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Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
In the oncology setting, plerixafor works by inhibiting the alpha CXCR4 chemokine receptor, thus blocking binding of its cognate ligand stromal cell derived factor-1 (SDF-1α). SDF-1α and CXCR4 have been shown to play a role in the trafficking and homing of hematopoietic stem cells (HSC) to the marrow compartment. In the form of its zinc complex, plerixafor acts as an antagonist or partial agonist of CXCR4, and an allosteric agonist of the related CXCR7 which strongly induces mobilization of hematopoietic stem cells from the bone marrow into the bloodstream as peripheral blood stem cells. This mobilization process is important as a prelude to gathering hematopoietic stem cells for transplantation. Mobilization can also be performed using granulocyte-colony stimulating factor (G-CSF) alone but is ineffective in around 15–20% of patients. However, a combination of plerixafor and G-CSF increases the percentage of patients responding to the therapy and allows the production of enough stem cells for transplantation. In this context, it is used for patients with lymphoma and multiple myeloma.
Cell Recruitment for Intervertebral Disc
Published in Raquel M. Gonçalves, Mário Adolfo Barbosa, Gene and Cell Delivery for Intervertebral Disc Degeneration, 2018
Catarina Leite Pereira, Sibylle Grad, Mário Adolfo Barbosa, Raquel M. Gonçalves
CXCL12, first identified as stromal cell derived factor-1α (SDF-1α) in the supernatant of BM stromal cells, is one of the most studied and important chemokines, due to its role in hematopoietic stem and progenitor cell homing and localization in the BM (Rankin 2012). Previous studies reported that SDF-1α activation occurs through two main receptors: CXCR4 and CXCR7. While SDF-1α/CXCR4 plays an important role in stem/progenitor cell migration, CXCR7 functions as a specific scavenger for SDF-1α and was described to modulate the activity of the ubiquitously expressed CXCR4, suggesting a key role in the fine-tuning of stem cell mobility (Naumann et al. 2010).
Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity
Published in OncoImmunology, 2022
Yuan-Na Lin, Marcel O. Schmidt, Ghada M. Sharif, Eveline E. Vietsch, Amber J. Kiliti, Megan E. Barefoot, Anna T. Riegel, Anton Wellstein
CXCL12 is a ligand for CXCR4 and CXCR7.30–32 To examine whether the CXCL12 effect is CXCR4-mediated, resistant PDAC cell spheroids in edT cell co-culture were treated with both CXCL12 and the antagonist AMD3100 (plerixafor). In the presence of AMD3100 we observed a significant decrease of cancer apoptotic rate to a similar level as the untreated group in C8R cells (Figure 5(d)). Consistent with D10R cells not showing a significant CXCL12 effect, AMD3100 treatment also did not significantly decrease cancer cell apoptosis in edT cell co-culture. The lack of an effect was not related to an altered CD8+/CD4+ ratio, or altered T cell apoptosis rate (Suppl. Fig. S6C). Considering that CXCR4 can be expressed on both cancer and T cells,32 CXCR4 protein expression was analyzed via flow cytometry and we found that CXCR4 is expressed on both resistant PDAC cell lines and edT cells (Suppl. Fig. S7A-B). However, CXCR4 surface expression was >3-fold and >10-fold higher on edT CD4+ and CD8+ cells, respectively, relative to PDAC cells (Suppl. Fig. S7B vs A). It is noteworthy that CXCL12 did not impact resistant PDAC spheroid apoptosis in the absence of edT cells (Suppl. Fig. S7C). We conclude from these data that CXCL12 treatment increased killing of resistant PDAC cells through improved effector T cell functionality and increased CD8+ T cell infiltration into spheroids via CXCL12/CXCR4 signaling in CD8+ edT cells.
Role and implications of the CXCL12/CXCR4/CXCR7 axis in atherosclerosis: still a debate
Published in Annals of Medicine, 2021
Hussam A. S. Murad, Misbahuddin M. Rafeeq, Thamer M. A. Alqurashi
CXCR4 is also a receptor for macrophage migration inhibition factor (MIF), which is a Chemokine Like Factor (CLF), and it is implicated in various pathological processes such as chemotaxis, leukocyte recruitment, inflammation and epithelial-mesenchymal interaction in tumours. MIF also acts as a partial allosteric agonist of CXCR4 [33,34]. CXCR4 heterodimerizes with other receptors, such as CXCR3, the Na+/H + exchanger regulatory factor 1 (NHERF1), CCR7, CCR2, CCR5, α1-AR and opioid receptors, resulting in differential signalling; however, their roles in atherosclerosis are still uncertain [35]. CXCR4/CXCR3 heterodimerization delays CXCR4 signalling [36]. CXCR4 itself is expressed in monomeric or dimeric forms, and they are both located at the outer cell membrane and intracellular structures [37]. Recently, it has been reported that actin-dependent nanoclustering of CXCR4 is also required for optimal CXCL12 signalling [38,39]. Complex interactions of CXCR4 with another receptor, CXCR7 (ACKR3), are discussed below.
The mechanism of miR-16-5p protection on LPS-induced A549 cell injury by targeting CXCR3
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Guo-Pan Liu, Wei-Wei Wang, Wen-Ying Lu, An-Quan Shang
miRNAs are short-chain non-coding endogenous small RNAs that can participate in the development of cancers through regulating the translational synthesis of post-transcriptional regulatory proteins [1]. miR-16-5p plays an important role in a variety of cancers [2], but its role in lung cancer has not been reported. Chemokines can be divided into four families according to the number and spacing of N-terminal cysteine residues, C, CC, CXC and CX3C [3]. In addition, CXC chemokines are mainly involved in tumor progression by binding to specific receptors. The CXC receptor that has been found so far was CXCR1-CXCR7. The affinities of different chemokines and their receptors are also different, and the biological effects they produce are also diverse [4]. CXCR3 is a 7-transmembrane G-protein coupled receptor whose N-terminal region and C-terminal region are located in the transmembrane portion of the cell membrane. The N-terminal region outside the cell membrane can bind to cytokines, resulting in a series of cell signaling [5]. CXCR3 is expressed in a variety of cancers, such as breast cancer, gastric cancer and prostate cancer [6–8]. However, the role and mechanism of CXCR3 in lung cancer has not been clear yet. In this study, human lung adenocarcinoma cell line A549 was used to detect the expression of CXCR3 and miR-16-5p in LPS-induced A549 cell injury. The effects of overexpression of miR-16-5p, knockdown of CXCR3 and overexpression of CXCR3 on LPS were also observed. The induced apoptosis of A549 cells and the expression of IL-6 and TNF-α revealed that the mechanism of miR-16-5p may be related to the targeted regulation of CXCR3, which will provide a new target for the prevention and treatment of lung cancer.