binding to NRP1, decreased CXCR4 expression in patient CLL cells (n=8, p<0.05). This decrease in CXCR4 levels correlated with reduced migration of SEMA3A treated CLL cells towards CXCL12 (88 +/− 12.7% of control levels, n=8, p<0.05). Treatment of CLL cells with the VEGFR signalling inhibitor SU5416 decreased CLL cell survival which correlated with VEGFR1 expression levels (n=16, R=0.745, p<0.01) but not with VEGFR2 expression levels. These results show that signalling through the VEGF co-receptor NRP1 plays an important role in regulating CXCR4 levels in CLL cells, as well as CLL cell migration along a CXCL12 gradient. Our results also suggest that VEGF signalling through VEGFR1 may be particularly important in regulating CLL cell survival. Thus, the VEGFR/NRP1 signalling pathway may represent an important therapeutic target in B-CLL.
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Tiveron, Marie-Catherine, and Harold Cremer. "CXCL12/CXCR4 signalling in neuronal cell migration." Current Opinion in Neurobiology 18, no. 3 (June 2008): 237–44. http://dx.doi.org/10.1016/j.conb.2008.06.004.
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Boujedidi, Hédia, Olivier Robert, Alexandre Bignon, Anne-Marie Cassard-Doulcier, Marie-Laure Renoud, Hélène Gary-Gouy, Patrice Hemon, et al. "CXCR4 dysfunction in non-alcoholic steatohepatitis in mice and patients." Clinical Science 128, no. 4 (October 17, 2014): 257–67. http://dx.doi.org/10.1042/cs20130833.
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The CXCL12/CXCR4 signalling pathway contributes in both mice and patients to the enhanced recruitment of CD4+ T-cells in NASH. An increased affinity of the chemokine CXCL12 to its main receptor CXCR4 is involved in this process.
Dissertations / Theses on the topic "CXCR4 signalling"
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Ablett, Matthew. "Discovery and investigation of CXCR4 signalling in breast stem cell-enriched populations." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/discovery-and-investigation-of-cxcr4-signalling-in-breast-stem-cellenriched-populations(feed5c92-01b0-4a07-95fe-72e4babda0b0).html.
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C-X-C chemokine receptor type 4 (CXCR4) is known to regulate lung, pancreatic and prostate cancer stem cells. In breast cancer, CXCR4 signalling via stromal cell-derived factor-1 (SDF-1) has been reported to be a mediator of metastasis, and is linked to poor prognosis. However its role in normal and malignant breast stem cell function has not been investigated. Anoikis-resistant (AR) cells were collected from mammosphere culture from 2 immortalised (MCF10A, 226L) and 3 malignant (MCF7, T47D, SKBR3) breast cell lines. For all cell lines, AR cells had a significantly higher mammosphere forming efficiency (MFE) than unsorted cells. The AR cells of the normal cell lines also demonstrated increased formation of 3D structures using the Matrigel assay. In vivo, MCF7 and T47D AR cells demonstrated increased capacity to form tumours compared with unsorted cells. This suggests that AR cells are enriched for normal and malignant breast stem cells. We performed an Agilent custom gene microarray and demonstrated up-regulation of CXCR4 mRNA expression in AR cells. CXCR4 protein expression was also higher in AR cells, shown by flow cytometry. The effects of AMD3100 (CXCR4 antagonist) and SDF-1 (CXCR4 ligand) on stem cell activity were investigated in the mammosphere assay. In the normal cell lines, SDF-1 significantly reduced MFE and this decrease was rescued by AMD3100. Incubation with AMD3100 increased MFE in the estrogen receptor positive breast cancer cell lines (MCF7 and T47D) and patient-derived metastatic tumour samples. AMD3100 reduced the self-renewal of T47D cells, as assessed by second generation mammospheres. MCF7 cells were retro-virally transfected to over-express CXCR4 or sorted for CXCR4 cell surface expression. Mammosphere formation was significantly increased in CXCR4+ and CXCR4 over-expressing cells compared with CXCR4- and parental cells. There was a greater reduction in self-renewal following AMD3100 treatment in the CXCR4 over-expressing cells compared with parental cells. AMD3100 has been shown to have an agonistic effect on the novel chemokine receptor CXCR7, a scavenging receptor for SDF-1. All cell lines demonstrated cell surface expression of CXCR7, measured by flow cytometry and mRNA expression. Potential interactions between CXCR4, CXCR7 and SDF-1 must be considered in future investigation of the role of CXCR4 signalling. Our data establish that CXCR4 signalling has contrasting effects on normal and malignant breast stem cell activity. CXCR4 influences self-renewal of malignant stem cells which may account for its role in tumorigenesis. CXCR4 signalling may be important in tumour formation at the sites of metastases as well as in cell migration. Its role in stem cell migration merits further investigation. In conclusion, CXCR4-targeted therapy, alongside current standards of care, may improve breast cancer outcomes.
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Karatt, Vellatt Aneesh. "Investigating the potential of antibody and peptide blockade of CXCL12/CXCR4 signalling." Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708501.
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Goh, Poh. "Roles of protein kinase C and arrestin in migration of cells via CXCR4/CXCL12 signalling axis." Thesis, University of East Anglia, 2018. https://ueaeprints.uea.ac.uk/67806/.
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Aim: The chemokine system not only coordinates leukocyte migration in immunity and inflammation, but it is also implicated in the pathogenesis of many human diseases, including cancer. The expression of chemokines and their receptors is altered in many malignancies and leads to aberrant chemokine receptor signalling. Emerging evidence indicates that the tumour microenvironment has critical roles in all aspects of cancer biology, including growth, angiogenesis, metastasis and progression. One of the important representatives of this system are the chemokine ligand CXCL12 and its receptor, CXCR4 as they are most commonly found on human and murine cancer cells. Our aims are to study and understand if there are any differences in activation of signalling molecules in the downstream signalling cascades in CXC- chemokine receptors in different cell types, and to identify the importance of different effector proteins in migration of cells; the two proteins of interest include Protein Kinase C (PKC) and arrestins. Methodology: Experimentation was undertaken in MCF-7 breast cancer cells and Jurkat leukemic T-lymphocytes which both naturally express the chemokine receptor CXCR4. Small molecule inhibition and protein overexpression was used in chemotaxis and calcium release assays to measure cellular responses. Immunocytochemistry was used to determine the effect of protein blocking and protein overexpression on receptor internalisation, protein localisation and the formation of cellular structures associated with migration. Results: Inhibition of PKC has no effect on Jurkat cell migration, but it blocks MCF-7 cell migration showing that there is a difference in the usage of PKC in different cell types. Arrestin 3 is important for migration in both suspension Jurkat cells and adherent breast cancer MCF-7 cells. Conclusion: Our study shows that CXCL12-induced migration may be arrestin 3 mediated. We have also shown that activation of signalling molecules needed for CXCL12-induced migration can differ between different cell lines. Overall, the research in this thesis has identified potential signalling molecules that can be targeted to interfere with migration of cells.
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Sotsios, Yannis. "Chemokines and T cells : activation requirements for RANTES secretion and CXCR4 signalling in mature T cells." Thesis, University of Bath, 2000. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323606.
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Chow, Yan Ching Ken. "Role and Molecular Basis of the CXCL12-signalling Axis in the Pathogenesis of WHIM syndrome and the carcinogenesis associated with human papillomavirus (HPV) infection." Paris 7, 2008. http://www.theses.fr/2008PA077129.
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Le syndrome WHIM (SW) est un déficit rare caractérisé par une leuco-neutropénie (e. X. Myélokathexis) et la profusion des verrues cutanées et de carcinomes ano-génitaux due au Papillomavirus Humain (HPV). Il est associé à des dysfonctions du chimiorécepteur CXCR4 en réponse à son ligand SDF-1/CXCL12, qui sont souvent liées à des mutations hétérozygotes de CXCR4 conduisant à la troncation de l'extrémité C-terminale du récepteur impliquée dans le recrutement de l'arrestine (βarr) pour le processus de désensibilisation. Le récepteur muté (e. X. CXCR4¹º¹³) qui n'est donc plus désensibilisé et présente un gain de fonction confère aux leucocytes des patients des réponses exacerbées à CXCL12 dont nous proposons qu'elles contribuent à la pathogenèse du SW. Dans cette thèse, nous montrons que ces dysfonctions impliquent une association inattendue entre CXCR4¹º¹³ et βarr2. Cette interaction se traduit par une activation accrue et prolongée des voies de signalisation dépendantes de βarr2 en aval du récepteur et également de l' intégrité de la troisième boucle intracellulaire de CXCR4¹º¹³. Nous identifions que CXCR4¹º¹³ forme des dimères avec son homologue sauvage au sein desquels une association possible renforcée entre barr2 et CXCR4¹º¹³ pourrait contribuer aux réponses exacerbées à CXCL12. L'expression anormale de CXCL12 que nous avions identifiée dans les lésions dues à HPV provenant d'individus souffrants ou non du SW et le rôle critique de cette chimiokine dans le développement de nombreux cancers suggèrent l'implication de cet axe de signalisation dans la pathogénie virale. Dans les kératinocytes immortalisés par HPV à haut-risque, nous observons une expression anormale de CXCL12 et de ses deux récepteurs que nous caractérisons comme étant dépendante des protéines virales HPV-E6/7 et nécessaire à la prolifération et la migration des kératinocytes. Dans le contexte du SW, ce processus en coopération avec l'activation incontrôlée de CXCR4¹º¹³ pourrait contribuer à la maîignisation des lésions ano-génitales alors même que nous y avons identifié la seule présence d'HPV à faible potentiel cancérogène (bas-risque)The WHIM syndrome (WS) is a rare immunodeficiency characterised by severe leukoneutropenia (e. G. Myelokathexis) and profuse human papillomavirus (HPV)-associated skin lesions and malignant ano-genital cohdyloma. The disease links to dysfunctions of the CXCR4 chemokine receptor in response to its ligand SDF-1/CXCL12, and associates in many cases to heterozygous mutations causing truncation in the cytoplasmic tail of the receptor that is important for the β-arrestin (βarr)-mediated receptor desensitisation process. Such truncated receptor (e. G. CXCR4¹º¹³) displays no desensitisation and thus manifests a gain of function in response to CXCL12 in leukocytes derived from WS patients, which likely contribute to the pathogenesis of the disorder. In this study, we demonstrated that such dysfunctions are in fact dependent on an unexpected interaction between βarr2 and CXCR4¹º¹³. Upon CXCL12 stimulation, the CXCR4¹º¹³receptor displays an augmented and prolonged |3arr2-dépendent signalling that relies on the integrity of the third intracellular loop of the receptor. We have also observed the existence of CXCR4wt/CXCR4¹º¹³ heterodimer from which the possible enhanced parr2/CXCR4¹º¹³ interaction may contribute to the augmented response of the receptor to CXCL12. With the abnormal expression of CXCL12 we observed in HPV-induced lesions derived from both WS and non-WS patients, and the critical role of the chemokine in tumor growth and metastasis, we speculate on the existence of an HPV/CXCL12 interplay that could be crucial for the viral-mediated pathogenesis. Using keratinocytes immortalised by the subgenomic fragment of high-risk HPV, we showed an HPV-E6/7-dependent expression of CXCL12 and its receptors and the critical role of this signalling axis in the prolifération and motility of these cells. In WS, such HPV/CXCL12-interplay may synergise with the hyperfunctioning of CXCR4, and contribute to the malignant development of ano-genital condyloma that is unusually associated with low-risk HPV - the only viral subtype we identified in these lesions
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Greaves, Sarah Jennifer. "Analysis of cd9b in CXCR4b signalling." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/13921/.
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CXCR4b, CXCR7b and their ligand, CXCL12a, are essential for the migration of the posterior lateral line primordium (pLLP) and primordial germ cells (PGCs) in zebrafish (Dambly-Chaudière et al. 2007, Boldajipour et al. 2008). A number of tetraspanins have been shown to affect CXCR4-mediated processes through regulating CXCR4 trafficking or downstream signalling (Yoshida et al. 2008, Li et al. 2011, Leung et al. 2011). Based upon these results we set out to identify candidate tetraspanins that may play a similar role in CXCR4b signalling during pLLP and PGC migration. CD9b, one of the zebrafish homologs of human CD9, was identified as a good candidate gene. Morpholino knock down of cd9b, using either a translation-blocking or splice-site blocking morpholino, resulted in reduced neuromast deposition and abnormal structure of the posterior lateral line. However, morpholinos often have nonspecific effects and so two CD9b knockout lines were created using TALENs. Surprisingly CD9b homozygous mutants showed normal lateral line structure. Preliminary results suggest that the phenotype differences between CD9b morphants and mutants may be due to residual functionality in the wildtype N-terminal of CD9b, upstream of the mutation site, in CD9b mutants. As well as assessment of PGC and pLLP migration, CD9b mutants were also assessed for fertility defects. Significantly reduced numbers of pups are born to CD9 knockout mice. This is due to a requirement of CD9 on the egg membrane for efficient sperm-egg fusion in the CD9-/- female mice (Kaji et al. 2000, Le Naour et al. 2000, Miyado et al. 2000). CD9b -/- zebrafish also appear to have fertility defects. Fewer eggs were laid by CD9b -/- zebrafish pairs and of the eggs laid, a lower percentage were fertilised.
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Steele, Colin W. "Investigating the role of CXCR2 signalling in pancreatic inflammation and cancer." Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5809/.
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C-X-C motif receptor 2 (CXCR2) is a G-protein coupled receptor normally expressed on granulocytes, in particular CD11b +, Gr1+, Ly6G+ bone marrow derived suppressor cells (BMDCs) and once differentiated neutrophils.
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Korniejewska, Anna. "Characterisation of the chemokine receptor CXCR3 and its atypical variants in human T lymphocytes." Thesis, University of Bath, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518106.
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The chemokine receptor CXCR3 and its agonists CXCL9/Mig, CXCL10/IP-10 and CXCL11/I-TAC are involved in a variety of inflammatory disorders including multiple sclerosis, rheumatoid arthritis, psoriasis and sarcoidosis. CXCL11 has also been reported to bind to an additional receptor, namely CXCR7, which also interacts with CXCL12. Two alternatively spliced variants of the human CXCR3 receptor have been described, namely CXCR3-B and CXCR3-alt. The human CXCR3-B has been found to bind CXCL9, CXCL10, CXCL11 as well as an additional agonist CXCL4/PF4. In contrast, CXCR3-alt only binds CXCL11. This work demonstrates that CXCL4 like the original CXCR3 agonists is capable of inducing biochemical signalling, namely intra-cellular calcium elevation, and activation of p44/p42 MAPK and PI3K/Akt pathways in activated human T lymphocytes. Phosphorylation of p44/p42 MAPK and Akt was inhibited by pertussis toxin, suggesting coupling to Gi protein. In contrast CXCR3 antagonists blocked CXCR3 agonists but not CXCL4-mediated responses. Surprisingly, stimulation of T cells with CXCL4 failed to elicit migratory responses of these cells and did not lead to loss of surface CXCR3 expression. Collectively our evidence shows that although CXCL4 is coupled to downstream biochemical machinery, its function in T cells is distinct from the function of CXCR3 agonists. The work presented in this thesis also indicates that despite considerably lower surface expression in comparison to the full length CXCR3, CXCR3-B and CXCR3-alt transduce biochemical signals in response to CXCL11 in transfected cells. According to previous reports the role of CXCR7 in signalling and chemotaxis in T cells could not be detected. In T cells and transfected cells system CXCR7 was localised at the plasma membrane and was efficiently internalized in response to CXCL11 and CXCL12. Studies of the involvement of methylation in T cell chemotaxis suggest that this modification may be required in this process as it was partially inhibited by methylation inhibitor- MTA. Moreover T cell co-stimulation caused increased levels of arginine mono-methylated proteins suggesting the importance of methylation in T lymphocyte signalling.
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Willox, Ian. "Role of the chemokine receptor CXCR3 in human mast cell degranulation and signalling." Thesis, University of Bath, 2009. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.518109.
Full textAbstract:
The chemokine receptor CXCR3, which has three known variants (CXCR3-A, CXCR3-B and CXCR3-Alt), has been implicated in the recruitment of mast cells to tissues in many different chronic diseases with its agonists found in elevated levels in many pulmonary diseases. All three variants of CXCR3 were detected in cord blood-derived mast cells at the mRNA level. Using an antibody that is unable to distinguish individual CXCR3 isoforms, we detected a marked down-regulation of intracellular protein during maturation from progenitor cells, with no concomitant changes in the modest surface expression of CXCR3. The known CXCR3 agonists CXCL9, CXCL10 and CXCL11 as well as the reported CXCR3-B agonist CXCL4, were able to induce Akt and ERK1/2 phosphorylation, as well as partial degranulation. Responses to all agonists were inhibited by pre-treatment with selective CXCR3 antagonists and pertussis toxin. Use of novel isoform-selective inhibitors indicates that the p110 isoform of PI3K is required for degranulation and signalling responses to CXCR3 agonists. Unexpectedly, dual (but not individual) isoform inhibition of the class I and isoforms substantially inhibited signalling and degranulation responses, indicating a hitherto unrecognised synergy between these isoforms, which provide a conduit for CXCR3 signalling in mast cells.
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Georgiou, Kristen Renée. "Role of Wnt/β-catenin and CXCL12/CXCR4 signalling axes in the damage and recovery of the bone marrow microenvironment following methotrexate chemotherapy." Thesis, 2011. http://hdl.handle.net/2440/69318.
Full textAbstract:
The bone marrow microenvironment is home to mesenchymal and haematopoietic stem cells and their respective progeny. Mesenchymal stem cells are multipotent and have the capacity to differentiate into a number of cell types, namely osteoblasts, adipocytes and chondrocytes. These cells and cells of the haematopoietic lineage maintain close interactions within the marrow cavity and are responsible for bone and bone marrow maintenance throughout life. Disruptions to cell populations and steady-state interactions within the bone marrow such as that seen following cancer chemotherapy treatment are associated with bone-related complications in later life such as osteoporosis. However, the underlying mechanisms of these defects and the subsequent recovery potential remain unclear. The studies presented herein have investigated the effects of the commonly used antimetabolite methotrexate (MTX) on the damage and recovery of the bone marrow microenvironment and potential signalling pathways involved, focusing on Wnt/β-catenin and CXCL12/CXCR4 signalling axes. Using a short-term rat MTX model of 5 consecutive daily doses at 0.75mg/kg, histological techniques were employed to assess bone/fat formation and cell culture techniques were used to investigate differentiation potential of bone marrow mesenchymal and haematopoietic cells. These investigations were further supported by protein expression and quantitative RT-PCR analyses of associated genes over the MTX timecourse. The bone marrow cavity was observed to undergo a number of changes when assessed histologically, with damage obvious on days 6 and 9 and recovery apparent by day 14. This was identified by an increased adipogenic marrow and reduced trabecular bone volume, parallel to a reduction in
mineralising potential yet increased adipogenic potential of isolated marrow stromal cells. This was further supported by changes in bone marrow stromal cell gene expression, whereby adipogenic transcription factor PPARγ was increased concurrent to a reduction in osteogenic transcription factor Osterix, indicating a switch in lineage commitment. In order to characterise molecular mechanisms underlying such altered lineage commitment, the role of Wnt/β-catenin signalling was investigated, known to critically function in mesenchymal stem cell differentiation. Interestingly, MTX induced notable changes in Wnt signalling-associated genes assessed in the stromal cell population. Concurrent administration of the synthetic GSK-3β inhibitor BIO abrogated the above transient changes in bone/fat volumes osteogenic/adipogenic commitment and gene expression. This demonstrates a potential role for Wnt/β-catenin signalling in MTX chemotherapy-induced changes to osteogenic/adipogenic commitment and a therapeutic potential for preventing bone loss and marrow adiposity by promoting Wnt signalling via GSK-3β inhibition. Furthermore, to clarify the mechanisms associated with the recovery response of the bone marrow microenvironment, the current project also examined the CXCL12/CXCR4 signalling axis, known to be involved in mobilisation, homing and maintenance of a quiescent stem cell pool, enabling reestablishment of a functioning marrow in response to damaging conditions. After MTX, coinciding with the reduction of marrow cellularity, CXCL12 protein expression was observed to decrease on day 9, accompanied by an increase in CXCL12-degrading metalloproteinase MMP-9. In vitro studies confirmed that recombinant MMP-9 was able to degrade CXCL12 protein. In addition, changes in gene expression of CXCL12 and its receptor CXCR4 in the bone marrow stromal cell population as well as
the non-adherent fraction were observed following MTX treatment. This further suggests the CXCL12/CXCR4 axis is deregulated over the MTX damage/repair time-course and is potentially involved in the regulation of bone marrow damage and recovery.Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2011
Book chapters on the topic "CXCR4 signalling"
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Masyuk, Maryna, and Beate Brand-Saberi. "Recruitment of Skeletal Muscle Progenitors to Secondary Sites: A Role for CXCR4/SDF-1 Signalling in Skeletal Muscle Development." In Results and Problems in Cell Differentiation, 1–23. Berlin, Heidelberg: Springer Berlin Heidelberg, 2014. http://dx.doi.org/10.1007/978-3-662-44608-9_1.
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Korniejewska, Anna, Malcolm Watson, and Stephen Ward. "Analysis of CXCR3 and Atypical Variant Expression and Signalling in Human T Lymphocytes." In Methods in Molecular Biology, 125–47. Totowa, NJ: Humana Press, 2010. http://dx.doi.org/10.1007/978-1-60761-461-6_9.
Full textConference papers on the topic "CXCR4 signalling"
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Tsaouli, G., F. Ferrandino, G. Bernardini, P. Grazioli, AF Campese, D. Bellavia, S. Checquolo, I. Screpanti, and MP Felli. "PO-393 Notch3 and CXCR4 cross-signalling sustains acute T-cell leukaemia progression." In Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.905.
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Ablett, Matthew, Yasushi Kojima, Peter Charlton, Akira Orimo, and Robert Clarke. "Abstract 3339: A role for CXCR4 signalling in the regulation of normal and malignant breast stem cell activity." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-3339.
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