Open Access Research

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

Antonella Rigo1†, Michele Gottardi1†, Alberto Zamò2, Pierluigi Mauri3, Massimiliano Bonifacio1, Mauro Krampera1, Ernesto Damiani4, Giovanni Pizzolo1 and Fabrizio Vinante1*

Author Affiliations

1 Department of Medicine, Section of Hematology, University of Verona, Verona, Italy

2 Department of Pathology and Diagnostics, Section of Pathological Anatomy, University of Verona, Verona, Italy

3 Proteomics and Metabolomics Unit, Institute for Biomedical Technologies, CNR, Milan, Italy

4 Department of Experimental Biomedical Sciences, University of Padua, Padua, Italy

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Molecular Cancer 2010, 9:273 doi:10.1186/1476-4598-9-273

Published: 14 October 2010

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.