Inhibition of stromal CXCR4 impairs development of lung metastases

Crescenzo D'Alterio, Antonio Barbieri, Luigi Portella, Giuseppe Palma, Marianeve Polimeno, Anna Riccio, Caterina Ieranó, Renato Franco, Giosué Scognamiglio, Jane Bryce, Antonio Luciano, Domenica Rea, Claudio Arra, Stefania Scala

Research output: Contribution to journalArticle

Abstract

Compelling evidence has emerged in recent years indicating that stromal cells play a critical role in disease progression. CXCR4 is a G-protein-coupled receptor with a major role in lymphocyte homing. Its ligand, CXCL12, is a highly eYcient chemotactic factor for T cells, monocytes, pre-B cells, dendritic cells and myeloid bone marrow-derived cells (BMDCs). In addition, the CXCR4-CXCL12 axis plays a central role in tumor growth and metastasis. To evaluate the eVect of genetic CXCR4 reduction on metastasis development, murine melanoma B16 cells were injected into the tail vein of C57BL/6 CXCR4+/+ and CXCR4+/- mice in the presence of the CXCR4 inhibitor, Plerixafor (previously named AMD3100). Although lung metastases developed in wild-type CXCR4+/+ and heterozygote CXCR4+/- mice, nodules were signiWcantly smaller in the latter. CXCR4 pharmacological inhibition by Plerixafor further reduced lung metastases in CXCR4+/- mice, preserving the pulmonary architecture (4.18 $ 1.38 mm2 vs. 1.11 $ 0.60 mm2, p = 0.038). A reduction in LY6G-positive myeloid/granulocytic cells and in p38 MAPK activation was detected in lungs from CXCR4+/- mice compared to CXCR4+/+ mice [LY6G-positive myeloid CXCR4+/- vs. CXCR4+/+ (p = 0.0004); CXCR4+/+ vs. CXCR4+/+ Plerixafor-treated (p = 0.0031)] suggesting that CXCR4 reduction on myeloid-derived cells reduced their recruitment to the lung, consequently impairing lung metastases. Our Wndings argue in favor of a speciWc role of CXCR4 expressed in stromal cells that condition the protumor microenvironment. In this scenario, CXCR4 antagonists will target neoplastic cells as well as the pro-tumor stromal microenvironment.

Original languageEnglish
Pages (from-to)1713-1720
Number of pages8
JournalCancer Immunology, Immunotherapy
Volume61
Issue number10
DOIs
Publication statusPublished - Oct 2012

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Neoplasm Metastasis
Lung
Myeloid Cells
Stromal Cells
Experimental Melanomas
B-Lymphoid Precursor Cells
Tumor Microenvironment
Chemotactic Factors
p38 Mitogen-Activated Protein Kinases
Heterozygote
G-Protein-Coupled Receptors
Bone Marrow Cells
Dendritic Cells
Disease Progression
Tail
Monocytes
Veins
Pharmacology
Lymphocytes
Ligands

Keywords

  • CXCR4
  • Heterozygote mice
  • Melanoma
  • Plerixafor
  • Pulmonary metastases

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Immunology
  • Immunology and Allergy

Cite this

D'Alterio, C., Barbieri, A., Portella, L., Palma, G., Polimeno, M., Riccio, A., ... Scala, S. (2012). Inhibition of stromal CXCR4 impairs development of lung metastases. Cancer Immunology, Immunotherapy, 61(10), 1713-1720. https://doi.org/10.1007/s00262-012-1223-7

Inhibition of stromal CXCR4 impairs development of lung metastases. / D'Alterio, Crescenzo; Barbieri, Antonio; Portella, Luigi; Palma, Giuseppe; Polimeno, Marianeve; Riccio, Anna; Ieranó, Caterina; Franco, Renato; Scognamiglio, Giosué; Bryce, Jane; Luciano, Antonio; Rea, Domenica; Arra, Claudio; Scala, Stefania.

In: Cancer Immunology, Immunotherapy, Vol. 61, No. 10, 10.2012, p. 1713-1720.

Research output: Contribution to journalArticle

D'Alterio, C, Barbieri, A, Portella, L, Palma, G, Polimeno, M, Riccio, A, Ieranó, C, Franco, R, Scognamiglio, G, Bryce, J, Luciano, A, Rea, D, Arra, C & Scala, S 2012, 'Inhibition of stromal CXCR4 impairs development of lung metastases', Cancer Immunology, Immunotherapy, vol. 61, no. 10, pp. 1713-1720. https://doi.org/10.1007/s00262-012-1223-7
D'Alterio C, Barbieri A, Portella L, Palma G, Polimeno M, Riccio A et al. Inhibition of stromal CXCR4 impairs development of lung metastases. Cancer Immunology, Immunotherapy. 2012 Oct;61(10):1713-1720. https://doi.org/10.1007/s00262-012-1223-7
D'Alterio, Crescenzo ; Barbieri, Antonio ; Portella, Luigi ; Palma, Giuseppe ; Polimeno, Marianeve ; Riccio, Anna ; Ieranó, Caterina ; Franco, Renato ; Scognamiglio, Giosué ; Bryce, Jane ; Luciano, Antonio ; Rea, Domenica ; Arra, Claudio ; Scala, Stefania. / Inhibition of stromal CXCR4 impairs development of lung metastases. In: Cancer Immunology, Immunotherapy. 2012 ; Vol. 61, No. 10. pp. 1713-1720.
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AU - Polimeno, Marianeve

AU - Riccio, Anna

AU - Ieranó, Caterina

AU - Franco, Renato

AU - Scognamiglio, Giosué

AU - Bryce, Jane

AU - Luciano, Antonio

AU - Rea, Domenica

AU - Arra, Claudio

AU - Scala, Stefania

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