At the Bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer

Luker, Gary D.; Yang, Jinming; Richmond, Ann; Scala, Stefania; Festuccia, Claudio; Schottelius, Margret; Wester, Hans; Zimmermann, Johann

doi:10.1002/jlb.2bt1018-715rr

Cited by 31 publications

(25 citation statements)

References 321 publications

(563 reference statements)

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“…Balixafortide (POL6326) is a cyclic peptide CXCR4 antagonist that effectively mobilizes HSCs. Balixafortide treatment versus eribulin is currently being evaluated in a phase 3 trial after the objective response of balixafortide plus eribulin in the treatment of metastatic Her-negative breast cancers ( 119 ). Table 1 lists CXCR4 inhibitors in clinical development.…”

Section: Targeting the Cxcl12/cxcr4/cxcr7 Axis In Combination Therapymentioning

confidence: 99%

CXCR4 and CXCR7 Signaling Pathways: A Focus on the Cross-Talk Between Cancer Cells and Tumor Microenvironment

et al. 2021

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The chemokine receptor 4 (CXCR4) and 7 (CXCR7) are G-protein-coupled receptors (GPCRs) activated through their shared ligand CXCL12 in multiple human cancers. They play a key role in the tumor/tumor microenvironment (TME) promoting tumor progression, targeting cell proliferation and migration, while orchestrating the recruitment of immune and stromal cells within the TME. CXCL12 excludes T cells from TME through a concentration gradient that inhibits immunoactive cells access and promotes tumor vascularization. Thus, dual CXCR4/CXCR7 inhibition will target different cancer components. CXCR4/CXCR7 antagonism should prevent the development of metastases by interfering with tumor cell growth, migration and chemotaxis and favoring the frequency of T cells in TME. Herein, we discuss the current understanding on the role of CXCL12/CXCR4/CXCR7 cross-talk in tumor progression and immune cells recruitment providing support for a combined CXCR4/CXCR7 targeting therapy. In addition, we consider emerging approaches that coordinately target both immune checkpoints and CXCL12/CXCR4/CXCR7 axis.

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Section: Targeting the Cxcl12/cxcr4/cxcr7 Axis In Combination Therapymentioning

confidence: 99%

CXCR4 and CXCR7 Signaling Pathways: A Focus on the Cross-Talk Between Cancer Cells and Tumor Microenvironment

et al. 2021

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“…Chemokine CXCL12 and its receptor, CXCR4, contribute to organ-specific chemotaxis of circulating tumor cells and subsequent metastasis in breast cancer and multiple other malignancies (1, 2). Crucial functions of CXCL12-CXCR4 signaling in metastatic cancer motivate ongoing efforts to target this signaling pathway with novel therapies (3).…”

Section: Introductionmentioning

confidence: 99%

Cell-to-cell variability of dynamic CXCL12-CXCR4 signaling and morphological processes in chemotaxis

Srivastava

Kinnunen

et al. 2022

Preprint

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Chemotaxis drives critical processes in cancer metastasis. While commonly studied at the population scale, metastasis arises from small numbers of cells that successfully disseminate, underscoring the need to analyze chemotaxis at single-cell resolution. Here we focus on chemotaxis driven by the CXCL12-CXCR4 pathway, a signaling network that promotes metastasis in more than 20 different human cancers. CXCL12-CXCR4 activates ERK and Akt, kinases known to promote chemotaxis, but how cells couple signaling to chemotaxis remain poorly defined. To address this challenge, we implemented single-cell analysis of MDA-MB-231 breast cancer cells migrating in a chemotaxis device towards chemokine CXCL12. We integrated live, single-cell imaging with advanced computational analysis methods to discover processes defining subsets of cells that move efficiently toward a CXCL12 gradient. We identified dynamic oscillations in ERK and Akt signaling and associated morphological transitions as key determinants of successful chemotaxis. Cells with effective chemotaxis toward CXCL12 exhibit faster and more persistent movement than non-migrating cells, but both cell populations show similar random motion. Migrating cells exhibit higher amplitude fluctuations in ERK and Akt signaling and greater frequencies of generating lateral cell membrane protrusions. Interestingly, computational analysis reveals less correlated network coupling of signaling and morphological changes in migrating cells. These data reveal processing events that enable cells to convert a signaling input to chemotaxis and highlight how cells in a uniform environment produce heterogeneous responses.

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“…In cancer progression and metastasis, the expression of chemokine receptor 4 (CXCR4) and chemokine receptor 7 (CCR7) is of particular importance [4]. Since the first demonstration of their tumour-promoting role in breast cancer [5], the significant contribution of Life 2021, 11, 1049. https://doi.org/10.3390/life11101049 https://www.mdpi.com/journal/life these receptors to the metastatic progression in a number of cancers is now firmly established [6][7][8][9][10]. Furthermore, the expression of both CXCR4 and/or CCR7 are of significant prognostic value in multiple other cancers.…”

Section: Introductionmentioning

confidence: 99%

CXCR4-CCR7 Heterodimerization Is a Driver of Breast Cancer Progression

Poltavets

Faulkner

Dhatrak

et al. 2021

Life

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Metastatic breast cancer has one of the highest mortality rates among women in western society. Chemokine receptors CXCR4 and CCR7 have been shown to be linked to the metastatic spread of breast cancer, however, their precise function and underlying molecular pathways leading to the acquisition of the pro-metastatic properties remain poorly understood. We demonstrate here that the CXCR4 and CCR7 receptor ligands, CXCL12 and CCL19, cooperatively bind and selectively elicit synergistic signalling responses in invasive breast cancer cell lines as well as primary mammary human tumour cells. Furthermore, for the first time, we have documented the presence of CXCR4-CCR7 heterodimers in advanced primary mammary mouse and human tumours where number of CXCR4-CCR7 complexes directly correlate with the severity of the disease. The functional significance of the CXCR4-CCR7 association was also demonstrated when their forced heterodimerization led to the acquisition of invasive phenotype in non-metastatic breast cancer cells. Taken together, our data establish the CXCR4-CCR7 receptor complex as a new functional unit, which is responsible for the acquisition of breast cancer cell metastatic phenotype and which may serve as a novel biomarker for invasive mammary tumours.

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At the Bench: Pre-clinical evidence for multiple functions of CXCR4 in cancer

Cited by 31 publications

References 321 publications

CXCR4 and CXCR7 Signaling Pathways: A Focus on the Cross-Talk Between Cancer Cells and Tumor Microenvironment

CXCR4 and CXCR7 Signaling Pathways: A Focus on the Cross-Talk Between Cancer Cells and Tumor Microenvironment

Cell-to-cell variability of dynamic CXCL12-CXCR4 signaling and morphological processes in chemotaxis

CXCR4-CCR7 Heterodimerization Is a Driver of Breast Cancer Progression

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