%0 Journal Article
%T Macrophages may promote cancer growth via a GM-CSF/HB-EGF paracrine loop that is enhanced by CXCL12
%A Antonella Rigo
%A Michele Gottardi
%A Alberto Zam¨°
%A Pierluigi Mauri
%A Massimiliano Bonifacio
%A Mauro Krampera
%A Ernesto Damiani
%A Giovanni Pizzolo
%A Fabrizio Vinante
%J Molecular Cancer
%D 2010
%I BioMed Central
%R 10.1186/1476-4598-9-273
%X 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.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.Over the last few years, a great deal of attention has been paid to the clinical significance of macrophages that infiltrate cancer. A number of studies provide evidence that tumour-associated macrophages are a negative prognostic factor of survival [1,2]. A recent gene-profiling study demonstrates that the overexpression of a macrophage signature and an increased number of tumour-infiltrating macrophages in diagnostic lymph-nodes are associated with poor outcome in classic Hodgkin's lymphoma patients [3]. Other studies underline pathways leading to
%U http://www.molecular-cancer.com/content/9/1/273