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

Santagata, Sara; Ieranò, Caterina; Trotta, Anna Maria; Capiluongo, Anna; Auletta, Federica; Guardascione, Giuseppe; Scala, Stefania

doi:10.3389/fonc.2021.591386

Cited by 53 publications

(48 citation statements)

References 143 publications

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“…Over 90% of publications concerning ACKR3/CXCR7 enlisted in PubMed stem from research in the context of various cancers, where ACKR3/CXCR7 has been shown to play a decisive role in cancer progression, angiogenesis and even prognostic outcome [ 46 , 195 , 196 , 197 ]. Given the level of our current scientific understanding on ACKR3/CXCR7, it is perhaps neither advisable nor reasonable to continuously trigger this receptor by the prolonged use of an agonist.…”

Section: Discussionmentioning

confidence: 99%

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

Chatterjee

2022

Cells

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The manifold actions of the pro-inflammatory and regenerative chemokine CXCL12/SDF-1α are executed through the canonical GProteinCoupledReceptor CXCR4, and the non-canonical ACKR3/CXCR7. Platelets express CXCR4, ACKR3/CXCR7, and are a vital source of CXCL12/SDF-1α themselves. In recent years, a regulatory impact of the CXCL12-CXCR4-CXCR7 axis on platelet biogenesis, i.e., megakaryopoiesis, thrombotic and thrombo-inflammatory actions have been revealed through experimental and clinical studies. Platelet surface expression of ACKR3/CXCR7 is significantly enhanced following myocardial infarction (MI) in acute coronary syndrome (ACS) patients, and is also associated with improved functional recovery and prognosis. The therapeutic implications of ACKR3/CXCR7 in myocardial regeneration and improved recovery following an ischemic episode, are well documented. Cardiomyocytes, cardiac-fibroblasts, endothelial lining of the blood vessels perfusing the heart, besides infiltrating platelets and monocytes, all express ACKR3/CXCR7. This review recapitulates ligand induced differential trafficking of platelet CXCR4-ACKR3/CXCR7 affecting their surface availability, and in regulating thrombo-inflammatory platelet functions and survival through CXCR4 or ACKR3/CXCR7. It emphasizes the pro-thrombotic influence of CXCL12/SDF-1α exerted through CXCR4, as opposed to the anti-thrombotic impact of ACKR3/CXCR7. Offering an innovative translational perspective, this review also discusses the advantages and challenges of utilizing ACKR3/CXCR7 as a potential anti-thrombotic strategy in platelet-associated cardiovascular disorders, particularly in coronary artery disease (CAD) patients post-MI.

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Section: Discussionmentioning

confidence: 99%

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

Chatterjee

2022

Cells

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“…Radiation-resistant PaCa cell lines with high expression of CXCR4 exhibited enhanced invasion ability compared with normal PaCa cell lines, and the invasion ability was further enhanced by the addition of CXCL12 or coculture with FBs. C-X-C chemokine receptor type 7 (CXCR7) is another receptor for CXCL12 and has also been reported to play important roles in cancer invasion ( 55 ). Therefore, we evaluated the mRNA levels of CXCR7 in normal and radiation-resistant PaCa cell lines using RT-qPCR; however, our results showed that CXCR7 expression was not enhanced in radiation-resistant PaCa cell lines (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation‑resistant pancreatic cancer

et al. 2022

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Pancreatic cancer (PaCa) exhibits one of the poorest prognoses among all gastrointestinal cancers due to the rapid development of treatment resistance, which renders chemotherapy and radiotherapy no longer effective. However, the mechanisms through which PaCa becomes resistant to radiotherapy are unknown. Here, we established radiation-resistant PaCa cell lines to investigate the factors involved in radiation resistance. The role of the C-X-C motif chemokine ligand 12 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis in radiation resistance in PaCa and the effects of a CXCR4 antagonist on radiation-resistant PaCa cell lines were investigated. As confirmed by immunofluorescence staining, reverse transcription quantitative polymerase chain reaction, and western blotting, the expression of CXCR4 was higher in radiation-resistant PaCa cell lines than that noted in normal PaCa cell lines. The invasion ability of radiation-resistant PaCa cell lines was greater than that of normal cell lines and was enhanced by CXCL12 treatment and coculture with fibroblasts; this enhanced invasion ability was suppressed by the CXCR4 antagonist AMD070. Irradiation after treatment with the CXCR4 antagonist suppressed the colonization of radiation-resistant PaCa cell lines. In conclusion, the CXCL12/CXCR4 axis may be involved in the radiation resistance of PaCa. These findings may facilitate the development of novel treatments for PaCa.

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“…Our results are in accord with recent evidence that FOXC1 controls CXCL12 expression in CXCL12-abundant reticular (CAR) progenitors and Schwann cells 62,63 , and we also identified putative FOXC binding sites 53,54,55 in evolutionarily conserved regions of the human CXCL12 locus (Supplementary Figure 10B and Methods). EC-derived CXCL12 promotes angiogenesis via an autocrine mechanism 24 , and CXCL12-CXCR4 signaling cooperates with VEGF to enhance angiogenic processes such as the morphogenesis and sprouting of vascular tubes 64 .…”

Section: Discussionmentioning

confidence: 99%

Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia-reperfusion injury

Tan

Norden

Liu

et al. 2022

Preprint

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Intestinal ischemia induces mucosal damage while simultaneously activating intestinal stem cells (ISCs), which subsequently regenerate the damaged intestinal epithelium. However, whether angiocrine factors secreted from vascular endothelial cells (ECs) - blood and lymphatic ECs (BECs and LECs, respectively) – regulate ISC-mediated regeneration have yet to be elucidated. Here, we identify FOXC1 and FOXC2 as essential regulators of angiocrine signaling in regeneration of the small intestine after ischemia-reperfusion (I/R) injury. EC- and LEC-specific deletions of Foxc1, Foxc2, or both in mice augment I/R-induced intestinal damage by causing defects in vascular regrowth, expression of the chemokine CXCL12 and the Wnt activator R-spondin 3 in BECs and LECs, respectively, and activation of Wnt signaling in ISCs. Treatment with CXCL12 and R-spondin 3 rescues the I/R-induced intestinal damage in EC- and LEC-Foxc mutant mice, respectively. This study provides evidence that FOXC1 and FOXC2 are required for intestinal regeneration by stimulating angiocrine CXCL12 and Wnt signaling.

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

Cited by 53 publications

References 143 publications

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

Enhanced CXCL12/CXCR4 signaling increases tumor progression in radiation‑resistant pancreatic cancer

Endothelial FOXC1 and FOXC2 promote intestinal regeneration after ischemia-reperfusion injury

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