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A Unidirectional Transition from Migratory to Perivascular Macrophage Is Required for Tumor Cell Intravasation

Esther N Arwert1, Allison S Harney2, David Entenberg2

  • 1Tumour Cell Biology Laboratory, Francis Crick Institute, London, UK; Gruss-Lipper Biophotonics Center and the Integrated Imaging Program, Albert Einstein College of Medicine, New York, NY, USA.

Cell Reports
|May 3, 2018
PubMed

Insights

Newly arrived monocytes, recruited via CCR2 signaling, differentiate into sessile perivascular macrophages. This process, regulated by CXCL12 and CXCR4, is crucial for tumor metastasis and cancer cell intravasation.

Area of Science:

  • Immunology
  • Cancer Biology
  • Cell Biology

Background:

  • Tumor-associated macrophages (TAMs) play a critical role in tumor metastasis.
  • Two TAM subsets, migratory and sessile perivascular macrophages, facilitate cancer cell intravasation.
  • The relationship and potential inter-conversion between these TAM subsets remain largely unknown.

Purpose of the Study:

  • To elucidate the inter-relationship and differentiation pathway between distinct TAM subsets.
  • To investigate the molecular mechanisms regulating TAM behavior during metastasis.
  • To understand how TAMs facilitate cancer cell intravasation.

Main Methods:

  • Monocyte recruitment via CCR2 signaling.
  • CXCL12 and CXCR4 signaling pathways.
  • TGF-β-dependent gene upregulation in monocytes.
  • TAM differentiation into perivascular macrophages.
  • Analysis of vascular leakiness and cancer cell intravasation.

Main Results:

  • Motile, streaming TAMs are newly arrived monocytes recruited via CCR2 signaling.
  • These monocytes differentiate into sessile perivascular macrophages in a unidirectional process.
  • CXCL12 and CXCR4 signaling regulate this differentiation.
  • Cancer cells induce TGF-β-dependent CXCR4 upregulation in monocytes.
  • CXCL12 attracts motile TAMs and cancer cells to blood vessels, promoting intravasation.

Conclusions:

  • The study reveals a novel, unidirectional differentiation pathway for TAMs from circulating monocytes to sessile perivascular macrophages.
  • This process is orchestrated by specific molecular signals (CCR2, CXCL12, CXCR4, TGF-β) and is essential for promoting cancer cell intravasation.
  • Understanding this TAM inter-conversion offers potential therapeutic targets for inhibiting tumor metastasis.
Keywords:
CCR2CXCR4MenaTAMsTGF betaTMEMbreast cancermetastasistumor associated macrophages

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