The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting

Martine J. Smit; Géraldine Schlecht-Louf; Maria Neves; Jelle Van Den Bor; Petronila Penela; Marco Siderius; Françoise Bachelerie; Federico Mayor

doi:10.1146/annurev-pharmtox-010919-023340

The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting

Martine J. Smit^*, Géraldine Schlecht-Louf, Maria Neves, Jelle Van Den Bor, Petronila Penela, Marco Siderius, Françoise Bachelerie, Federico Mayor

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

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Abstract

Elevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression. We discuss current and emerging avenues that target the CXCL12/CXCR4/ACKR3 axis. Coordinately targeting both RTKs and CXCR4/ACKR3 and/or CXCL12 is an attractive approach to consider in multitargeted cancer therapies. In addition, inhibiting infiltrating immune cells or reactivating the immune system along with modulating the CXCL12/CXCR4/ACKR3 axis in the TME has therapeutic promise.

Original language	English
Pages (from-to)	541-563
Number of pages	23
Journal	Annual Review of Pharmacology and Toxicology
Volume	61
Early online date	21 Sept 2020
DOIs	https://doi.org/10.1146/annurev-pharmtox-010919-023340
Publication status	Published - 2021

Funding

The authors would like to thank the consortium members of ONCORNET for their valuable discussions and input on studies of CXCR4 and ACKR3. Our laboratories are supported by the European Union (H2020-MSCA Program, grant agreements 641833-ONCORNET and 860229-ONCORNET 2.0 to M.J.S., M.S. F.B., G.S.-L., and F.M.), Agencia Estatal de Investi-gación of Spain (grant SAF2017-84125-R to F.M.), CIBERCV-Instituto de Salud Carlos III (grant CB16/11/00278 to F.M., cofunded with European FEDER contribution), Fundación Ramón Are-ces (to F.M.), Programa de Actividades en Biomedicina de la Comunidad de Madrid-B2017/BMD-3671-INFLAMUNE (to F.M.), ERA-Net Infect-ERA HPV-MOTIVA (ANR-15-IFEC-0004-01 to F.B. and G.S.-L.), Agence Nationale de la Recherche (ANR-19-CE14-0035-01 to F.B.), LabEx LERMIT (ANR-10-LABX-33) under the program Investissements d’Avenir (ANR-11-IDEX-0003-01 to F.B. and G.S.-L.), and the Dutch Research Council [NWO Vici 016.140.657 and ENPPS.TA.019.003 (MAGNETIC) to M.J.S.]. Our labs participate in the European COST action networks on GPCRs (CM1207/GLISTEN and CA18133/ERNEST).

Funders	Funder number
Agencia Estatal de Investi-gación of Spain	SAF2017-84125-R
CIBERCV-Instituto de Salud Carlos III	CB16/11/00278
Fundación Ramón Areces	ANR-15-IFEC-0004-01, Madrid-B2017/BMD-3671-INFLAMUNE
Horizon 2020 Framework Programme	860229
H2020 Marie Skłodowska-Curie Actions	860229-ONCORNET 2.0, 641833-ONCORNET
European Commission

Keywords

ACKR3
cancer
chemokine receptors
CXCR4
GPCRs
therapeutics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1146/annurev-pharmtox-010919-023340

The CXCL12 CXCR4 ACKR3 Axis in the Tumor MicroenvironmentFinal published version, 13 MBLicence: Article 25fa Dutch Copyright Act

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title = "The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting",

abstract = "Elevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression. We discuss current and emerging avenues that target the CXCL12/CXCR4/ACKR3 axis. Coordinately targeting both RTKs and CXCR4/ACKR3 and/or CXCL12 is an attractive approach to consider in multitargeted cancer therapies. In addition, inhibiting infiltrating immune cells or reactivating the immune system along with modulating the CXCL12/CXCR4/ACKR3 axis in the TME has therapeutic promise. ",

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year = "2021",

doi = "10.1146/annurev-pharmtox-010919-023340",

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AU - Smit, Martine J.

AU - Schlecht-Louf, Géraldine

AU - Neves, Maria

AU - Van Den Bor, Jelle

AU - Penela, Petronila

AU - Siderius, Marco

AU - Bachelerie, Françoise

AU - Mayor, Federico

PY - 2021

Y1 - 2021

N2 - Elevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression. We discuss current and emerging avenues that target the CXCL12/CXCR4/ACKR3 axis. Coordinately targeting both RTKs and CXCR4/ACKR3 and/or CXCL12 is an attractive approach to consider in multitargeted cancer therapies. In addition, inhibiting infiltrating immune cells or reactivating the immune system along with modulating the CXCL12/CXCR4/ACKR3 axis in the TME has therapeutic promise.

AB - Elevated expression of the chemokine receptors CXCR4 and ACKR3 and of their cognate ligand CXCL12 is detected in a wide range of tumors and the tumor microenvironment (TME). Yet, the molecular mechanisms by which the CXCL12/CXCR4/ACKR3 axis contributes to the pathogenesis are complex and not fully understood. To dissect the role of this axis in cancer, we discuss its ability to impinge on canonical and less conventional signaling networks in different cancer cell types; its bidirectional crosstalk, notably with receptor tyrosine kinase (RTK) and other factors present in the TME; and the infiltration of immune cells that supporttumor progression. We discuss current and emerging avenues that target the CXCL12/CXCR4/ACKR3 axis. Coordinately targeting both RTKs and CXCR4/ACKR3 and/or CXCL12 is an attractive approach to consider in multitargeted cancer therapies. In addition, inhibiting infiltrating immune cells or reactivating the immune system along with modulating the CXCL12/CXCR4/ACKR3 axis in the TME has therapeutic promise.

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The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting

Abstract

Funding

Keywords

UN SDGs

Access to Document

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ONCORNET2.0: Horizon2020 ONCOgenic Receptor Network of Excellence and Training 2.0

Cite this

The CXCL12/CXCR4/ACKR3 Axis in the Tumor Microenvironment: Signaling, Crosstalk, and Therapeutic Targeting

Abstract

Funding

Keywords

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Projects

ONCORNET2.0: Horizon2020 ONCOgenic Receptor Network of Excellence and Training 2.0

Cite this