C-X-C Chemokine Receptor 4 in Diffuse Large B Cell Lymphoma: Achievements and Challenges

Du, Huarui; Gao, Lei; Luan, Jing; Zhang, Hangfan; Xiao, Taiwu

doi:10.1159/000497430

Cited by 17 publications

(19 citation statements)

References 83 publications

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“…Survival analysis revealed a trend for high CXCR4 expression associated with poor survival, in concordance with the findings of two other research groups [13,14,20]. Together with the fact that CXCR4-CXCL12 signaling activates several pathways like Janus kinases-signal transducer and activator of transcription (JAK-STAT), phosphoinositide 3-kinase (PI3K), protein kinase B (PKB, AKT), mitogen-activated protein kinase (MAPK), and NF-κB [43,44,45], we hypothesize that the high co-occurrence of the receptor and its ligand influences the resistance of lymphomas toward anti-lymphoma therapy. Hence, we expect that low or even no CXCR4 expression leads to none or low activation of the mentioned pathways, thus leading to a higher therapeutic sensitivity of the lymphoma cells.…”

Section: Discussionsupporting

confidence: 84%

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Pansy

Feichtinger

Ehall

et al. 2019

IJMS

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In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

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Section: Discussionsupporting

confidence: 84%

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Pansy

Feichtinger

Ehall

et al. 2019

IJMS

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“…Consistent with this, in recent years genomic findings have provided important insights into the relevance of the CXCL12/CXCR4 axis for pathogenesis, prognostication, and treatment outcome of cancer. As CXCL12 regulates hematopoietic cell trafficking to positioning in the BM [20], it is not surprising that aberrant CXCR4 expression on cancer cells from several hematopoietic malignancies influences neoplasia progression by controlling cancer cell migration to BM as well as to lymph nodes, suggesting CXCR4 as a novel, reliable prognostic biomarker [21]. In particular, somatic CXCR4 mutations have been reported in indolent forms of B-cell nHL, follicular lymphoma, and WM [22,23].…”

Section: Waldenstrom's Macroglobulinaemiamentioning

confidence: 99%

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

Milanesi

Locati

Borroni

2020

IJMS

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Given its pleiotropic functions, including its prominent role in inflammation, immune responses and cancer, the C-X-C chemokine receptor type 4 (CXCR4) has gained significant attention in recent years and has become a relevant target in drug development. Although the signaling properties of CXCR4 have been extensively studied, several aspects deserve deeper investigations. Mutations in the C-term tail of the CXCR4 gene cause WHIM syndrome, a rare congenital immunodeficiency associated by chronic leukopenia. Similar mutations have also been recently identified in 30% of patients affected by Waldenstrom’s macroglobulinaemia, a B-cell neoplasia with bone marrow accumulation of malignant cells. An ample body of work has been generated to define the impact of WHIM mutations on CXCR4 signaling properties and evaluate their role on pathogenesis, diagnosis, and response to therapy, although the identity of disease-causing signaling pathways and their relevance for disease development in different genetic variants are still open questions. This review discusses the current knowledge on biochemical properties of CXCR4 mutations to identify their prototypic signaling profile potentially useful to highlighting novel opportunities for therapeutic intervention.

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“…CXCL10 also named interferon-γ-inducible protein 10 (IP-10) is identified as a Th1 cell-attracting chemokines that is bound to CXCR3 which is mainly expressed on Th1 cells (24,25) . CCL20 also named liver-and activation-regulated chemokine (LARC) is identified as a Th17 cell-attracting chemokines that is bound to CCR6 which is mainly expressed on Th17 cells (24,25) . The capacity of CagA-positive HP strains to induce higher amounts of CXCL10 and CCL20 indicate that these strains induces higher accumulation FIGURE 8.…”

Section: Discussionmentioning

confidence: 99%

The H. Pylori-Related Virulence Factor Caga Influences the Expression of Chemokines Cxcl10, Ccl17, Ccl20, Ccl22, and Their Receptors by Peripheral Blood Mononuclear Cells From Peptic Ulcer Patients

Jalalpour

Mirzaee

Taheri

et al. 2020

Arq. Gastroenterol.

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BACKGROUND: During the Helicobacter pylori (HP) infection, the infiltration of the leukocytes into stomach mucosa is directed by locally produced chemokines that play a decisive role in infection outcome. The CagA is the most potent virulence factor of HP, so that the infection with CagA + strains is associated with more severe complications than infection with CagA - HP. OBJECTIVE: The aim was to determine the expression of chemokines CXCL10, CCL17, CCL20 and CCL22, and their receptors by CagA + HP- and CagA - HP-derived crude extract (HP-CE)-stimulated peripheral blood mononuclear cells (PBMCs) from peptic ulcer (PU) patients. METHODS: The serum and the PBMCs were collected from 20 HP-infected PU patients, 20 HP-infected asymptomatic subjects (HIA) and 20 non-infected healthy subjects (NHS). The PBMCs were cultured in absence of stimulator or with 10 µg CagA + HP crude extract (CagA + CE), 10 µg CagA - HP crude extract (CagA - CE). Chemokines and receptors were measured by ELISA and real time-PCR respectively. RESULTS: In PU patients, the production of chemokines CXCL10, CCL17, CCL20 and CCL22, and the expression of chemokine receptors CXCR3, CCR4 and CCR6 by CagA + CE-induced PBMCs were significantly higher than non-stimulated and CagA - CE stimulated cultures. The CXCL10 production by CagA + CE stimulated PBMCs from HIA subjects was significantly higher than the equal cultures from PU and NHS groups. The CCL17 and the CCL20 production by non-stimulated, CagA + CE stimulated, and CagA - CE stimulated PBMCs from PU subjects were significantly higher than the equal cultures from NHS and HIA groups. The CCL22 production by non-stimulated, CagA + CE stimulated and CagA - CE stimulated PBMCs from NHS group were significantly higher than the equal cultures from HIA and PU groups. The CagA + CE stimulated PBMCs from HIA subjects expressed lower amounts of CCR6 in comparison with CagA + CE stimulated PBMCs from NHS and PU groups. The serum levels CXCL10 and CCL20 in PU and HIA groups were significantly higher than NHS subjects. NHS and HIA groups displayed higher serum levels of CCL22 in comparison with PU patients. CONCLUSION: Results indicated that the CagA status of bacterium influence the expression of chemokines and receptors by HP-CE stimulated PBMCs from PU patients.

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C-X-C Chemokine Receptor 4 in Diffuse Large B Cell Lymphoma: Achievements and Challenges

Cited by 17 publications

References 83 publications

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

The CXCR4–CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Aberrant CXCR4 Signaling at Crossroad of WHIM Syndrome and Waldenstrom’s Macroglobulinemia

The H. Pylori-Related Virulence Factor Caga Influences the Expression of Chemokines Cxcl10, Ccl17, Ccl20, Ccl22, and Their Receptors by Peripheral Blood Mononuclear Cells From Peptic Ulcer Patients

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