Macrophages may promote cancer growth via a GM-CSF/HB-EGF paracrine loop that is enhanced by CXCL12

Mol Cancer. 2010 Oct 14;9:273. doi: 10.1186/1476-4598-9-273.

Abstract

Background: Increased numbers of tumour-associated macrophages correlate with shortened survival in some cancers. The molecular bases of this correlation are not thoroughly understood. Events triggered by CXCL12 may play a part, as CXCL12 drives the migration of both CXCR4-positive cancer cells and macrophages and may promote a molecular crosstalk between them.

Results: Samples of HER1-positive colon cancer metastases in liver, a tissue with high expression of CXCL12, were analysed by immunohistochemistry. In all of the patient biopsies, CD68-positive tumour-associated macrophages presented a mixed CXCL10 (M1)/CD163 (M2) pattern, expressed CXCR4, GM-CSF and HB-EGF, and some stained positive for CXCL12. Cancer cells stained positive for CXCR4, CXCL12, HER1, HER4 and GM-CSF. Regulatory interactions among these proteins were validated via experiments in vitro involving crosstalk between human mononuclear phagocytes and the cell lines DLD-1 (human colon adenocarcinoma) and HeLa (human cervical carcinoma), which express the above-mentioned ligand/receptor repertoire. CXCL12 induced mononuclear phagocytes to release HB-EGF, which activated HER1 and triggered anti-apoptotic and proliferative signals in cancer cells. The cancer cells then proliferated and released GM-CSF, which in turn activated mononuclear phagocytes and induced them to release more HB-EGF. Blockade of GM-CSF with neutralising antibodies or siRNA suppressed this loop.

Conclusions: CXCL12-driven stimulation of cancer cells and macrophages may elicit and reinforce a GM-CSF/HB-EGF paracrine loop, whereby macrophages contribute to cancer survival and expansion. The involvement of mixed M1/M2 GM-CSF-stimulated macrophages in a tumour-promoting loop may challenge the paradigm of tumour-favouring macrophages as polarized M2 mononuclear phagocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • Apoptosis / drug effects
  • Blotting, Northern
  • Cell Line
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Chemokine CXCL12 / pharmacology*
  • Colonic Neoplasms / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • ErbB Receptors / metabolism
  • Flow Cytometry
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • HeLa Cells
  • Heparin-binding EGF-like Growth Factor
  • Humans
  • Immunochemistry
  • In Vitro Techniques
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Macrophages / drug effects*
  • Macrophages / metabolism*
  • Mass Spectrometry
  • Mice
  • Phosphorylation
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Chemokine CXCL12
  • HBEGF protein, human
  • Hbegf protein, mouse
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • ErbB Receptors